Evidence review for the pharmacologicalmanagement of fatigue

Guideline Updates Team (UK)

Evidence review for the pharmacologicalmanagement of fatigue

Multiple sclerosis in adults: management

Evidence review D

NICE Guideline, No. 220

Authors

Guideline Updates Team (UK).

London: National Institute for Health and Care Excellence (NICE); 2022 Jun.

ISBN-13: 978-1-4731-4607-5

1. Pharmacological management of fatigue

1.1. Review question

For adults with MS, including people receiving palliative care, what is the clinical and cost effectiveness of pharmacological interventions for fatigue?

1.1.1. Introduction

Fatigue is thought to be the commonest and one of the most debilitating symptoms of multiple sclerosis. It can affect up to 80% of the MS population. Causes can be multifactorial with both physical and cognitive implications. There are recognised associations with heat, overexertion, stress or maybe the time of the day. The symptoms appear completely out of proportion to prior activity levels.

Fatigue is a universal experience; it is a self-recognised phenomenon that is subjective in nature. It is a common symptom in the general population and can be caused by a variety of medical problems such as anaemia or thyroid disease. Amantadine is available to treat fatigue in people with MS – but the mechanism of action, risks or benefits are unclear and have not been quantified. If trialled, medication such as amantadine found to directly help fatigue only benefits a proportion of MS sufferers and does not always eliminate the problem altogether. In addition to fatigue being a primary symptom of MS, some medication to control other MS symptoms may cause drowsiness and exacerbate underlying fatigue further.

There is no clear pharmacological management and therefore possible disparity in practice. New treatments may be available to help treat and manage fatigue in MS.

1.1.2. Summary of the protocol

Table 1

PICO characteristics of review question.

For full details see the review protocol in Appendix A.

1.1.3. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document. Declarations of interest were recorded according to NICE’s conflicts of interest policy.

1.1.4. Effectiveness evidence

1.1.4.1. Included studies

Seventeen randomised controlled trial studies (from twenty-one papers) were included in the review;¹^, ²^, ⁴^, ⁷^–¹⁰^, ¹²^–¹⁶^, ¹⁹^, ²²^, ²⁴^–²⁶ these are summarised in Table 2 below. These studies included 12 parallel trials;²^, ⁴^, ⁷^, ⁹^, ¹⁰^, ¹²^–¹⁵^, ²²^, ²⁴^, ²⁶ and 5 crossover trials¹^, ⁸^, ¹⁶^, ¹⁹^, ²⁵. Evidence from these studies is summarised in the clinical evidence summary below (Table 3).

These studies include the following comparisons:

Amantadine compared to aspirin²⁵
Amantadine compared to modafinil¹⁴^, ¹⁹
Amantadine compared to placebo¹^, ²^, ⁸^, ¹³^, ¹⁴^, ¹⁶^, ¹⁹^, ²²
SSRIs compared to placebo (analysed as a class, the formulations included are):
- Fluoxetine compared to placebo⁴^, ⁷
- Paroxetine compares to placebo⁹
Aspirin compared to placebo²⁴
Modafinil compared to placebo¹⁰^, ¹⁴^, ¹⁵^, ¹⁹^, ²⁶
Combination of pharmacological therapies (amantadine and aspirin) compared to amantadine¹²

No relevant clinical studies comparing any intervention with usual care were identified. There was limited evidence comparing active treatments to each other and comparing combinations of treatments to other treatments and placebo. No studies reported the following outcomes:

Visual Analogue Scale (VAS) measure of fatigue
Impact on patients/carers

All studies used oral preparations and conventional doses of the study medication. The majority of outcomes were reported at less than 3 months. These outcomes were included in the review but downgraded for outcome indirectness as they did not fulfil a period of 3–6 months as stated in the protocol (see indirectness section for further information).

Inconsistency

Two outcomes had significant statistical heterogeneity (I² >50%). In both cases, the meta-analysis included two or three studies and so there was insufficient data to populate subgroups to complete a subgroup analysis. These outcomes were therefore analysed using a random effects model and were downgraded for inconsistency.

Indirectness

The majority of outcomes in this review were downgraded for indirectness. This was due to one of two reasons:

Outcome indirectness – the majority of studies had less than 3 months follow up.
Population indirectness – one study⁹ included participants with multiple sclerosis and major depressive disorder. As fatigue can be a symptom of both conditions, this was considered as a source of indirectness.

Meta-analysis

Studies reported continuous outcomes in various ways across and within studies. For example, within a single study the same protocol outcome category could be reported in multiple scales that are not comparable (such as cognitive functions where, the symbol digit modalities test could be reported in the same study as the California verbal learning test-II).

In these cases, all forms of the outcome have been extracted and pooled with other studies reporting outcomes in the same scale.

All studies reported final values. Where possible, parallel and crossover trials have been combined (using generic inverse variance analysis as appropriate).

Studies not using pharmacological interventions specifically for fatigue

Four studies did not specifically use pharmacological interventions to manage fatigue. In these studies, the agents were either used for neuroprotection (Cambron 2016⁵, Chataway 2020⁷), depression (Ehde 2008⁹) or for cognitive function (Ford-Johnson 2016¹⁰). These studies were included in the review as they also investigated the effect on fatigue.

Previously included studies and outcomes

All studies included in the previous version of the guideline were included in this updated version of the review. However, four studies that were published before 2014 but were not included in the previous version of the guideline were included in this review (Ashtari 2009², Hamzei-Moghaddam 2011¹², Möller 2011¹⁵ and Stankoff 2005²⁶). For Moghaddam 2011¹², Möller 2011¹⁵ and Stankoff 2005²⁶, this is because they included interventions that were excluded in the previous version of the guideline (combinations of treatments and modafinil respectively) but were relevant to the current review protocol. For Ashtari 2009², it is unclear why it was not identified as part of the previous version of this review. A fifth study fulfilled the inclusion criteria but was not included in the previous version of the guideline (Rosenberg 1988²³). This study was not included as it was a small study (n=10) from before the date limitation which was unlikely to add sufficient data to impact the recommendations from this review. In studies that were previously included in the guideline, some outcomes were not included in analyses. This was either because the outcomes reported in the paper did not fall into categories stated in protocol (such as reporting total adverse events) or because the outcomes were reported in a way where meta-analysis would not be possible and would make interpretation difficult.

See also the study selection flow chart in Appendix C, study evidence tables in Appendix D, forest plots in Appendix E and GRADE tables in Appendix F.

1.1.4.2. Excluded studies

Of the thirty-two papers excluded from the review after reviewing full texts, this included two Cochrane reviews. These reviews were excluded either because of incorrect population (post-stroke fatigue)²⁷ or because the systematic review was withdrawn by the Cochrane and PaPaS review group as it did not meet their timelines and expectations²¹.

See the excluded studies list in Appendix J.

1.1.5. Summary of studies included in the effectiveness evidence

1.1.5.1. Amantadine compared to aspirin

Table 2

Summary of studies included in the evidence review.

1.1.5.2. Amantadine compared to modafinil

Table 3

Summary of studies included in the evidence review.

1.1.5.3. Amantadine compared to placebo

Table 4

Summary of studies included in the evidence review.

1.1.5.4. SSRIs compared to placebo

Table 5

Summary of studies included in the evidence review.

1.1.5.5. Aspirin compared to placebo

Table 6

Summary of studies included in the evidence review.

1.1.5.6. Modafinil compared to placebo

Table 7

Summary of studies included in the evidence review.

1.1.5.7. Combination of pharmacological therapies (amantadine and aspirin) compared to amantadine

Table 8

Summary of studies included in the evidence review.

See Appendix D for full evidence tables.

1.1.6. Summary of the effectiveness evidence

1.1.6.1. Amantadine compared to aspirin

Table 9

Clinical evidence summary: amantadine compared to aspirin.

1.1.6.2. Amantadine compared to modafinil

Table 10

Clinical evidence summary: amantadine compared to modafinil.

1.1.6.3. Amantadine compared to placebo

Table 11

Clinical evidence summary: amantadine compared to placebo.

1.1.6.4. SSRIs compared to placebo

Table 12

Clinical evidence summary: SSRIs compared to placebo.

1.1.6.5. Aspirin compared to placebo

Table 13

Clinical evidence summary: aspirin compared to placebo.

1.1.6.6. Modafinil compared to placebo

Table 14

Clinical evidence summary: modafinil compared to placebo.

1.1.6.7. Combination of pharmacological therapies (amantadine and aspirin) compared to amantadine

Table 15

Clinical evidence summary: combination of pharmacological therapies (amantadine and aspirin) compared to amantadine.

See Appendix F for full GRADE tables.

1.1.7. Economic evidence

1.1.7.1. Included studies

No health economic studies were included.

1.1.7.2. Excluded studies

No relevant health economic studies were excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in Appendix G.

1.1.8. Summary of included economic evidence

None

1.1.9. Economic model

This area was not prioritised for new cost-effectiveness analysis.

1.1.10. Unit costs

Table 16

Unit cost of drugs for the management of fatigue.

For modafinil, the BNF states that an electrocardiogram (ECG) is required before initiation. The unit cost of an ECG is £61.80 (NHS reference cost 2019/2020,¹⁸ currency code: EY51Z).

1.1.11. Evidence statements

Effectiveness

See summary of evidence in Tables 14–20.

Economic

No relevant economic evaluations were identified.

1.1.12. The committee’s discussion and interpretation of the evidence

1.1.12.1. The outcomes that matter most

The committee agreed that all outcomes included in the protocol were of critical importance for decision-making. The outcomes included patient-reported measures to assess MS fatigue, Visual Analogue Scale (VAS), adverse effects of treatment, Health-related Quality of Life (HRQoL), impact on patients and carers, cognitive functions, and psychological symptoms assessed by validated and disease-specific scales or questionnaires.

No evidence from randomised controlled trials was identified for VAS or impact on patients/carers.

1.1.12.2. The quality of the evidence

Seventeen randomised controlled trials including all 8 studies from the previous guideline were included in the review. Twelve of these were parallel trials and 5 were crossover trials. Evidence was available for the following comparisons:

Amantadine compared to aspirin
Amantadine compared to modafinil
Amantadine compared to placebo
SSRIs compared to placebo (analysed as a class, the formulations included are):
- Fluoxetine compared to placebo
- Paroxetine compares to placebo
Aspirin compared to placebo
Modafinil compared to placebo
Combination of pharmacological therapies (amantadine and aspirin) compared to amantadine

There was no evidence available comparing any intervention with usual care or clinical effectiveness beyond 6 months. There was limited evidence comparing active treatments to each other and comparing combinations of treatments to other treatments and placebo. There was also very limited evidence on adverse events.

In general, the quality of the evidence as assessed by GRADE was very low. Downgrading was most often due to indirectness for follow up as the majority of studies had a follow up time of less than 3 months and did not fulfil a period of 3–6 months as stated in the protocol. In addition, risk of bias due to selection or attrition bias was another reason for downgrading the evidence. In some scenarios, baseline values were different which could have influenced the effect on the meta-analysis. This information was presented to the committee to inform their confidence in the relative treatment effect. Imprecision in the outcomes was common. There was inconsistency in the evidence for Modified Fatigue Impact Scale in studies comparing amantadine to modafinil and for studies comparing amantadine to placebo with statistical heterogeneity being present. In these scenarios, only two or three studies were included in the meta-analysis and therefore there was an insufficient number of studies to produce substantial subgroups for a subgroup analysis. Therefore, the outcomes were analysed using random effects and downgraded for inconsistency.

