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Review
. 2022 Sep 1;9(9):CD002202.
doi: 10.1002/14651858.CD002202.pub3.

Hydroxyurea (hydroxycarbamide) for sickle cell disease

Angela E Rankine-Mullings  1 , Sarah J Nevitt  2
Affiliations
Review

Hydroxyurea (hydroxycarbamide) for sickle cell disease

Angela E Rankine-Mullings et al. Cochrane Database Syst Rev. .

Abstract

Background: Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea (hydroxycarbamide), an oral chemotherapeutic drug, ameliorates some of the clinical problems of SCD, in particular that of pain, by raising foetal haemoglobin (HbF). This is an update of a previously published Cochrane Review.

Objectives: The aims of this review are to determine through a review of randomised or quasi-randomised studies whether the use of hydroxyurea in people with SCD alters the pattern of acute events, including pain; prevents, delays or reverses organ dysfunction; alters mortality and quality of life; or is associated with adverse effects. In addition, we hoped to assess whether the response to hydroxyurea in SCD varies with the type of SCD, age of the individual, duration and dose of treatment, and healthcare setting.

Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. The date of the most recent search was 17 February 2022.

Selection criteria: Randomised and quasi-randomised controlled trials (RCTs and quasi-RCTs), of one month or longer, comparing hydroxyurea with placebo or standard therapy in people with SCD.

Data collection and analysis: Authors independently assessed studies for inclusion, carried out data extraction, assessed the risk of bias and assessed the quality of the evidence using GRADE.

Main results: We included nine RCTs recruiting 1104 adults and children with SCD (haemoglobin SS (HbSS), haemoglobin SC (HbSC) or haemoglobin Sβºthalassaemia (HbSβºthal) genotypes). Studies lasted from six to 30 months. We judged the quality of the evidence for the first two comparisons below as moderate to low as the studies contributing to these comparisons were mostly large and well-designed (and at low risk of bias); however, the evidence was limited and imprecise for some outcomes such as quality of life, deaths during the studies and adverse events, and the results are applicable only to individuals with HbSS and HbSβºthal genotypes. We judged the quality of the evidence for the third and fourth comparisons to be very low due to the limited number of participants, the lack of statistical power (both studies were terminated early with approximately only 20% of their target sample size recruited) and the lack of applicability to all age groups and genotypes. Hydroxyurea versus placebo Five studies (784 adults and children with HbSS or HbSβºthal) compared hydroxyurea to placebo; four recruited individuals with only severe disease and one recruited individuals with all disease severities. Hydroxyurea probably improves pain alteration (using measures such as pain crisis frequency, duration, intensity, hospital admissions and opoid use) and life-threatening illness, but we found no difference in death rates (10 deaths occurred during the studies, but the rates did not differ by treatment group) (all moderate-quality evidence). Hydroxyurea may improve measures of HbF (low-quality evidence) and probably decreases neutrophil counts (moderate-quality evidence). There were no consistent differences in terms of quality of life and adverse events (including serious or life-threatening events) (low-quality evidence). There were fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. Hydroxyurea and phlebotomy versus transfusion and chelation Two studies (254 children with HbSS or HbSβºthal also with risk of primary or secondary stroke) contributed to this comparison. There were no consistent differences in terms of pain alteration, death or adverse events (low-quality evidence) or life-threatening illness (moderate-quality evidence). Hydroxyurea with phlebotomy probably increased HbF and decreased neutrophil counts (moderate-quality evidence), but there were more occurrences of acute chest syndrome and infections. Quality of life was not reported. In the primary prevention study, no strokes occurred in either treatment group but in the secondary prevention study, seven strokes occurred in the hydroxyurea and phlebotomy group (none in the transfusion and chelation group) and the study was terminated early. Hydroxyurea versus observation One study (22 children with HbSS or HbSβºthal also at risk of stoke) compared hydroxyurea to observation. Pain alteration and quality of life were not reported. There were no differences in life-threatening illness, death (no deaths reported in either group) or adverse events (very low-quality evidence). We are uncertain if hydroxyurea improves HbF or decreases neutrophil counts (very low-quality evidence). Treatment regimens with and without hydroxyurea One study (44 adults and children with HbSC) compared treatment regimens with and without hydroxyurea. Pain alteration, life-threatening illness and quality of life were not reported. There were no differences in death rates (no deaths reported in either group), adverse events or neutrophil levels (very low-quality evidence). We are uncertain if hydroxyurea improves HbF (very low-quality evidence).