1.1.12.2.1. Amantadine compared to aspirin

One outcome was reported (patient-reported outcome measures to assess MS fatigue at 3–6 months) including one small study (N=52). This outcome was rated as very low quality due to risk of bias, outcome indirectness and imprecision.

1.1.12.2.2. Amantadine compared to modafinil

Six outcomes were reported, including evidence from two studies. The outcomes were all of very low quality (apart from Epworth Sleepiness Scale at 3–6 months which was of low quality) and were commonly downgraded for risk of bias, outcome indirectness and imprecision. The patient-reported outcome measures to assess MS fatigue outcome was downgraded for inconsistency due to heterogeneity in the outcome.

1.1.12.2.3. Amantadine compared to placebo

Twenty-six outcomes were reported, including evidence from eight studies. The outcomes were all of very low quality (apart from Epworth Sleepiness Scale at 3–6 months which was of low quality) and were commonly downgraded for risk of bias, outcome indirectness and imprecision. The patient-reported outcome measures to assess MS fatigue outcome was downgraded for inconsistency due to heterogeneity in the outcome. The adverse events leading to withdrawal and cardiac events/arrhythmias outcomes were also downgraded for inconsistency due to zero events in some, but not all, studies included in the meta-analysis.

1.1.12.2.4. SSRIs compared to placebo

Sixteen outcomes were reported, including evidence from 3 studies. The outcomes ranged from high to very low quality, with the majority being of moderate-low quality. Outcomes were commonly downgraded for risk of bias, population or outcome indirectness (in this case, population indirectness is due to the inclusion of participants who have major depressive disorder as well as multiple sclerosis, and outcome indirectness being due to the outcome being at a later time period than 1 year).

1.1.12.2.5. Aspirin compared to placebo

One outcome was reported (withdrawal due to adverse events at 3–6 months) including one study (N=120). This outcome was rated as very low quality due to risk of bias, outcome indirectness and imprecision.

1.1.12.2.6. Modafinil compared to placebo

Twenty outcomes were reported, including evidence from five studies. The outcomes ranged from moderate to very low quality, with the majority of outcomes being of very low quality. Outcomes were commonly downgraded for risk of bias, outcome indirectness and imprecision.

1.1.12.2.7. Combination of pharmacological therapies (amantadine and aspirin) compared to amantadine

One outcome was reported (patient-reported outcome measures to assess MS fatigue at 3–6 months) including one small study (N=45). This was of moderate quality, being downgraded for outcome indirectness.

1.1.12.3. Benefits and harms

1.1.12.3.1. Amantadine

The effects of amantadine were investigated in ten studies and was compared to: aspirin, modafinil, combination of pharmacological therapies (amantadine and aspirin) and placebo. When compared to placebo at 3–6 months the evidence was mixed. Five outcomes (including evidence from three studies) reported a clinically important benefit for patient reported outcome measures to assess MS fatigue. There was a further patient-reported outcome measure assessing MS fatigue where the overall result of three pooled studies was ‘no clinically important difference’ between the two groups, but there was heterogeneity with one study suggesting better outcome with amantadine, one suggesting very little difference and the other suggesting worse outcome in the amantadine group. A clinically important benefit was also seen for the mental component of the SF-36 (health-related quality of life). However, the evidence for both outcomes was unclear as for patient reported outcome measures to assess MS fatigue three outcomes (including evidence from one study) showed no clinically important difference, and the physical component of SF-36 showed a clinically important harm. No clinically important difference was seen in withdrawal due to adverse events, cardiac events/arrhythmias, psychological symptoms and Epworth sleepiness scale. The evidence was unclear for cognitive functions, where one outcome showed a clinically important harm but 9 showed no clinically important difference. Disruption of sleep was observed to cause a clinically important harm (in two studies); disruption of sleep was noted to be due to insomnia in studies. Evidence was not available at the more than 6 months to 1 year time-point.

When compared to other interventions at 3–6 months, there was limited evidence. Amantadine appeared to be superior to modafinil in patient reported outcome measures to assess MS fatigue in one outcome populated by two studies. Otherwise, the same effects seen when compared to placebo were apparent for withdrawal due to adverse events, cardiac events/arrhythmias, health-related quality of life and the Epworth sleepiness scale. When compared to aspirin there was no clinically important difference between the two in patient reported outcome measures to assess MS fatigue. When compared to a combination of amantadine and aspirin, amantadine alone was inferior to the combination in patient reported outcome measures to assess MS fatigue, based on evidence from one study including 45 participants. Evidence was not available at the more than 6 months to 1 year time-point.

The committee discussed the heterogeneity in the patient-reported outcome measures to assess MS fatigue outcomes when compared to placebo. They noted that the Nourbakhsh 2021 study, a more recent study with a larger number of participants, showed no clinically important difference when compared to the other studies that showed clinically important benefits. They noted the limitations in this interpretation (as the Nourbakhsh study was a crossover trial with four study arms with a short treatment period for each intervention of 6 weeks). An additional, parallel trial (Rocca 2021) that reported the outcome at only 4 weeks suggested worse outcome with amantadine compared to the placebo group difference. This study consisted of only 15 participants in each arm. They concluded that while overall the evidence showed a clinically important benefit of amantadine, the quality of the evidence was very low and so they could not be confident in the result.

The committee discussed the clinically important harm in disruption of sleep with amantadine compared to placebo. Sleep disturbance is a common side effect of amantadine. In the included studies, amantadine was taken twice daily. Clinical experience stated that amantadine can cause sleep disturbance if taken before sleeping, as by treating fatigue it will cause disruption to sleep. The studies did not state when amantadine was taken. The committee noted that amantadine should be taken earlier in the day to minimise the possibility of sleep disturbance.

The committee noted their experiences with amantadine for fatigue. Currently amantadine is used as an initial treatment for fatigue. Lay member and clinician experience stated that amantadine can be an effective treatment for some people, but not for everyone. Currently it is unknown as to whether there are specific groups of people where this treatment would be more effective.

Based on this evidence the committee concluded that there appear to be benefits from amantadine with harms that likely could be minimised through giving people clear instructions on when to take amantadine. However, they noted the very low quality of the evidence.

1.1.12.3.2. SSRIs

The effects of SSRIs were investigated in three studies and was compared to placebo only. At 3–6 months the evidence was limited (being based on one study with 42 participants). This showed clinically important benefits in patient reported outcome measures to assess MS fatigue, the mental component of SF-36 (health-related quality of life), cognitive functions and psychological symptoms. There was no clinically important difference in the physical component of SF-36. Evidence from 2 studies was available at the more than 6 months to 1 year time-point. However, this evidence showed no clinically important differences in patient reported outcome measures to assess MS fatigue (based on high quality evidence), withdrawal due to adverse events, disruption of sleep, cardiac events/arrhythmias, health-related quality of life, cognitive functions and psychological symptoms.

The committee noted that benefits were seen for SSRIs at 3–6 months. However, the quality of the evidence was very low and based on one small study, which meant they were less confident in the result. Contrarily, at the more than 6 months to 1 year time-point there were no clinically important differences seen based on 2 larger studies with evidence that varied between high and very low quality. The committee agreed that there are potential benefits from using SSRIs for fatigue with no harms being found in this review.

1.1.12.3.3. Aspirin

The evidence on the effects of aspirin was very limited. Aspirin was compared to amantadine and placebo. When compared to placebo the only outcome reported that could be extracted as per the protocol was withdrawal due to adverse events, which showed no clinically important difference based on one study. When compared to amantadine, aspirin showed no clinically important difference in patient-reported outcome measures to assess MS fatigue. These outcomes were all at 3–6 months, with no evidence being available at the more than 6 months to 1 year time-point.

The committee noted there was an absence of evidence for this intervention. Experiences of the committee members noted that aspirin may be given by some people to treat inflammatory pain before exercise rather than to treat fatigue itself. In doing this, and reducing pain, it may help people to exercise more before feeling fatigued. As there was no evidence to show clinical benefit, the committee decided to not make a recommendation on aspirin. Instead, they made a research recommendation in order to investigate this further in the future.

1.1.12.3.4. Modafinil

The effects of modafinil were investigated in five studies and was compared to amantadine and placebo. When compared to placebo at 3–6 months, there was an unclear effect on health-related quality of life, with a clinically important benefit in four outcomes (based on one small study with 36 participants) while there was no clinically important difference in five outcomes (based on three studies). For all other outcomes there was no clinically important difference, including: patient reported outcome measures to assess MS fatigue, withdrawal due to adverse events, disruption of sleep, cardiac events/arrhythmias, cognitive function, psychological symptoms and Epworth sleepiness scale. There was no evidence available at the more than 6 months to 1 year time-point.

When compared to amantadine at 3–6 months, there was limited evidence. Modafinil appeared to be inferior to amantadine in patient reported outcome measures to assess MS fatigue in one outcome populated by two studies. There was an unclear effect on health-related quality of life (based on one small study with 30 participants) where modafinil appeared to be superior in the physical component of SF-36 (health-related quality of life) and inferior in the mental component of SF-36. Otherwise, the same effects seen when compared to placebo were apparent for withdrawal due to adverse events, cardiac events/arrhythmias and the Epworth sleepiness scale. There was no evidence available at the more than 6 months to 1 year time-point.

The committee acknowledged that there was limited evidence showing a benefit for health-related quality of life only. However, the quality for all outcomes was between moderate and very low, therefore they were ultimately not confident in the results. The committee noted that although modafinil is commonly prescribed in secondary care, the person should be offered modafinil as a first line option. In the committee’s experience, modafinil could be particularly effective for people with excessive sleepiness. This subgroup was not investigated in this review.

Based on the absence of harms and potential benefits, modafinil was included in the list of drugs to be considered for people with MS wishing to try a medicine for fatigue. The committee noted that the evidence was of low quality and that, based on clinical experience and consensus within the committee, there may be specific groups of people that would benefit more from modafinil (for example, people with fatigue and excessive sleepiness). Based on this, they made a research recommendation to gain more information about groups where this treatment could be more effective.

Amantadine, SSRIs and modafinil were all recommended as first line options for the treatment of fatigue. Due to the lack of evidence the committee were unable to suggest a preference for what medication should be tried first and emphasised that individual patient factors need to be taken into consideration when discussing options. Response should be monitored and reviewed so that people do not remain on ineffective treatment.

1.1.12.3.5. Combination of pharmacological therapies (amantadine and aspirin)

There was very limited evidence on the efficacy of combination of pharmacological therapies. One study reported comparing amantadine and aspirin to amantadine alone at 3–6 months. In this there was a clinically important benefit of the combination of pharmacological therapies in patient reported outcome measures to assess MS fatigue (based on one small study including 45 participants). There was no evidence available at the more than 6 months to 1 year time-point.

The committee noted the limited evidence for this comparison and for aspirin alone compared to placebo. Based on this they decided to not make a recommendation discussing combinations of pharmacological therapies. Instead, they made a research recommendation in order to investigate this further in the future.

1.1.12.4. Cost effectiveness and resource use

No relevant health economic analyses were identified for this review; therefore, unit costs were presented to aid committee consideration of cost-effectiveness. The annual unit cost of amantadine ranged between approximately £350 and £701, which was significantly more expensive than the other drugs in the clinical studies. The estimated cost of modafinil was between £78 and £157 per year, in addition there is a one of cost of an ECG prior to drug initiation (£62). Aspirin was less costly at £18 per year while the SSRIs fluoxetine and paroxetine were costed at £14-£22 and £56-£41 per year, respectively.

Amantadine

The clinical evidence summarised in the section above reported a clinically important benefit for patient reported outcome measures to assess MS fatigue for amantadine vs placebo. A clinically important benefit was also seen for the mental component of the SF-36 (health-related quality of life). A clinically important harm was reported in disruption of sleep with amantadine compared to placebo. The committee noted that this likely could be minimised through giving people clear instructions on when to take amantadine. There was limited evidence comparing amantadine to other comparators. The previous MS guideline made an ‘offer’ recommendation for the use of amantadine to treat fatigue in people with MS, however, it was noted that the cost of amantadine had increased since the development of the last guideline. Experiences of committee members noted that amantadine is usually the conventional treatment for MS-related fatigue and can be an effective treatment for some people, but not for everyone. At the current cost, prescribing amantadine is likely to have a substantial resource impact, as annual costs start at £350, and any treatment costing over £100 affecting 10% of the MS population would be considered a substantial resource impact. Given the lack of published health economic evidence, the increased cost and the very low quality of clinical evidence, a ‘consider’ recommendation was made for amantadine.

Modafinil

The committee acknowledged that there was limited or unclear evidence showing the benefit of modafinil in terms of health-related quality of life when compared to placebo or amantadine. Some committee members suggested there could be potential improvements to quality of life in terms of employment, as this would improve productivity for people with MS, however, there was no clinical evidence for this and health economic evidence for NICE guidelines does not consider the impact of employment in terms of GDP or productivity of the workforce. The committee acknowledged that there would be a resource impact for recommending modafinil, however, they highlighted that a lower dose (100mg) than what was shown in the studies is commonly prescribed. If 10% of people with MS were treated with the lower dose (~£40 per year) then this would be below the threshold of what is considered a substantial resource impact. Given the limited clinical evidence and lack of cost-effective evidence the committee agreed on a ‘consider’ recommendation for modafinil.

SSRIs

Clinically important benefits were reported for patient reported outcome measures to assess MS fatigue, the mental component of SF-36 (health-related quality of life), cognitive functions and psychological symptoms. Both SSRIs were also less costly than amantadine. No clinically important harms were found in the clinical review, however, the quality of evidence for benefits seen for SSRIs at 3–6 months was very low and based on one study. Given the potential benefits from SSRIs for fatigue and lack of serious adverse events based on the clinical review, committee agreed on a ‘consider’ recommendation for SSRIs.

Aspirin

Experiences of committee members noted that aspirin would not be given to treat fatigue specifically but rather to alleviate inflammatory pain before exercising. Alongside this, there was no evidence of clinical benefit of aspirin for treating fatigue and as such the committee agreed not to make a recommendation for the use of aspirin to manage MS-related fatigue.

In conclusion, based on the limited clinical and economic evidence, the committee agreed to make a consider recommendation for amantadine, modafinil and SSRIs. In terms of current practice, amantadine is currently the first-line pharmacological treatment and modafinil is mostly provided in secondary care settings. Given that all three drugs are considered equally, there may be a decrease in use of amantadine and increase in use of modafinil and SSRIs. Given that the unit cost of amantadine is greater than that of modafinil and SSRIs the resource impact of this recommendation is unlikely to be significant.

1.1.12.5. Other factors the committee took into account

The committee noted that currently modafinil is mostly prescribed by secondary care physicians, while amantadine is prescribed by a range of professionals across sectors. Through this recommendation, they believe that practice may change and so modafinil may be prescribed more by different professionals and in primary care.

The committee noted the safety concerns for modafinil, including that it should not be used during pregnancy and that precautions should be taken if prescribing it for women able to have children, in line with the 2020 MHRA safety advice on modafinil. The committee noted additional advice on monitoring, stopping treatment and cautions for use in the 2014 MHRA safety advice on modafinil and in the summary of product characteristics for modafinil and amantadine.

1.1.13. Recommendations supported by this evidence review

This evidence review supports recommendations 1.5.12 to 1.5.16 and the research recommendation on pharmacological management of fatigue.

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13.: Krupp LB, Coyle PK, Doscher C, Miller A, Cross AH, Jandorf L et al Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology. 1995; 45(11):1956–1961 [PubMed: 7501140]

14.: Ledinek AH, Sajko MC, Rot U. Evaluating the effects of amantadin, modafinil and acetyl-L-carnitine on fatigue in multiple sclerosis - result of a pilot randomized, blind study. Clinical Neurology and Neurosurgery. 2013; 115(Supp 1):S86–89 [PubMed: 24321164]

15.: Möller F, Poettgen J, Broemel F, Neuhaus A, Daumer M, Heesen C. HAGIL (Hamburg Vigil Study): a randomized placebo-controlled double-blind study with modafinil for treatment of fatigue in patients with multiple sclerosis. Multiple Sclerosis. 2011; 17(8):1002–1009 [PubMed: 21561959]

16.: Murray TJ. Amantadine therapy for fatigue in multiple sclerosis. Canadian Journal of Neurological Sciences. 1985; 12(3):251–254 [PubMed: 3902184]

17.: National Institute for Health and Care Excellence. Developing NICE guidelines: the manual [updated 2020]. London. National Institute for Health and Care Excellence, 2014. Available from: http://www.nice.org.uk/article/PMG20/chapter/1%20Introduction%20and%20overview [PubMed: 26677490]

18.: NHS England and NHS Improvement. 2019/20 National Cost Collection Data Publication. 2021. Available from: https://www.england.nhs.uk/publication/2019-20-national-cost-collection-data-publication/ Last accessed: 04 October 2021.

19.: Nourbakhsh B, Revirajan N, Morris B, Cordano C, Creasman J, Manguinao M et al Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial. The Lancet Neurology. 2021; 20(1):38–48 [PMC free article: PMC7772747] [PubMed: 33242419]

20.: Nourbakhsh B, Revirajan N, Waubant E. Treatment of fatigue with methylphenidate, modafinil and amantadine in multiple sclerosis (TRIUMPHANT-MS): Study design for a pragmatic, randomized, double-blind, crossover clinical trial. Contemporary Clinical Trials. 2018; 64:67–76 [PubMed: 29113955]

21.: Payne C, Wiffen PJ, Martin S. Interventions for fatigue and weight loss in adults with advanced progressive illness. Cochrane Database of Systematic Reviews 2017, Issue 4. Art. No.: CD008427. DOI: 10.1002/14651858.cd008427.pub3. [PubMed: 22258985] [CrossRef]

22.: Rocca MA, Valsasina P, Colombo B, Martinelli V, Filippi M. Cortico-subcortical functional connectivity modifications in fatigued multiple sclerosis patients treated with fampridine and amantadine. European Journal of Neurology. 2021; 28(7):2249–2258 [PubMed: 33852752]

23.: Rosenberg GA, Appenzeller O. Amantadine, fatigue, and multiple sclerosis. Archives of Neurology. 1988; 45(10):1104–1106 [PubMed: 2972270]

24.: Sadeghi-Naini M, Ghazi-zadeh Esslami G, Fayyazi S, Nabavi SM, Morsali D, Ghaffarpour M. Low dose aspirin for MS-related fatigue: Results of a pilot, double-blind, randomized trial. Neurology Psychiatry and Brain Research. 2017; 25:24–30

25.: Shaygannejad V, Janghorbani M, Ashtari F, Zakeri H. Comparison of the effect of aspirin and amantadine for the treatment of fatigue in multiple sclerosis: a randomized, blinded, crossover study. Neurological Research. 2012; 34(9):854–858 [PubMed: 22979982]

26.: Stankoff B, Waubant E, Confavreux C, Edan G, Debouverie M, Rumbach L et al Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology. 2005; 64(7):1139–1143 [PubMed: 15824337]

27.: Wu S, Kutlubaev MA, Chun HYY, Cowey E, Pollock A, Macleod MR et al Interventions for post-stroke fatigue. Cochrane Database of Systematic Reviews 2015, Issue 7. Art. No.: CD007030. DOI: 10.1002/14651858.cd007030.pub3. [PMC free article: PMC7387276] [PubMed: 26133313] [CrossRef]

Appendices

Appendix A. Review protocols

Review protocol for pharmacological management of fatigue (PDF, 242K)

Health economic review protocol (PDF, 157K)

Appendix B. Literature search strategies

This literature search strategy was used for the following review:

The clinical and cost effectiveness of pharmacological interventions for fatigue for adults with MS, including people receiving palliative care.

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual.¹⁷

For more information, please see the Methodology review published as part of the accompanying documents for this guideline.

B.1. Clinical search literature search strategy (PDF, 162K)

B.2. Health Economics literature search strategy (PDF, 166K)

Appendix H. Economic evidence tables

None.

Appendix I. Health economic model

No original health economic modelling was undertaken as other areas of the guideline were prioritised.

Appendix J. Excluded studies

Clinical studies

Table 26

Studies excluded from the clinical review.

Health Economic studies

Download PDF (94K)

Appendix K. Research recommendations – full details

K.1.1. Research recommendation

For adults with MS, including people receiving palliative care, what is the clinical and cost effectiveness of pharmacological interventions for fatigue?

K.1.2. Why this is important

Fatigue is a major problem for people with MS. Studies indicate that between 80–90% of all people with MS experience fatigue and up to 40% describe it as the most disabling symptom of the condition. Much is written regarding the effects on daily life including its impact on employment, where fatigue is one of the key factors leading to early retirement. MS fatigue is often described as primary fatigue (directly related to the condition due to causes such as nerve fibre fatigue, heat sensitive fatigue or lassitude) or secondary fatigue, where other factors may worsen the fatigue experienced, such as infection, low mood or environmental challenges. Although medications exist which may reduce fatigue, but further research is needed to identify the benefits and harms of interventions to manage these symptoms.

K.1.3. Rationale for research recommendation

Download PDF (170K)

K.1.4. Modified PICO table

Download PDF (133K)

Final

Evidence reviews underpinning recommendations 1.5.12 to 1.5.16 and research recommendations in the NICE guideline

National Institute for Health and Care Excellence

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK585274PMID: 36279388

Table 1PICO characteristics of review question

Population	Inclusion: Adults (≥18 years) with MS, including people receiving palliative care, who are experiencing fatigue. Exclusion: Children and young people (≤18 years).
Interventions	Amantadine SSRIs Aspirin specifically before exercise Modafinil Combinations of the above
Comparisons	Interventions will be compared to each other (both within and between classes), placebo/sham, or usual care.
Outcomes	All outcomes are considered equally important for decision making and therefore have all been rated as critical. Patient-reported outcome measures to assess MS fatigue, including MFIS Fatigue Severity Scale (FSS), National Fatigue Index (NFI), MS-specific FSS (MFSS), Modified Fatigue Impact Scale (MFIS), Visual Analogue Scale (VAS) for fatigue Adverse effects of treatment. Adverse events leading to withdrawal Disruption of sleep cardiac events/arrhythmias Health-related Quality of Life, for example EQ-5D, SF-36, Leeds MS quality of life scale, MS Impact Scale. Impact on patients/carers. Cognitive functions, such as memory and concentration Psychological symptoms assessed by validated and disease-specific scales, questionnaire or similar instruments. Epworth sleepiness scale Follow up: 3–6 months (minimum of 3 months but can include 1–3 months and downgrade) >6 months – 1 year (data from >1 year follow up may be included but will be downgraded)
Study design	Systematic reviews of RCTs and RCTs Crossover RCTs with a washout period of at least 1 week will be included

Table 2Summary of studies included in the evidence review

Study

Intervention and comparison

Population

Outcomes

Comments

Shaygannejad 2012²⁵

Amantadine (n=26)

Oral amantadine 100mg twice daily for 4 weeks

Aspirin (n=26)

Oral aspirin 500mg once daily for 4 weeks

Concomitant therapy: All people had received interferon-beta treatment for the past year.