Authors' conclusions: There is evidence to suggest that hydroxyurea may be effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSβºthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemia at risk of primary stroke by maintaining transcranial Doppler velocities. However, there is still insufficient evidence on the long-term benefits of hydroxyurea, particularly with regard to preventing chronic complications of SCD, or recommending a standard dose or dose escalation to maximum tolerated dose. There is also insufficient evidence about the long-term risks of hydroxyurea, including its effects on fertility and reproduction. Evidence is also limited on the effects of hydroxyurea on individuals with the HbSC genotype. Future studies should be designed to address such uncertainties.

PubMed Disclaimer

Conflict of interest statement

Sarah Nevitt: none known.

Angela E Rankine‐Mullings: none known.

Figures

1
1
Study flow diagram for this review (2022)
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 1: Pain crises
1.2
1.2. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 2: Proportion experiencing pain
1.3
1.3. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 3: Proportion experiencing life‐threatening events during study
1.4
1.4. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 4: Number of life‐threatening events during study
1.5
1.5. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 5: Deaths during the study
1.6
1.6. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 6: Change from baseline in foetal haemoglobin (HbF%)
1.7
1.7. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 7: Change from baseline in absolute neutrophil count (ANC, x10⁹/L)
1.8
1.8. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 8: Foetal haemoglobin (HbF%) after treatment
1.9
1.9. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 9: Neutrophil response (x10⁹/L) after treatment
1.10
1.10. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 10: Change from baseline in haemoglobin (g/L)
1.11
1.11. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 11: Change from baseline in mean corpuscular volume (fL)
1.12
1.12. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 12: Change from baseline in white blood cell (WBC) count (x10⁹/L)
1.13
1.13. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 13: Change from baseline in absolute reticulocyte count (x10⁹/L)
1.14
1.14. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 14: Change from baseline in reticulocytes (%)
1.15
1.15. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 15: Change from baseline in platelet count (10⁹/L)
1.16
1.16. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 16: Change from baseline in creatinine (mg/dL)
1.17
1.17. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 17: Change from baseline in total bilirubin (mg/L)
1.18
1.18. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 18: Change from baseline in alanine transferase (ALT) (U/L)
1.19
1.19. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 19: Haemoglobin (g/dL)
1.20
1.20. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 20: Mean corpuscular volume (fL)
1.21
1.21. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 21: White blood cells (WBC) count at the end of the study
1.22
1.22. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 22: Reticulocytes (10⁹/L)
1.23
1.23. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 23: Reticulocytes (10⁵/mm³) at 18 months
1.24
1.24. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 24: Total bilirubin (mg/L)
1.25
1.25. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 25: Platelet count (10⁹/L)
1.26
1.26. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 26: Platelet count (10³/mm³) at 18 months
1.27
1.27. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 27: Packed cell volume
1.28
1.28. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 28: F reticulocytes
1.29
1.29. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 29: F cells
1.30
1.30. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 30: Red blood count
1.31
1.31. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 31: Dense cells
1.32
1.32. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 32: Leucocytes
1.33
1.33. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 33: Alanine transferase (ALT) (U/L)
1.34
1.34. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 34: Creatinine (mg/dL) at the end of the study
1.35
1.35. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 35: Aspartate aminotransferase
1.36
1.36. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 36: Alkaline phosphatase
1.37
1.37. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 37: Change from baseline in growth
1.38
1.38. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 38: Quality of life: general health perception
1.39
1.39. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 39: Quality of life: pain recall
1.40
1.40. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 40: Quality of life: social function
1.41
1.41. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 41: Changes in 'Ladder of Life'
1.42