Disease modifying treatment status: All participants were receiving disease modifying treatment.

Multiple Sclerosis

N = 52

Age (mean [SD]): 35.3 (7.8) years

Type of multiple sclerosis:

Relapsing-remitting: 44.

Secondary progression: 8.

EDSS (mean [SD]): 1.6 (1.6)

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at 3–6 months

This study was included in the previous version of the guideline.

This study was a crossover trial (two-week washout).

Table 3Summary of studies included in the evidence review

Study

Intervention and comparison

Population

Outcomes

Comments

Ledinek 2013¹⁴

Amantadine (n=15)

Amantadine 200mg orally daily for 1 month

Modafinil (n=15)

Modafinil 200mg orally daily for 1 month

Placebo (n=15)

A fourth group receiving acetyl-l-carnitine (n=15) was not extracted as it did not fulfil the inclusion criteria in the protocol.

Concomitant therapy: No additional information.

Disease modifying treatment status: Not stated/unclear.

Multiple Sclerosis

N = 60

Age (mean [SD]): 38.0 (6.1) years

Type of multiple sclerosis: Not stated/unclear.

EDSS: 2.7 (1.1)

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at 3–6 months

Health-related Quality of Life at 3–6 months

This study was included in the previous version of the guideline.

Nourbakhsh 2021¹⁹

Subsidiary studies: Nourbakhsh 2018²⁰

Amantadine (n=141)

Oral amantadine (up to 100mg twice daily)

Modafinil (n=141)

Oral modafinil (up to 100mg twice daily)

Placebo (n=141)

A fourth group receiving methylphenidate (n=141) was reported. The results for this group was not extracted as they did not fulfil the inclusion criteria in the protocol.

Concomitant therapy: Not stated/unclear.

Disease modifying treatment status: Not stated/unclear.

Multiple Sclerosis

N = 141

Age (mean [SD]): 46.8 (10.7) years

Type of multiple sclerosis:

Relapsing-remitting MS: 106

Secondary progressive MS: 19

Primary progressive MS: 15.

EDSS (median [IQR]): 3 (2–4.5)

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at 3–6 months

Withdrawal due to adverse events at 3–6 months

Cardiac events/arrhythmia at 3–6 months

Epworth Sleepiness scale at 3–6 months

Clinicaltrials.gov number: NCT03185065.

This study was a crossover trial (two-week washout).

Table 4Summary of studies included in the evidence review

Study

Intervention and comparison

Population

Outcomes

Comments

Anonymous 1987¹

Amantadine (n=115)

100mg orally twice a day for 3 weeks (with a 2-week washout period before the study, and a 2-week washout period before crossing over to placebo treatment for 3 weeks).

Placebo (n=115)

Concomitant therapy:

The only concomitant medications permitted were small doses of muscle relaxants (baclofen, dantrolene) to control spasticity; anticholinergics (oxybutynin) for bladder control; and short-acting benzodiazepines at bedtime.

Disease modifying treatment status: Not stated/unclear.

Multiple Sclerosis

N = 115

Age (mean [SE]): 40.8 (1) years

Type of multiple sclerosis:

Relapsing-remitting: 57

Relapsing/progressing: 33

Chronic progressing: 22

Benign: 3

EDSS (mean [SE]): 4.2 (0.2)

People receiving palliative care: Not stated/unclear.

Adverse events leading to withdrawal at 3–6 months

Disruption of sleep at 3–6 months

Cardiac events/arrhythmia at 3–6 months

Cognitive functions at 3–6 months

Psychological symptoms at 3–6 months

Trial by the Canadian MS Research Group.

This study was a crossover trial (two-week washout).

This study was included in the previous version of the guideline.

Ashtari 2009²

Amantadine (n=21)

Oral amantadine 200mg per day for 2 months

Placebo (n=21)

Concomitant therapy: No additional information.

Disease modifying treatment status: All were receiving treatment with disease modifying agents (either interferon-beta, cytotoxic drugs or a combination of both).

Multiple Sclerosis

N = 41

Age (mean [SD]): 25.48 (5.12) years

Type of multiple sclerosis: Relapsing-remitting.

EDSS (mean [SD]): 2.56 (3.67)

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at 3–6 months

Withdrawal due to adverse events at 3–6 months

Cohen 1989⁸

Amantadine (n=29)

Amantadine 100mg orally twice a day for 4 weeks

Placebo (n=29)

Concomitant therapy:

No additional information

Disease modifying treatment status: Not stated/unclear.

Multiple Sclerosis

N = 29

Age (mean [SD]): 44.5 (9.3) years

Type of multiple sclerosis: 13 demonstrated a chronic deteriorating or relapsing/deteriorating course of illness, while 16 exhibited either a benign or remitting/relapsing course.

EDSS: <6 (people with a score >6 were excluded)

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at 3–6 months

Withdrawal due to adverse events at 3–6 months

This study was a crossover trial (two-week washout).

This study was included in the previous version of the guideline.

Krupp 1995¹³

Subsidiary studies: Geisler 1996¹¹

Amantadine (n=31)

Amantadine 100mg twice a day for 2 months

Placebo (n=35)

A third group receiving pemoline (n=27) was not included in this review as they did not fulfil the inclusion criteria in the protocol.

Concomitant therapy: No additional information.

Disease modifying treatment status: Not stated/unclear.

Multiple Sclerosis

N = 93

Age (mean [SD]): 41.1 (6.5) years

Type of multiple sclerosis: 90–94% had relapsing-remitting multiple sclerosis

EDSS: 2.38 (1.54)

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at 3–6 months

Withdrawal due to adverse events at 3–6 months

Sleep disturbance at 3–6 months

Cardiac disorder/arrhythmia at 3–6 months

Cognitive functions at 3–6 months

The patient-reported outcome measures to assess MS fatigue and cognitive functions outcomes were extracted from Geisler 1996 which only included a subset of the participants included in the original Krupp study (as these values were only reported in a manner that could be meta-analysed in the Geisler study).

This study was included in the previous version of the guideline. In the previous version of the guideline these studies were reported separately. Due to the participants in the Geisler study being a subset of those from the Krupp study, they were combined in this analysis for this version.

Ledinek 2013¹⁴

Amantadine (n=15)

Amantadine 200mg orally daily for 1 month

Modafinil (n=15)

Modafinil 200mg orally daily for 1 month

Placebo (n=15)

A fourth group receiving acetyl-l-carnitine (n=15) was not extracted as it did not fulfil the inclusion criteria in the protocol.

Concomitant therapy: No additional information.

Disease modifying treatment status: Not stated/unclear.

Multiple Sclerosis

N = 60

Age (mean [SD]): 38.0 (6.1) years

Type of multiple sclerosis: Not stated/unclear.

EDSS: 2.7 (1.1)

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at 3–6 months

Health-related Quality of Life at 3–6 months

This study was included in the previous version of the guideline.

Murray 1985¹⁶

Amantadine (n=32)

Amantadine 100mg orally twice a day for 3 weeks, then placebo orally twice a day for 3 weeks (1 week washout period between doses)

Placebo (n=32)

Concomitant therapy: Not stated/unclear.

Disease modifying treatment status: Not stated/unclear.

Multiple Sclerosis

N = 32

Age (mean [SD]): Not stated/unclear.

Type of multiple sclerosis: Not stated/unclear.

EDSS: Most of the participants were in the 0–3 range in the EDSS.

People receiving palliative care: Not stated/unclear.

Withdrawal due to adverse events at 3–6 months

This study was a crossover trial (1 week washout).

This study was included in the previous version of the guideline.

Nourbakhsh 2021¹⁹ (TRIUMPHANT-MS)

Subsidiary studies: Nourbakhsh 2018²⁰

Amantadine (n=141)

Oral amantadine (up to 100mg twice daily)

Modafinil (n=141)

Oral modafinil (up to 100mg twice daily)

Placebo (n=141)

A fourth group receiving methylphenidate (n=141) was reported. The results for this group was not extracted as they did not fulfil the inclusion criteria in the protocol.

Concomitant therapy: Not stated/unclear.

Disease modifying treatment status: Not stated/unclear.

Multiple Sclerosis

N = 141

Age (mean [SD]): 46.8 (10.7) years

Type of multiple sclerosis:

Relapsing-remitting MS: 106

Secondary progressive MS: 19

Primary progressive MS: 15.

EDSS (median [IQR]): 3 (2–4.5)

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at 3–6 months

Withdrawal due to adverse events at 3–6 months

Cardiac events/arrhythmia at 3–6 months

Epworth Sleepiness scale at 3–6 months

Clinicaltrials.gov number: NCT03185065.

This study was a crossover trial (2-week washout).

Rocca 2021²²

Amantadine (n=15)

Oral amantadine (100mg twice daily for 4 weeks)

Placebo (n=15)

(One placebo tablet twice daily for 4 weeks)

A third group receiving fampridine (n=15) was reported but not extracted as this was not an intervention in the review protocol.

Concomitant therapy: Not stated/unclear.

Disease modifying treatment status: majority (>80%) were taking these treatments

Multiple Sclerosis

N = 30

Age (mean [IQR]): 41.2 (34–46) years in amantadine and 41.9 (33–49) years in placebo

Type of multiple sclerosis:

Relapsing-remitting MS: all relapsing remitting (inclusion criterion)

EDSS (median [IQR]): 2.5 (2 to 2.5) in amantadine group and 2 (1.5 to 2) in placebo group

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at 3–6 months

Withdrawal due to adverse events at 3–6 months

Trial registration: EudraCT 2010-023678-38.

Table 5Summary of studies included in the evidence review

Study

Intervention and comparison

Population

Outcomes

Comments

Cambron 2019⁴

(FLUOX-PMS trial)

Subsidiary studies: Cambron 2016⁵

Fluoxetine (n=74)

Fluoxetine 20mg orally for 4 weeks, followed by a daily single intake of 2 tablets of 20mg fluoxetine until week 108.

Placebo (n=77)

Concomitant therapy: Concomitant medications that could lead to clinically significant interactions with fluoxetine (such as monoamine oxidase inhibitors) were not allowed. The use of interferon beta or glatiramer acetate was allowed, as these drugs are ineffective in slowing down disability accrual in progressive MS. Patients using other immunosuppressive or immunomodulatory drugs could only be included if the drug was stopped at least for 2 months before randomisation.

Disease modifying treatment status: People were allowed to use some treatment (see concomitant therapies). However, only around 27% received them.

Multiple Sclerosis

N = 151

Age (mean [SD]): 52.6 (7.1) years

Type of multiple sclerosis:

Primary progressive MS: 77

Secondary progressive MS: 55

EDSS (mean [SD]): 13.3 (8.4)

People receiving palliative care: Not stated/unclear

Patient-reported outcome measures to assess MS fatigue at >6 months-1 year

Adverse events leading to withdrawal at >6 months-1 year

Disruption to sleep at >6 months-1 year

Cognitive functions at >6 months-1 year

Psychological symptoms at >6 months-1 year

EudraCT Number 2011-003775-11.