1.42. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 42: Proportion of participants with signs of organ damage
1.43
1.43. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 43: Signs of organ damage ‐ change from baseline in DTPA GFR
1.44
1.44. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 44: Signs of organ damage ‐ change from baseline in Howell‐Jolley body (per 106 red blood cells)
1.45
1.45. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 45: Signs of organ damage ‐ change from baseline in pitted cells (%)
1.46
1.46. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 46: Signs of organ damage ‐ change from baseline in spleen: liver ratio of counts
1.47
1.47. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 47: Signs of organ damage ‐ change from baseline in spleen volume (cm3)
1.48
1.48. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 48: Signs of organ damage ‐ change from baseline in creatinine (mg/L)
1.49
1.49. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 49: Signs of organ damage ‐ change from baseline in Schwartz GFR
1.50
1.50. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 50: Signs of organ damage ‐ change from baseline in cystatin C
1.51
1.51. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 51: Signs of organ damage ‐ change from baseline in urine osmolality
1.52
1.52. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 52: Signs of organ damage ‐ change from baseline in urine pH
1.53
1.53. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 53: Signs of organ damage ‐ change from baseline in urine‐specific gravity
1.54
1.54. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 54: Signs of organ damage ‐ change from baseline in total kidney volume
1.55
1.55. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 55: Signs of organ damage ‐ change from baseline in TCD ultrasound velocity (time‐averaged mean maximum velocity)
1.56
1.56. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 56: Signs of organ damage ‐ change from baseline in CNS measures
1.57
1.57. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 57: Proportion of participants experiencing adverse events and toxicity
1.58
1.58. Analysis
Comparison 1: Hydroxyurea versus placebo for participants with sickle cell disease, Outcome 58: Proportion with SCA‐related events (composite outcome)
2.1
2.1. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 1: Proportion experiencing pain
2.2
2.2. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 2: Proportion experiencing life‐threatening events during study
2.3
2.3. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 3: Deaths during the study
2.4
2.4. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 4: Change from baseline in foetal haemoglobin (HbF %)
2.5
2.5. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 5: Change from baseline in absolute neutrophil count (x10⁹/L)
2.6
2.6. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 6: Change from baseline in mean corpuscular volume (fL)
2.7
2.7. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 7: Change from baseline in sickle haemoglobin (%)
2.8
2.8. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 8: Change from baseline in haemoglobin (g/L)
2.9
2.9. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 9: Change from baseline in absolute reticulocyte count (10⁹ / L)
2.10
2.10. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 10: Change from baseline in white blood count (10⁹ / L)
2.11
2.11. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 11: Change from baseline in platelets (10⁹/L)
2.12
2.12. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 12: Change from baseline in total bilirubin (mg/L)
2.13
2.13. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 13: Change from baseline in liver iron concentration
2.14
2.14. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 14: Change from baseline in serum ferritin (ng/mL)
2.15
2.15. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 15: Change from baseline in lactate dehydrogenase (U/L)
2.16
2.16. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 16: Signs of organ damage ‐ CNS measures at the end of the study
2.17
2.17. Analysis
Comparison 2: Hydroxyurea and phlebotomy compared to transfusion and chelation for participants with SCD and risk of stroke, Outcome 17: Proportion of participants experiencing non‐neurological adverse events and toxicity
3.1
3.1. Analysis
Comparison 3: Hydroxyurea compared to observation for participants with SCD and risk of stroke, Outcome 1: Proportion experiencing life‐threatening events during the study
3.2
3.2. Analysis
Comparison 3: Hydroxyurea compared to observation for participants with SCD and risk of stroke, Outcome 2: Signs of organ damage ‐ proportion of participants with a change in CNS measures
3.3
3.3. Analysis
Comparison 3: Hydroxyurea compared to observation for participants with SCD and risk of stroke, Outcome 3: Signs of organ damage ‐ change from baseline in CNS measures
3.4
3.4. Analysis
Comparison 3: Hydroxyurea compared to observation for participants with SCD and risk of stroke, Outcome 4: Adverse events and toxicity
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References

References to studies included in this review

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    1. Aygun B, Wruck LM, Schultz WH, Mueller BU, Brown C, Luchtman-Jones L, et al. Chronic transfusion practices for prevention of primary stroke in children with sickle cell anemia and abnormal TCD velocities. American Journal of Hematology 2012;87(4):428-30. - PubMed
    1. Aygun B, Mortier N, Rogers ZR, Owen W, Fuh B, George A, et al. Iron unloading by therapeutic phlebotomy in previously transfused children with sickle cell anemia: the twitch experience. Blood 2016;128(22):1018. [CFGD REGISTER: SC276i]
    1. De Montalembert M, Benkerrou M, Grosse R, Kordes U, Brousse V, Pondarre C, et al. Assessment of hematological data in a cohort of European children with sickle cell anemia treated with hydroxyurea: can European centers apply today the lessons from the twitch study? Blood 2016;128(22):2494. [CFGD REGISTER: SC276k]
    1. Helton KJ, Roberts D, Schultz WH, Davis BR, Kalfa TA, Pressel SL, et al. Effects of chronic transfusion therapy on MRI and MRA in children with sickle cell anemia. Blood 2014;124(21):4052. [CENTRAL: 1261883]
    1. Imran H, Aygun B, Davis BR, Pressel SL, Herbert Schultz W, Jackson SM, et al. Effects of chronic transfusion therapy on transcranial doppler ultrasonography velocities in children with sickle cell anemia at risk for primary stroke: baseline findings from the Twitch trial. Blood 2014;124(21):87. [CENTRAL: 1261882]