Chataway 2020⁷ (MS-SMART trial)

Subsidiary studies: Chataway 2015⁶

Fluoxetine (n=111)

Fluoxetine 20mg orally once a day for 4 weeks, then twice a day from week 4 to week 96.

Placebo (n=112)

Two additional groups were reported in the study reporting participants receiving amiloride and riluzole (both n=111). These were excluded from this review as they were not included in the protocol.

Concomitant therapy: No additional information.

Disease modifying treatment status: Not stated/unclear.

Multiple Sclerosis

N = 445

Age (mean [95% CI]):

Fluoxetine: 55.5 (50.7 to 60.2) years

Placebo: 56.4 (49.2 to 60.4) years

Type of multiple sclerosis: Secondary progressive multiple sclerosis.

EDSS (mean [95% CI]):

Fluoxetine: 6 (5.5 to 6.5)

Placebo: 6 (5.5 to 6.5)

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at >6 months-1 year

Cardiac events/arrhythmia at >6 months-1 year

Health-related Quality of Life at >6 months-1 year

Cognitive functions at >6 months-1 year

ClinicialTrials.gov registry = NCT01910259.

Edhe 2008⁹

Paroxetine (n=22)

Paroxetine 10mg per day, up titrated to 20mg/day after 1 week (2 capsules) and then could be further up titrated a maximum of 40mg/day in subsequent weeks dependent on symptoms or down titrated due to adverse events.

Placebo (n=20)

Concomitant therapy: No additional information.

Disease modifying treatment status: Not stated/unclear.

Multiple Sclerosis

N = 42

Age (mean [SD]): 45 (10.1) years

Type of multiple sclerosis: Not stated/unclear.

EDSS: Mixed. Mild (0–4): 22, Moderate (4.5–6.5): 16, Severe (8–9.5): 4.

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at 3–6 months

Withdrawal due to adverse events at 3–6 months

Health-related Quality of Life at 3–6 months

Cognitive functions at 3–6 months

Psychological symptoms at 3–6 months

This study was included in the previous version of the guideline.

Table 6Summary of studies included in the evidence review

Study

Intervention and comparison

Population

Outcomes

Comments

Sadeghi-Naini 2017²⁴

Aspirin (n=64)

Oral low dose aspirin (80mg) daily for 8 weeks

Placebo (n=56)

Concomitant therapy: All people were using the different disease modifying therapies including beta-interferons which were prescribed for them.

Disease modifying treatment status: All participants were receiving disease modifying therapy.

Multiple Sclerosis

N = 120

Age (mean [SD]): 33.2 (9.1) years

Type of multiple sclerosis:

Relapsing-remitting MS: 80

Secondary progressive MS: 18

Primary progressive MS: 2

EDSS: 1.8 (1.2)

People receiving palliative care: Not stated/unclear.

Withdrawal due to adverse events at 3–6 months

Table 7Summary of studies included in the evidence review

Study

Intervention and comparison

Population

Outcomes

Comments

Ford-Johnson 2016¹⁰

Modafinil (n=9)

Modafinil 200mg once a day orally for 2 weeks, followed by 1 week washout, then placebo once a day orally for 2 weeks.

Placebo (n=9)

Concomitant therapy: No additional information.

Disease modifying treatment status: Not stated/unclear.

Multiple Sclerosis

N = 18

Age (mean [SD]): 42.44 (8.06) years

Type of multiple sclerosis:

Relapsing-remitting: 10

Primary progressive: 1

Secondary progressive: 3

Progressive relapsing: 0

Unknown: 2

EDSS: 3.9 (2.2)

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at 3–6 months

Withdrawal due to adverse events at 3–6 months

Health-related Quality of Life at 3–6 months

Cognitive functions at 3–6 months

Psychological symptoms at 3–6 months

Clinicaltrials.gov - NCT00142402.

Ledinek 2013¹⁴

Amantadine (n=15)

Amantadine 200mg orally daily for 1 month

Modafinil (n=15)

Modafinil 200mg orally daily for 1 month

Placebo (n=15)

A fourth group receiving acetyl-l-carnitine (n=15) was not extracted as it did not fulfil the inclusion criteria in the protocol.

Concomitant therapy: No additional information.

Disease modifying treatment status: Not stated/unclear.

Multiple Sclerosis

N = 60

Age (mean [SD]): 38.0 (6.1) years

Type of multiple sclerosis: Not stated/unclear.

EDSS: 2.7 (1.1)

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at 3–6 months

Health-related Quality of Life at 3–6 months

This study was included in the previous version of the guideline.

Möller 2011¹⁵ (HAGIL study)

Modafinil (n=62)

Modafinil oral 200mg/day up titrated over 1 week, then continued for 8 weeks in total.

Placebo (n=59)

Concomitant therapy: Not stated/unclear.

Disease modifying treatment status: Mixed. 50.4% were on immunotherapy.

Multiple Sclerosis

N = 121

Age (mean [SD]): 41.1 (10.3) years

Type of multiple sclerosis:

Relapsing-remitting MS: 63

Secondary-progressive MS: 31

Primary-progressive MS: 26.

EDSS: 3.3 (1.4).

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at 3–6 months

Health-related Quality of Lfe at 3–6 months

Epworth Sleepiness scale at 3–6 months

Nourbakhsh 2021¹⁹

Subsidiary studies: Nourbakhsh 2018²⁰

Amantadine (n=141)

Oral amantadine (up to 100mg twice daily)

Modafinil (n=141)

Oral modafinil (up to 100mg twice daily)

Placebo (n=141)

A fourth group receiving methylphenidate (n=141) was reported. The results for this group was not extracted as they did not fulfil the inclusion criteria in the protocol.

Concomitant therapy: Not stated/unclear.

Disease modifying treatment status: Not stated/unclear.

Multiple Sclerosis

N = 141

Age (mean [SD]): 46.8 (10.7) years

Type of multiple sclerosis:

Relapsing-remitting MS: 106

Secondary progressive MS: 19

Primary progressive MS: 15.

EDSS (median [IQR]): 3 (2–4.5)

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at 3–6 months

Withdrawal due to adverse events at 3–6 months

Cardiac events/arrhythmia at 3–6 months

Epworth Sleepiness scale at 3–6 months

Clinicaltrials.gov number: NCT03185065.

This study was a crossover trial (two-week washout).

Stankoff 2005²⁶

Modafinil (n=59)

Oral modafinil 200mg for 1 week, increased by 100mg every week up to 400mg/day and remaining at that dose between day 31 and day 35 (5 weeks treatment in total).

Placebo (n=56)

Concomitant therapy: Disease-modifying therapies such as beta interferon, glatiramer acetate, azathioprine or methotrexate were allowed, but had to be a stable dose for at least 6 months before treatment. All symptomatic treatment for fatigue had to be withdrawn at least 14 days before randomisation.

Disease modifying treatment status: Unclear. People were allowed to continue previous treatment.

Multiple Sclerosis

N = 115

Age (mean [SD]): 43.9 (8.5) years

Type of multiple sclerosis:

Relapsing-remitting or progressive MS.

EDSS (mean [SD]): 3.5 (1.7)

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS at 3–6 months

Withdrawal due to adverse events at 3–6 months

Table 8Summary of studies included in the evidence review

Study

Intervention and comparison

Population

Outcomes

Comments

Hamzei-Moghaddam 2011¹²

Combination of pharmacological therapies (amantadine and aspirin) (n=21)

Amantadine 100mg and aspirin 500mg twice a day for 6 weeks.

Amantadine (n=24)

Amantadine 100mg and placebo twice a day for 6 weeks.

Concomitant therapy: No additional information.

Disease modifying treatment status: Not stated/unclear.

Multiple Sclerosis

N = 45

Age (mean [SD]): 33.1 (7.5) years

Type of multiple sclerosis:

Relapsing-remitting: 36. Secondary progressive: 9.

EDSS: Mixed

EDSS <2: 13.

EDSS 2–5: 14.

EDSS >5: 18.

People receiving palliative care: Not stated/unclear.

Patient-reported outcome measures to assess MS fatigue at 3–6 months

Iranian Randomised Clinical trial number: 201112208430N3.

Table 9Clinical evidence summary: amantadine compared to aspirin

Outcomes

№ of participants (studies) Follow up

Certainty of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with aspirin

Risk difference with amantadine

Patient-reported outcome measures to assess MS fatigue (FSS, 1–7, lower values are better, final value, crossover trial) at 3–6 months

(1 RCT)

follow up: 10 weeks

⊕◯◯◯

VERY LOW^a^,^b^,^c

The mean patient-reported outcome measures to assess MS fatigue was 3.55

MD 0.2 higher

(0.63 lower to 1.03 higher)

: Explanations

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

b: Downgraded by 1 or 2 increments because of outcome indirectness

c: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs

Table 10Clinical evidence summary: amantadine compared to modafinil

Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with modafinil	Risk difference with amantadine
Patient-reported outcome measures to assess MS fatigue (MFIS, 0–84, lower values are better, final value, parallel trial and crossover trial) at 3–6 months	278 (2 RCTs) follow up: mean 5 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^c^,^d	-	-	MD 7.51 lower (27.58 lower to 12.56 higher)
Withdrawal due to adverse events at 3–6 months (crossover)	252 (1 RCT) follow up: 6 weeks	⊕◯◯◯ VERY LOW^a^,^c^,^d	RR 2.95 (0.31 to 28.01)	8 per 1,000	16 more per 1,000 (6 fewer to 216 more)
Cardiac events/arrhythmias at 3–6 months (crossover)	252 (1 RCT) follow up: 6 weeks	⊕◯◯◯ VERY LOW^a^,^c^,^d	RR 0.59 (0.14 to 2.42)	40 per 1,000	16 fewer per 1,000 (34 fewer to 57 more)
Health-related Quality of Life (SF-36 physical component summary, 0–100, higher values are better, final value, parallel trial) at 3–6 months	30 (1 RCT) follow up: 4 weeks	⊕◯◯◯ VERY LOW^a^,^c^,^d	-	The mean health-related Quality of Life was 41.5	MD 7.1 lower (12.21 lower to 1.99 lower)
Health-related Quality of Life (SF-36 mental component summary, 0–100, higher values are better, final value, parallel trial) at 3–6 months	30 (1 RCT) follow up: 4 weeks	⊕◯◯◯ VERY LOW^a^,^c^,^d	-	The mean health-related Quality of Life was 42.8	MD 6 higher (1.01 higher to 10.99 higher)
Epworth Sleepiness scale (0–24, lower values are better, final value, crossover trial) at 3–6 months	248 (1 RCT) follow up: 6 weeks	⊕⊕◯◯ LOW^a^,^c	-	The mean Epworth Sleepiness scale was 8.3	MD 1 higher (0.02 higher to 1.98 higher)