References to studies excluded from this review

Abdullahi 2020a {published data only}
    1. Abdullahi SU, Sunusi SM, Sani Abba M, Sani S, Galadanci A, Inuwa H, et al. Low-versus moderate-dose hydroxyurea for secondary stroke prevention in children with sickle cell disease in sub-Saharan Africa: final results of a randomized controlled trial, sprint trial. Blood 2020;136(Suppl 1):5-6. [CFGD REGISTER: SC280b]
    1. NCT02675790. Low dose hydroxyurea for secondary stroke prevention in children with sickle cell disease in Sub-Saharan Africa (SPRINT). www.clinicaltrials.gov/ct2/show/NCT02675790 (first received 8 January 2016). [CFGD REGISTER: SC280a]
Abdullahi 2020b {published data only}
    1. Abdullahi SU, Jibir BW, Bello-Manga H, Gambo S, Inuwa H, Tijjani AG, et al. Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind, multicentre, randomised, phase 3 trial. Lancet. Haematology 2022;9(1):e26-e37. [CFGD REGISTER: SC293e] - PMC - PubMed
    1. Abdullahi SU, Jibir BW, Bello-Manga H, Gambo S, Inuwa H, Tijjani AG, et al. Randomized controlled trial of fixed low- vs moderate-dose hydroxyurea for primary stroke prevention in sub-Saharan Africa: final results of the spring trial. Blood 2020;136(Suppl 1):4-5. [CFGD REGISTER: SC293d]
    1. Abdullahi SU, Wudil BJ, Bello-Manga H, Musa AB, Gambo S, Galadanci NA, et al. Primary prevention of stroke in children with sickle cell anemia in sub-Saharan Africa: rationale and design of phase III randomized clinical trial. Pediatric Hematology and Oncology 2021;38(1):49-64. [CFGD REGISTER: SC293b] - PMC - PubMed
    1. Bello-Manga H, Galadanci AA, Abdullahi S, Ali S, Jibir B, Gambo S, et al. Low educational level of head of household, as a proxy for poverty, is associated with severe anaemia among children with sickle cell disease living in a low-resource setting: evidence from the SPRING trial. British Journal of Haematology 2020;190(6):939-44. [CFGD REGISTER: SC293c] - PMC - PubMed
    1. Bello-Manga H, Haliru L, Tabari AM, Farouk B, Suleiman A, Bahago GY, et al. Translating research to usual care of children with sickle cell disease in Northern Nigeria: lessons learned from the SPRING Trial Team. BMC Research Notes 2022;15(1):1. [CFGD REGISTER: SC293f] - PMC - PubMed
Al‐Nood 2011 {published data only}
    1. Al-Nood HA, Al-Khawlani MM, Al-Akwa A. Fetal hemoglobin response to hydroxyurea in Yemeni sickle cell disease patients. Hemoglobin 2011;35(1):13-21. - PubMed
Charnigo 2019 {published data only}
    1. Charnigo RJ, Beidler D, Rybin D, Pittman DD, Tan B, Howard J, et al. PF-04447943, a phosphodiesterase 9A inhibitor, in stable sickle cell disease patients: a phase Ib randomized, placebo-controlled study. Clinical and Translational Science 2019;12(2):180-8. [CENTRAL: CN-01937374] [CFGD REGISTER: SC345b] [EMBASE: 626983905] [PMID: ] - PMC - PubMed
    1. Charnigo RJ, Howard J, Beidler D, Rybin D, Tan B, Michelson AD, et al. A phase 1b, randomized, double-blind, placebo-controlled study of PF-04447943 in patients with stable sickle cell disease: changes in exploratory biomarkers. Blood 2017;130(Suppl 1):974. [CENTRAL: CN-01616847] [CFGD REGISTER: SC345a]
    1. NCT02114203. Safety, tolerability, pharmacokinetics, and pharmacodynamics study of PF-04447943, co-administered with and without hydroxyurea, in subjects with stable sickle cell disease [A phase 1b, randomized, double-blind (sponsor open), placebo controlled study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of pf 04447943, co-administered with and without hydroxyurea, in subjects with stable sickle cell disease]. www.clinicaltrials.gov/show/NCT02114203 (first received 15 April 2014).
Conran 2019 {published data only}
    1. Conran N, Fertrin KY, Maximo CDA, Oliveira T, Lobo C, Costa FF. Safe use of hydroxyurea in sickle cell disease patients hospitalized for painful vaso-occlusive episodes: results of the randomized, open-label helps study. Blood 2019;134:2303. [CFGD REGISTER: SC431b] - PubMed
    1. NCT03062501. Hydroxyurea in the emergency room to lessen pain in sickle cell crisis. www.ClinicalTrials.gov/show/NCT03062501 (first received 23 February 2017). [CFGD REGISTER: SC431a]
CTRI/2022/01/039317 {published data only}