: Explanations

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

b: Downgraded by 1 or 2 increments because heterogeneity, unexplained by subgroup analysis

c: Downgraded by 1 or 2 increments because of outcome indirectness

d: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs

Table 11Clinical evidence summary: amantadine compared to placebo

Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with placebo	Risk difference with amantadine
Patient-reported outcome measures to assess MS fatigue (FSS, 1–7, lower values are better, change score and final value, parallel trials) at 3–6 months	74 (2 RCTs) follow up: mean 2 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean patient-reported outcome measures to assess MS fatigue was 3.03	MD 0.56 lower (0.81 lower to 0.31 lower)
Patient-reported outcome measures to assess MS fatigue (MFIS, 0–84, lower values are better, final value, parallel trial and crossover trial) at 3–6 months	307 (3 RCTs) follow up: mean 5 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^c^,^d	-	-	MD 3.57 lower (15.06 lower to 7.91 higher)
Patient-reported outcome measures to assess MS fatigue (diary ratings of fatigue - energy level, 1–5, higher values are better, final values, crossover trial) at 3–6 months	44 (1 RCT) follow up: 10 weeks	⨁◯◯◯ VERY LOW^a^,^b^,^c	-	The mean patient-reported outcome measures to assess MS fatigue was 2.76	MD 0.28 higher (0.06 higher to 0.5 higher)
Patient-reported outcome measures to assess MS fatigue (diary ratings of fatigue - muscle strength, 1–5, higher values are better, final values, crossover trial) at 3–6 months	44 (1 RCT) follow up: 10 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean patient-reported outcome measures to assess MS fatigue was 2.75	MD 0.19 higher (0.03 lower to 0.41 higher)
Patient-reported outcome measures to assess MS fatigue (diary ratings of fatigue - concentration/memory, 1–5, higher values are better, final values, crossover trial) at 3–6 months	44 (1 RCT) follow up: 10 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean patient-reported outcome measures to assess MS fatigue was 2.98	MD 0.42 higher (0.18 higher to 0.66 higher)
Patient-reported outcome measures to assess MS fatigue (diary ratings of fatigue - motivation level, 1–5, higher values are better, final values, crossover trial) at 3–6 months	44 (1 RCT) follow up: 10 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean patient-reported outcome measures to assess MS fatigue was 2.98	MD 0.18 higher (0.06 lower to 0.42 higher)
Patient-reported outcome measures to assess MS fatigue (diary ratings of fatigue - ability to finish task, 1–5, higher values are better, final values, crossover trial) at 3–6 months	44 (1 RCT) follow up: 10 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean patient-reported outcome measures to assess MS fatigue was 3.02	MD 0.14 higher (0.1 lower to 0.38 higher)
Patient-reported outcome measures to assess MS fatigue (diary ratings of fatigue - ability to solve problem, 1–5, higher values are better, final values, crossover trial) at 3–6 months	44 (1 RCT) follow up: 10 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean patient-reported outcome measures to assess MS fatigue was 3.13	MD 0.24 higher (0.02 lower to 0.5 higher)
Patient-reported outcome measures to assess MS fatigue (diary ratings of fatigue - wellbeing, 1–5, higher values are better, final values, crossover trial) at 3–6 months	44 (1 RCT) follow up: 10 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean patient-reported outcome measures to assess MS fatigue was 2.9	MD 0.27 higher (0.07 higher to 0.47 higher)
Adverse events leading to withdrawal at 3–6 months (parallel trial and crossover trials)	741 (7 RCTs) follow up: mean 7 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^e^,^f	RD 0.00 (−0.02 to 0.02)	0 per 1,000	0 fewer per 1,000 (20 fewer to 20 more)^g
Disruption of sleep at 3–6 months (parallel trial and crossover trial)	296 (2 RCTs) follow up: mean 6 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^c	RR 1.81 (1.11 to 2.94)	133 per 1,000	108 more per 1,000 (15 more to 259 more)
Cardiac events/arrhythmias at 3–6 months (parallel trial and crossover trials)	547 (3 RCTs) follow up: mean 6 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^e^,^f	RD 0.00 (−0.01 to 0.02)	0 per 1,000	0 fewer per 1,000 (10 fewer to 20 more)^g
Health-related Quality of Life (SF-36 physical component summary, 0–100, higher values are better, final value, parallel trial) at 3–6 months	30 (1 RCT) follow up: 4 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean health-related Quality of Life was 41.5	MD 7.1 lower (12.21 lower to 1.99 lower)
Health-related Quality of Life (SF-36 mental component summary, 0–100, higher values are better, final value, parallel trial) at 3–6 months	30 (1 RCT) follow up: 4 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean health-related Quality of Life was 40.4	MD 8.4 higher (2.9 higher to 13.9 higher)
Cognitive functions (13-item activities of daily living intellectual function factor, 0–50, lower values are better, final value, crossover trial) at 3–6 months	172 (1 RCT) follow up: 3 weeks	⊕◯◯◯ VERY LOW^a^,^b	-	The mean cognitive functions was 8.25	MD 0.58 lower (1.54 lower to 0.38 higher)
Cognitive functions (selective reminding - long-term retrieval, higher values are better, final value) at 3–6 months	32 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean cognitive functions was 45.2	MD 3 lower (13.23 lower to 7.23 higher)
Cognitive functions (selective reminding - delayed recall, higher values are better, final value) at 3–6 months	32 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean cognitive functions was 8.9	MD 0 (2.33 lower to 2.33 higher)
Cognitive functions (selective reminding - sum of recall, higher values are better, final value) at 3–6 months	32 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean cognitive functions was 53.5	MD 1.2 lower (7.14 lower to 4.74 higher)
Cognitive functions (Benton Visual Retention, lower values are better, final value) at 3–6 months	32 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean cognitive functions was 2.8	MD 1.5 higher (0.03 higher to 2.97 higher)
Cognitive functions (WAIS-R Digit Span, higher values are better, final value) at 3–6 months	32 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean cognitive functions was 16.5	MD 0.9 lower (3.07 lower to 1.27 higher)
Cognitive functions (Trail Making Test - Part A, lower values are better, final value) at 3–6 months	32 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean cognitive functions was 36.2	MD 5.3 lower (13.64 lower to 3.04 higher)
Cognitive functions (Trail Making Test - Part B, lower values are better, final value) at 3–6 months	32 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean cognitive functions was 83.1	MD 14.2 lower (35.14 lower to 6.74 higher)
Cognitive functions (symbol digit modalities test - written, higher values are better, final value) at 3–6 months	32 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean cognitive functions was 46.6	MD 2 higher (8.37 lower to 12.37 higher)
Cognitive functions (symbol digit modalities test - oral, higher values are better, final value) at 3–6 months	32 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean cognitive functions was 58.3	MD 0.5 lower (13.19 lower to 12.19 higher)
Psychological symptoms (Beck Depression Inventory, 0–63, lower values are better, final value, crossover trial) at 3–6 months	172 (1 RCT) follow up: 3 weeks	⊕◯◯◯ VERY LOW^a^,^b	-	The mean psychological symptoms was 7.59	MD 0.25 lower (2.54 lower to 2.04 higher)
Epworth Sleepiness scale (0–24, lower values are better, final value, crossover trial) at 3–6 months	247 (1 RCT) follow up: 6 weeks	⊕⨁◯◯ LOW^a^,^b	-	The mean Epworth Sleepiness scale was 9.4	MD 0.1 lower (1.08 lower to 0.88 higher)

: Explanations

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

b: Downgraded by 1 or 2 increments because of outcome indirectness

c: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs

d: Downgraded by 1 or 2 increments because heterogeneity, unexplained by subgroup analysis

e: Downgraded for heterogeneity due to conflicting number of events in different studies (zero events in one or more studies)

f: Downgraded by 1 to 2 increments for imprecision due to zero events and small sample size

g: Absolute effect calculated by risk difference due to zero events in at least one arm of one study

Table 12Clinical evidence summary: SSRIs compared to placebo

Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with placebo	Risk difference with SSRIs
Patient-reported outcome measures to assess MS fatigue (MFIS, 0–84, lower values are better, final value) at 3–6 months	42 (1 RCT) follow up: 4 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean patient-reported outcome measures to assess MS fatigue was 52.1	MD 12.8 lower (22.93 lower to 2.67 lower)
Patient-reported outcome measures to assess MS fatigue (Modified fatigue impact scale, Neurological Fatigue Index Summary Score [different scale ranges], lower values are better, final values, parallel trials) at >6 months-1 year	328 (2 RCTs) follow up: mean 54 weeks	⊕⊕⊕⊕ HIGH	-	-	SMD 0.16 higher (0.06 lower to 0.37 higher)
Adverse events leading to withdrawal at >6 months-1 year (parallel trial)^d	137 (1 RCT) follow up: 60 weeks	⊕◯◯◯ VERY LOW^a^,^c	RR 0.70 (0.23 to 2.11)	103 per 1,000	31 fewer per 1,000 (79 fewer to 114 more)
Disruption to sleep at >6 months-1 year (parallel trial)^d	137 (1 RCT) follow up: 60 weeks	⊕⊕⊕◯ MODERATE^a	OR 7.28 (0.14 to 367.07)	0 per 1,000	10 more per 1,000 (20 fewer to 50 more)^e
Cardiac events/arrhythmias at >6 months-1 year (parallel trial)	223 (1 RCT) follow up: 96 weeks	⊕⊕◯◯ LOW^c^,^f	RR 1.51 (0.26 to 8.88)	18 per 1,000	9 more per 1,000 (13 fewer to 141 more)
Health-related Quality of Life (SF-36 physical component summary, 0–100, higher values are better, final value, parallel trial) at 3–6 months	42 (1 RCT) follow up: 4 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean health-related Quality of Life was 35.5	MD 0.9 higher (6.87 lower to 8.67 higher)
Health-related Quality of Life (SF-36 mental component summary, 0–100, higher values are better, final value, parallel trial) at 3–6 months	42 (1 RCT) follow up: 4 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean health-related Quality of Life was 42.5	MD 5.9 higher (8.25 lower to 20.05 higher)
Health-related Quality of Life (EQ-5D-5L utility index score, −0.1–11, higher values are better, final value, parallel trial) at >6 months-1 year	194 (1 RCT) follow up: 48 weeks	⊕⊕◯◯ LOW^c	-	The mean health-related Quality of Life was 0.65	MD 0.01 higher (0.04 lower to 0.06 higher)
Health-related Quality of Life (EQ-5D-5L visual analogue scale score, 0–100, higher values are better, final value, parallel trial) at >6 months-1 year	194 (1 RCT) follow up: 48 weeks	⊕⊕⊕⊕ HIGH	-	The mean health-related Quality of Life was 62.96	MD 3.18 higher (2.6 lower to 8.96 higher)
Cognitive functions (PDQ, 0–100, lower values are better, final value, parallel trial) at 3–6 months	42 (1 RCT) follow up: 4 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean cognitive functions was 40.4	MD 11.3 lower (19.1 lower to 3.5 lower)
Cognitive functions (Symbol digit modalities test, higher values are better, final value, parallel trials) at >6 months-1 year	328 (2 RCTs) follow up: mean 54 weeks	⊕⊕⊕⊕ HIGH	-	The mean cognitive functions was 41.0	MD 0.77 lower (3.42 lower to 1.88 higher)
Cognitive functions (California verbal learning test-II, higher values are better, final value, parallel trial) at >6 months-1 year^d	134 (1 RCT) follow up: 60 weeks	⊕⊕⊕◯ MODERATE^a	-	The mean cognitive functions was 137	MD 0.5 higher (8.98 lower to 9.98 higher)
Cognitive functions (Controlled oral word association test - semantic, higher values are better, final value, parallel trial) at >6 months-1 year^d	134 (1 RCT) follow up: 60 weeks	⊕⊕⊕◯ MODERATE^a	-	The mean cognitive functions was 20	MD 0.4 higher (1.63 lower to 2.43 higher)
Cognitive functions (Controlled oral word association test - phonetic, higher values are better, final value, parallel trial) at >6 months-1 year^d	134 (1 RCT) follow up: 60 weeks	⊕⊕◯◯ LOW^a^,^c	-	The mean cognitive functions was 29.1	MD 5.5 higher (1.54 higher to 9.46 higher)
Psychological symptoms (HAM-D, 0–50, lower values are better, final value, parallel trial) at 3–6 months	42 (1 RCT) follow up: 4 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean psychological symptoms was 10.9	MD 4.5 lower (7.29 lower to 1.71 lower)
Psychological symptoms (Beck depression inventory-II, 0–63, lower values are better, final values, parallel trial) at >6 months-1 year^d	134 (1 RCT) follow up: 60 weeks	⊕⊕◯◯ LOW^a	-	The mean psychological symptoms was 11.3	MD 0.6 higher (2.1 lower to 3.3 higher)