    1. CTRI/2022/01/039317. Low dose hydroxyurea in sickle cell anemia [Efficacy, safety, and population pharmacokinetics of low-dose vs. standard dose hydroxyurea in paediatric patients suffering from sickle cell disease: a randomized double-blind active-control non-inferiority clinical trial]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2022/01/039317 (first received 27 January 2022).
De Montalembert 2006 {published data only}
    1. De Montalembert M, Bachir D, Hulin A, Gimeno L, Mogenet A, Bresson JL, et al. A phase 1 pharmacokinetics (PK) study of hydroxyurea (HU) 1,000 mg coated breakable tablets and 500mg capsules in pediatric and adult patients with sickle cell disease. Blood 2005;106(11). [ABSTRACT NO: 3194] [CFGD REGISTER: SC193a] [DOI: 10.1182/blood.V106.11.3194.3194] - DOI - PubMed
    1. Montalembert M, Bachir D, Hulin A, Gimeno L, Mogenet A, Bresson JL, et al. Pharmacokinetics of hydroxyurea 1,000 mg coated breakable tablets and 500 mg capsules in pediatric and adult patients with sickle cell disease. Haematologica 2006;91(12):1685-8. - PubMed
de Oliveira 2019 {published data only}
    1. Oliveira EAM, Assis Boy K, Santos APP, da Silva Machado C, Velloso-Rodrigues C, Gerheim PSAS, et al. Evaluation of hydroxyurea genotoxicity in patients with sickle cell disease. Einstein (Sao Paulo) 2019;17(4):eAO4742. [CENTRAL: CN-02174286] [CFGD REGISTER: SC394] - PMC - PubMed
Eleuterio 2019 {published data only}
    1. Eleuterio RM, Nascimento FO, Araujo TG, Castro MF, Filho TPA, Filho PA, et al. Double-blind clinical trial of arginine supplementation in the treatment of adult patients with sickle cell anaemia. Advances in Hematology 2019;eCollection 2019:4397150. [CENTRAL: CN-01916183] [CFGD REGISTER: SC383] [DOI: 10.1155/2019/4397150] [EMBASE: 626558583] - DOI - PMC - PubMed
Estepp 2016 {published data only}
    1. Estepp JH, Melloni C, Thornburg CD, Wiczling P, Rogers Z, Rothman JA, et al. Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia. Journal of Clinical Pharmacology 2016;56(3):298-306. [CENTRAL: CN-01137410] [CFGD REGISTER: SC393] [EMBASE: 607382494] - PMC - PubMed
Field 2020 {published data only}
    1. Field JJ, Kassim A, Brandow A, Embury SH, Matsui N, Wilkerson K, et al. Phase 2 trial of montelukast for prevention of pain in sickle cell disease. Blood Advances 2020;4(6):1159-65. [CFGD REGISTER: SC294b] - PMC - PubMed
    1. NCT01960413. Phase 2 study of montelukast for the treatment of sickle cell anemia. www.clinicaltrials.gov/show/NCT01960413 (first received 10 October 2013). [CFGD REGISTER: SC294a]
Meier 2020 {published data only}
    1. Meier ER, Creary SE, Heeney MM, Dong M, Appiah-Kubi AO, Nelson SC, et al. Hydroxyurea optimization through precision study (HOPS): study protocol for a randomized, multicenter trial in children with sickle cell anemia. Trials 2020;21(1):983. [CFGD REGISTER: SC430b] [DOI: ] - PMC - PubMed
    1. NCT03789591. Hydroxyurea optimization through precision study (HOPS). clinicaltrials.gov/show/nct03789591 (first received 28 Dec 2018). [CFGD REGISTER: SC430a]
Misra 2017 {published data only}
    1. Misra H, Bainbridge J, Berryman J, Abuchowski A, Galvez KM, Uribe LF, et al. A Phase Ib open label, randomized, safety study of SANGUINATETM in patients with sickle cell anemia. Revista Brasileira de Hematologia e Hemoterapia 2017;39(1):20-7. [CFGD REGISTER: SC290b] - PMC - PubMed
    1. NCT01848925. A phase I open-label, randomized, safety and efficacy study of SANGUINATE™ at two doses levels versus hydroxyurea in sickle cell disease (SCD) patients. www.clinicaltrials.gov/show/NCT01848925 (first received 8 May 2013). [CFGD REGISTER: SC290a]
NCT00000602 {published data only}
    1. NCT00000602. Pediatric hydroxyurea in sickle cell anemia (PED HUG). www.ClinicalTrials.gov/show/NCT00000602 (first received 28 October 1999).
NCT00001197 {published data only}
    1. NCT00001197. Hydroxyurea for the treatment of patients with sickle cell anemia. www.ClinicalTrials.gov/show/NCT00001197 (first received 4 November 1999).
NCT00004492 {published data only}
    1. NCT00004492. Phase I/II randomized study of hydroxyurea with or without clotrimazole in patients with sickle cell anemia. www.clinicaltrials.gov/show/NCT00004492 (first received 19 October 1999).
NCT00672789 {published data only}
    1. NCT00672789. Adherence to hydroxyurea in children with sickle cell anemia. clinicaltrials.gov/show/NCT00672789 (first received 6 May 2008). [CFGD REGISTER: SC422]
NCT00890396 {published data only}