: Explanations

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

b: Downgraded by 1 or 2 increments because of population indirectness

c: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs

d: This is not downgraded for indirectness as there was a period of 4 weeks where the fluoxetine dose was titrated up that was included in this follow up period. Therefore, the follow up is essentially 1 year.

e: Absolute effect calculated by risk difference due to zero events in at least one arm of one study

f: Downgraded by 1 or 2 increments due to outcome indirectness

Table 13Clinical evidence summary: aspirin compared to placebo

Outcomes

№ of participants (studies) Follow up

Certainty of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with placebo

Risk difference with aspirin

Withdrawal due to adverse events at 3–6 months (parallel trial)

120

(1 RCT)

follow up: 8 weeks

⊕◯◯◯

VERY LOW^a^,^b^,^c

RR 1.46

(0.36 to 5.83)

54 per 1,000

25 more per 1,000

(34 fewer to 259 more)

: Explanations

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

b: Downgraded by 1 or 2 increments due to outcome indirectness

c: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs

Table 14Clinical evidence summary: modafinil compared to placebo

Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with placebo	Risk difference with modafinil
Patient-reported outcome measures to assess MS fatigue (Modified Fatigue Impact Scale Total Score, 0–84, lower values are better, final value, parallel trial and crossover trials) at 3–6 months	549 (5 RCTs) follow up: mean 6 weeks	⊕⊕◯◯ LOW^a^,^b	-	-	MD 0.23 lower (2.68 lower to 2.22 higher)
Withdrawal due to adverse events (crossover trials) at 3–6 months	285 (2 RCTs) follow up: mean 6 weeks	⊕◯◯◯ VERY LOW^b^,^c	RR 1.00 (0.18 to 5.63)	13 per 1,000	0 fewer per 1,000 (12 fewer to 65 more)
Cardiac events/arrhythmias at 3–6 months (crossover trial)	249 (1 RCT) follow up: 6 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^c	RR 1.65 (0.40 to 6.77)	24 per 1,000	16 more per 1,000 (15 fewer to 140 more)
Health-related Quality of Life (HAQUAMS, scale range unclear, lower values are better, final value, parallel trial) at 3–6 months	121 (1 RCT) follow up: 8 weeks	⊕⊕◯◯ LOW^b^,^c	-	The mean health-related Quality of Life was 11.04	MD 0.45 higher (0.59 lower to 1.49 higher)
Health-related Quality of Life (SF-36 physical component summary, 0–100, higher values are better, final value, parallel trial) at 3–6 months	30 (1 RCT) follow up: 4 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean health-related Quality of Life was 40.2	MD 1.3 higher (3.81 lower to 6.41 higher)
Health-related Quality of Life (SF-36 mental component summary, 0–100, higher values are better, final value, parallel trial) at 3–6 months	30 (1 RCT) follow up: 4 weeks	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean health-related Quality of Life was 40.4	MD 2.4 higher (2.59 lower to 7.39 higher)
Health-related Quality of Life (Multiple Sclerosis Quality of Life Inventory - Bodily pain, scale range unclear, higher values are better, final value, crossover trial) at 3–6 months	36 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^b^,^c	-	The mean health-related Quality of Life was 7.57	MD 0 (1.89 lower to 1.89 higher)
Health-related Quality of Life (Multiple Sclerosis Quality of Life Inventory - Physical functioning, scale range unclear, higher values are better, final value, crossover trial) at 3–6 months	36 (1 RCT) follow up: 2 months	⊕⊕⊕◯ MODERATE^b	-	The mean health-related Quality of Life was 15.54	MD 6.24 higher (3.29 higher to 9.19 higher)
Health-related Quality of Life (Multiple Sclerosis Quality of Life Inventory - role physical, scale range unclear, higher values are better, final value, crossover trial) at 3–6 months	36 (1 RCT) follow up: 2 months	⊕⊕◯◯ LOW^a^,^b	-	The mean health-related Quality of Life was 4.57	MD 2.65 higher (2.12 higher to 3.18 higher)
Health-related Quality of Life (Multiple Sclerosis Quality of Life Inventory - vitality scale, scale range unclear, higher values are better, final value, crossover trial) at 3–6 months	36 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean health-related Quality of Life was 12	MD 4.11 higher (0.2 higher to 8.02 higher)
Health-related Quality of Life (Multiple Sclerosis Quality of Life Inventory - General health, scale range unclear, higher values are better, final value, crossover trial) at 3–6 months	36 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^b^,^c	-	The mean health-related Quality of Life was 17.11	MD 0.2 higher (2.63 lower to 3.03 higher)
Health-related Quality of Life (Multiple Sclerosis Quality of Life Inventory - Mental health, scale range unclear, higher values are better, final value, crossover trial) at 3–6 months	36 (1 RCT) follow up: 2 months	⊕⊕⊕◯ MODERATE^b	-	The mean health-related Quality of Life was 7.57	MD 18.54 higher (16.6 higher to 20.48 higher)
Cognitive functions (Digit Vigilance Test total errors, lower values are better, final value, crossover trial) at 3–6 months	36 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean cognitive function was 5.55	MD 1.34 lower (4.22 lower to 1.54 higher)
Cognitive functions (Weschler Adult Intelligence Scale-III Digit Span Total, higher values are better, final value, crossover trial) at 3–6 months	36 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean cognitive function was 17.25	MD 0.63 lower (3.76 lower to 2.5 higher)
Cognitive functions (Weschler Adult Intelligence Scale-III Letter Number Sequencing, higher values are better, final value, crossover trial) at 3–6 months	36 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^b^,^c	-	The mean cognitive function was 11	MD 0.06 lower (2.35 lower to 2.23 higher)
Cognitive functions (symbol digit modalities test, higher values are better, final value, crossover trial) at 3–6 months	36 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean cognitive functions was 51.13	MD 0.32 lower (9.5 lower to 8.86 higher)
Cognitive functions (California Verbal Learning Test - Second Edition, higher values are better, final value, crossover trial) at 3–6 months	36 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^a^,^b^,^c	-	The mean cognitive functions was 52.75	MD 2.56 lower (10.9 lower to 5.78 higher)
Psychological symptoms (The State Trait Anxiety Inventory, 0–60, lower values are better, final value, crossover trial) at 3–6 months	36 (1 RCT) follow up: 2 months	⊕⊕◯◯ LOW^b^,^c	-	The mean psychological symptoms was 25.56	MD 1.5 lower (6.82 lower to 3.82 higher)
Psychological symptoms (Chicago Multiscale Depression Inventory Total Score, scale range unclear, higher values are better, final value, crossover trial) at 3–6 months	36 (1 RCT) follow up: 2 months	⊕◯◯◯ VERY LOW^b^,^c	-	The mean psychological symptoms was 67.32	MD 0.37 higher (12.01 lower to 12.75 higher)
Epworth Sleepiness scale (0–24, lower values are better, final values, parallel trial and crossover trial) at 3–6 months	368 (2 RCTs) follow up: 7 weeks	⊕⊕⊕◯ MODERATE^b	-	-	MD 0.78 lower (1.62 lower to 0.07 higher)

: Explanations

a: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

b: Downgraded by 1 or 2 increments due to outcome indirectness

c: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs

Table 15Clinical evidence summary: combination of pharmacological therapies (amantadine and aspirin) compared to amantadine

Outcomes

№ of participants (studies) Follow up

Certainty of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with amantadine

Risk difference with combination of pharmacological therapies (amantadine and aspirin)

Patient-reported outcome measures to assess MS fatigue (FSS score, 1–7, lower values are better, final values, parallel trial) at 3–6 months

(1 RCT)

follow up: 6 weeks

⊕⊕⊕◯

MODERATE^a

The mean patient-reported outcome measures to assess MS fatigue was 3.96

MD 0.6 lower

(0.89 lower to 0.31 lower)

: Explanations

a: Downgraded by 1 or 2 increments due to outcome indirectness

Table 16Unit cost of drugs for the management of fatigue

Drug	Daily dose	Cost per day^(f)	Cost per month	Cost per year
Amantadine (capsule)	200–400mg^(a)	£0.96-£0.1.92	£29.19-£53.38	£350.27-£700.54
Fluoxetine (tablet)	20–40mg^(b)	£0.04-£0.06	£1.14-£1.83	£13.63-£21.90
Paroxetine (capsule)	10–40mg^(c)	£0.15-£0.11	£4.64-£3.39	£55.66-£40.64
Aspirin (tablet)	75mg^(d)	£0.05	£1.50	£17.99
Modafinil (tablet)	200–400mg^(e)	£0.22-£0.43	£6.54-£13.08	£78.48-£156.95

(a): BNF³, accessed February 2021. 100 mg daily for 1 week, dose to be taken in the morning, then increased to 100 mg twice daily: maximum 400 mg per day.

(b): 20mg orally once a day for 4 weeks, then up titrated to 40mg a day³^, ⁶

(c): 10mg daily, up titrated to 20mg/day after 1 week with a maximum dose of 40mg/day in subsequent weeks dependent on symptoms or down-titrated due to adverse events⁹. Note 10mg capsule is more expensive than 20mg tablet.

(d): BNF³. Accessed 25/02/2021: 75 mg once daily. Oral low dose aspirin (80mg tablets) daily for 8 weeks²².

(e): 200mg daily for 1 month, adjusted according to response to 200–400 mg/day¹⁰^, ¹⁴^, ¹⁵^, ¹⁹^, ²⁶.

(f): BNF³. Accessed 25/02/2021

Table 26Studies excluded from the clinical review

Study	Code [Reason]
Asano, Miho and Finlayson, Marcia L. (2014) Meta-analysis of three different types of fatigue management interventions for people with multiple sclerosis: exercise, education, and medication. Multiple sclerosis international 2014: 798285 [PMC free article: PMC4052049] [PubMed: 24963407]	- Systematic review used as source of primary studies
Bazzari, F. H. (2018) Available pharmacological options and symptomatic treatments of multiple sclerosis. Systematic Reviews in Pharmacy 9(1): 17–21	- Review article but not a systematic review
Cameron, M., Cohen, J., Miller, A. et al (2019) Inroads: A phase 3 study to assess the efficacy and safety of ADS-5102 (Amantadine) extended-release capsules in multiple sclerosis (MS) patients with walking impairment. Neurology 92(15 Suppl 1)	- Conference abstract - Full text paper not available
Chataway, J., De Angelis, F., Connick, P. et al (2018) MS-SMART Trial: A multi-arm phase 2b randomised double blind, parallel group, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis [NCT01910259]. Multiple Sclerosis Journal 24(2 Suppl): 986–987	- Conference abstract
Chen, M. H., Goverover, Y., Genova, H. M. et al (2020) Cognitive efficacy of pharmacologic treatments in multiple sclerosis: A systematic review. CNS Drugs 34(6): 599–628 [PMC free article: PMC7275014] [PubMed: 32361940]	- Systematic review used as source of primary studies
Cohen, J. A., Gudesblatt, M., Hunter, S. F. et al (2017) A phase 2 study of ADS-5102 (amantadine hydrochloride) extended-release capsules in multiple sclerosis patients with walking impairment. Multiple Sclerosis 23(Suppl 1): 22–23	- Conference abstract
Cotter, J., Muhlert, N., Talwar, A. et al (2018) Examining the effectiveness of acetylcholinesterase inhibitors and stimulant-based medications for cognitive dysfunction in multiple sclerosis: A systematic review and meta-analysis. Neuroscience and Biobehavioral Reviews 86: 99–107 [PubMed: 29406017]	- Systematic review used as source of primary studies
Filippi, M., Valsasina, P., Colombo, B. et al (2015) Fampridine modulates thalamic resting state functional connectivity and ameliorates fatigue in multiple sclerosis patients. Multiple Sclerosis 23(11 Suppl1): 331–332	- Conference abstract
Khan, F.; Amatya, B.; Galea, M. (2014) Management of fatigue in persons with multiple sclerosis. Frontiers in Neurology 5: 177 [PMC free article: PMC4163985] [PubMed: 25309504]	- Study does not contain an intervention relevant to this review protocol
Kratz, Anna L., Alschuler, Kevin N., Ehde, Dawn M. et al (2019) A randomized pragmatic trial of telephone-delivered cognitive behavioral-therapy, modafinil, and combination therapy of both for fatigue in multiple sclerosis: The design of the “COMBO-MS” trial. Contemporary clinical trials 84: 105821 [PubMed: 31400515]	- Data not reported in an extractable format or a format that can be analysed Protocol only
Lange R, Volkmer M, Heesen C et al (2009) Modafinil effects in multiple sclerosis patients with fatigue. Journal of neurology 256(4): 645–650 [PubMed: 19367356]	- Data not reported in an extractable format or a format that can be analysed - Not a peer-reviewed publication
Leavitt, V. M., Blanchard, A. R., Guo, C. Y. et al (2017) Aspirin improves exercise endurance in multiple sclerosis: Pilot findings from a double-blind randomized placebocontrolled crossover trial. Multiple Sclerosis Journal 23(3 Suppl 1): 413–414	- Conference abstract
Leavitt, V. M., Blanchard, A. R., Guo, C. Y. et al (2018) Aspirin is an effective pretreatment for exercise in multiple sclerosis: A double-blind randomized controlled pilot trial. Multiple Sclerosis Journal 24(11): 1511–1513 [PubMed: 29076760]	- Study design not relevant to this review protocol Inadequate washout period
Leavitt, V., Blanchard, A., Guo, C. Y. et al (2018) A randomized controlled pilot trial of aspirin to improve exercise performance in persons with multiple sclerosis. Neurology 90(15 Suppl 1)	- Conference abstract - Full text paper not available
Miller, Philippa and Soundy, Andrew (2017) The pharmacological and non-pharmacological interventions for the management of fatigue related multiple sclerosis. Journal of the neurological sciences 381: 41–54 [PubMed: 28991714]	- Study design not relevant to this review protocol Systematic review of systematic reviews
Nourbakhsh, B., Revirajan, N., Morris, B. et al (2019) Phase 3 randomized, controlled trial of methylphenidate, modafinil and amantadine for MS fatigue (TRIUMPHANTMS): Baseline data. Multiple Sclerosis Journal 25(Suppl 2): 794–795	- Conference abstract
Nourbakhsh, B.; Revirajan, N.; Waubant, E. (2017) Study design for a pragmatic clinical trial of fatigue medications in multiple sclerosis. Neurology 88(16 Suppl 1)	- Conference abstract - Full text paper not available
Payne, C.; Wiffen, P. J.; Martin, S. (2017) Interventions for fatigue and weight loss in adults with advanced progressive illness. Cochrane Database of Systematic Reviews 2017(4): cd008427 [PubMed: 22258985]	- Full text paper not available Withdrawn due to the update not meeting the timelines and expectations of Cochrane and the PaPaS review group
Perez, Dominique Q.; Espiritu, Adrian I.; Jamora, Roland Dominic G. (2020) Efficacy and safety of amantadine for the treatment of fatigue in multiple sclerosis: a systematic review and meta-analysis. Neurodegenerative disease management 10(6): 383–395 [PubMed: 33012266]	- Systematic review used as source of primary studies
Poulsen, M., Damgaard, B., Zerahn, B. et al (2015) Feasibility of treatment with modafinil to reduce fatigue after stroke. International Journal of Stroke 10(Suppl 2): 92	- Conference abstract
Rejdak, Konrad and Grieb, Pawel (2020) Adamantanes might be protective from COVID-19 in patients with neurological diseases: multiple sclerosis, parkinsonism and cognitive impairment. Multiple sclerosis and related disorders 42: 102163 [PMC free article: PMC7190496] [PubMed: 32388458]	- Study design not relevant to this review protocol
Rocca, M. A., Valsasina, P., Colombo, B. et al (2018) Modulation of cortico-subcortical functional connectivity occurs after symptomatic treatment of fatigue in patients with multiple sclerosis. Multiple Sclerosis Journal 24(Suppl 2): 317–318	- Conference abstract
Rosenberg, G. A. and Appenzeller, O. (1988) Amantadine, fatigue, and multiple sclerosis. Archives of neurology 45(10): 1104–1106 [PubMed: 2972270]	- Primary study from before the date limitation which is unlikely to add extra information that will impact the results of the review
Sailer, M., Heinze, H. J., Schoenfeld, M. A. et al (2000) Amantadine influences cognitive processing in patients with multiple sclerosis. Pharmacopsychiatry 33(1): 28–37 [PubMed: 10721881]	- Study reported outcomes not included in the protocol (electrophysiological parameters)
Santarnecchi, Emiliano, Rossi, Simone, Bartalini, Sabina et al (2015) Neurophysiological correlates of central fatigue in healthy subjects and multiple sclerosis patients before and after treatment with amantadine. Neural Plasticity 2015: 616242 [PMC free article: PMC4506817] [PubMed: 26236509]	- Study design not relevant to this review protocol
Shangyan, Hei, Kuiqing, Li, Yumin, Xu et al (2018) Meta-analysis of the efficacy of modafinil versus placebo in the treatment of multiple sclerosis fatigue. Multiple sclerosis and Related Disorders 19: 85–89 [PubMed: 29175676]	- Systematic review used as source of primary studies
Tsou, A., Treadwell, J., Erinoff, E. et al (2019) Which treatments improve fatigue and quality of life in Multiple Sclerosis? Evidence appraisal and development of visual interactive evidence maps. Neurology 92(15 Suppl 1)	- Conference abstract - Full text paper not available
Tur, Carmen (2016) Fatigue management in multiple sclerosis. Current Treatment Options in Neurology 18(6): 26 [PMC free article: PMC4834309] [PubMed: 27087457]	- Review article but not a systematic review
Wingerchuk, D., Keegan, M., Shuster, E. et al (2014) Aspirin is unlikely to have a clinically meaningful effect on multiple sclerosis-related fatigue: Data from a randomized controlled trial. Neurology 82(10 Suppl 1)	- Conference abstract - Full text paper not available
Wu, S., Kutlubaev, M. A., Chun, H. Y. Y. et al (2015) Interventions for post-stroke fatigue. Cochrane Database of Systematic Reviews [PMC free article: PMC7387276] [PubMed: 26133313]	- Population not relevant to this review protocol
Yang, Ting-Ting, Wang, Li, Deng, Xiao-Yang et al (2017) Pharmacological treatments for fatigue in patients with multiple sclerosis: A systematic review and meta-analysis. Journal of the neurological sciences 380: 256–261 [PubMed: 28870581]	- Systematic review used as source of primary studies
Zielinska-Nowak, E., Wlodarczyk, L., Kostka, J. et al (2020) New strategies for rehabilitation and pharmacological treatment of fatigue syndrome in multiple sclerosis. Journal of Clinical Medicine 9(11): 1–18 [PMC free article: PMC7695014] [PubMed: 33171768]	- Systematic review used as source of primary studies

Evidence review for the pharmacologicalmanagement of fatigue

Authors

1. Pharmacological management of fatigue

1.1. Review question

1.1.1. Introduction

1.1.2. Summary of the protocol

1.1.3. Methods and process

1.1.4. Effectiveness evidence

1.1.4.1. Included studies

Inconsistency

Indirectness

Meta-analysis

Studies not using pharmacological interventions specifically for fatigue

Previously included studies and outcomes

1.1.4.2. Excluded studies

1.1.5. Summary of studies included in the effectiveness evidence

1.1.5.1. Amantadine compared to aspirin

1.1.5.2. Amantadine compared to modafinil

1.1.5.3. Amantadine compared to placebo

1.1.5.4. SSRIs compared to placebo

1.1.5.5. Aspirin compared to placebo

1.1.5.6. Modafinil compared to placebo

1.1.5.7. Combination of pharmacological therapies (amantadine and aspirin) compared to amantadine

1.1.6. Summary of the effectiveness evidence

1.1.6.1. Amantadine compared to aspirin

1.1.6.2. Amantadine compared to modafinil

1.1.6.3. Amantadine compared to placebo

1.1.6.4. SSRIs compared to placebo

1.1.6.5. Aspirin compared to placebo

1.1.6.6. Modafinil compared to placebo

1.1.6.7. Combination of pharmacological therapies (amantadine and aspirin) compared to amantadine

1.1.7. Economic evidence

1.1.7.1. Included studies

1.1.7.2. Excluded studies

1.1.8. Summary of included economic evidence

1.1.9. Economic model

1.1.10. Unit costs

1.1.11. Evidence statements

Effectiveness

Economic

1.1.12. The committee’s discussion and interpretation of the evidence

1.1.12.1. The outcomes that matter most

1.1.12.2. The quality of the evidence

1.1.12.2.1. Amantadine compared to aspirin

1.1.12.2.2. Amantadine compared to modafinil

1.1.12.2.3. Amantadine compared to placebo

1.1.12.2.4. SSRIs compared to placebo

1.1.12.2.5. Aspirin compared to placebo

1.1.12.2.6. Modafinil compared to placebo

1.1.12.2.7. Combination of pharmacological therapies (amantadine and aspirin) compared to amantadine

1.1.12.3. Benefits and harms

1.1.12.3.1. Amantadine

1.1.12.3.2. SSRIs

1.1.12.3.3. Aspirin

1.1.12.3.4. Modafinil

1.1.12.3.5. Combination of pharmacological therapies (amantadine and aspirin)

1.1.12.4. Cost effectiveness and resource use

Amantadine

Modafinil

SSRIs

Aspirin

1.1.12.5. Other factors the committee took into account

1.1.13. Recommendations supported by this evidence review

1.1.14. References

Appendices

Appendix A. Review protocols

Appendix B. Literature search strategies

Appendix C. Effectiveness evidence study selection

Appendix D. Effectiveness evidence

Appendix E. Forest plots

Appendix F. GRADE and/or GRADE-CERQual tables

Appendix G. Economic evidence study selection

Appendix H. Economic evidence tables

Appendix I. Health economic model

Appendix J. Excluded studies

Clinical studies

Health Economic studies

Appendix K. Research recommendations – full details

K.1.1. Research recommendation

K.1.2. Why this is important