    1. NCT00890396. Long- term effects of hydroxyurea in children with sickle cell anemia (the BABY HUG follow-up study). clinicaltrials.gov/ct2/show/NCT00890396 (first received 29 April 2009).
NCT02090296 {published data only}
    1. NCT02090296. Risk-based therapy for sickle cell anemia: a feasibility study. www.ClinicalTrials.gov/show/NCT02090296 (first received 18 March 2014). [CFGD REGISTER: SC291]
NCT02149537 {published data only}
    1. NCT02149537. Risk stratification for clinical severity of sickle cell disease in Nigeria and assessment of efficacy and safety during treatment with hydroxyurea. www.clinicaltrials.gov/show/NCT02149537 (first received 24 May 2014). [CFGD REGISTER: SC289]
NCT03634488 {published data only}
    1. NCT03634488. Management of severe acute malnutrition in SCD, in Northern Nigeria. www.ClinicalTrials.gov/show/NCT03634488 (first received 16 August 2018).
NCT03825341 {published data only}
    1. NCT03825341. Hydroxyurea therapy: optimizing access in pediatric populations everywhere. clinicaltrials.gov/show/NCT03825341 (first received 31 January 2019). [CFGD REGISTER: SC432]
NCT04675645 {published data only}
    1. NCT04675645. Adherence to HU and HRQOL in patients with sickle cell disease: an intervention study using hu-go app. clinicaltrials.gov/show/NCT04675645 (first received 19 December 2020). [CFGD REGISTER: SC415]
NCT05142254 {published data only}
    1. A trial for prevention of recurrent ischemic priapism in men with sickle cell disease: a pilot study (PIN). www.clinicaltrials.gov/ct2/show/NCT05142254 (first received 2 December 2021).
    1. PACTR202105561969346. A randomized controlled double-blind trial for prevention of recurrent ischemic priapism in men with sickle cell disease: a pilot study. Priapism in Nigeria (PIN) trial. www.who.int/trialsearch/Trial2.aspx?TrialID=PACTR202105561969346 2021.
NDEPTH 2013 {published data only}
    1. George A, Aygun B, Mortier N, Sparreboom A, Ware R. A randomized controlled trial of a dose-prediction equation to determine maximum tolerated dose of hydroxyurea in children with sickle cell anemia. Pediatric Blood & Cancer 2013;60(Suppl). [ABSTRACT NO: 588] [CENTRAL: 1007869] [CFGD REGISTER: SC283b] [EMBASE: 71047876]
    1. George A, Dinu B, Estrada N, Minard C, Hurwitz RL, Mahoney D, et al. NDEPTH: a randomized controlled trial of a novel dose-prediction equation to determine maximum tolerated dose for hydroxyurea therapy in pediatric patients with sickle cell anemia. Blood 2019;134:2267. [CENTRAL: CN-02050621] [CFGD REGISTER: SC283c] [EMBASE: 630318481]
    1. George A, Dinu B, Estrada N, Minard CG, Hurwitz R, Mahoney DH, et al. Novel dose escalation to predict treatment with hydroxyurea (NDEPTH): a randomized controlled trial of a dose-prediction equation to determine maximum tolerated dose of hydroxyurea in pediatric sickle cell disease. American Journal of Hematology 2020;95(9):E242-4. [CENTRAL: CN-02131373] [CFGD REGISTER: SC283d] [EMBASE: 631937641] [PMID: ] - PubMed
    1. George A, Dinu BR, Ware RE. Ndepth: novel dose escalation to predict treatment with hydroxyurea. Blood 2015;126(23):3419. [CFGD REGISTER: SC283a]
NOHARM 2020 {published data only}
    1. John CC, Opoka R, Latham T, Hume H, Nakafeero M, Kasirye P, et al. Optimizing hydroxyurea dosing in sickle cell anemia: the Uganda MTD study. Blood 2019;134:520. [CENTRAL: CN-02051498] [CFGD REGISTER: SC435b] [EMBASE: 630317942]
    1. John CC, Opoka RO, Latham TS, Hume HA, Nabaggala C, Kasirye P, et al. Hydroxyurea dose escalation for sickle cell anemia in Sub-Saharan Africa. New England Journal of Medicine 2020;382(26):2524-33. [CENTRAL: CN-02133119] [CFGD REGISTER: SC435c] [PMID: ] - PubMed
    1. NCT03128515. Optimizing hydroxyurea therapy in children with SCA in malaria endemic areas [Optimizing hydroxyurea therapy in children with sickle cell anemia in malaria endemic areas: the NOHARM maximum tolerated dose (MTD) study]. www.clinicaltrials.gov/show/NCT03128515 (first received 25 April 2017). [CFGD REGISTER: SC435a]
Pushi 2000 {published data only}
    1. Pushi A. Hydroxyurea ameliorates importantly the clinical course of sickle cell disease reducing the frequency of painful crises. Hematology Journal 2000;1(Suppl 1):34. [ABSTRACT NO.: 130] [CFGD REGISTER: SC282]
Silva‐Pinto 2007 {published data only}
    1. Silva-Pinto AC, Carrara RC, Oliveira VC, Palma PV, Campos AD, Zago MA, et al. Hydroxyurea treatment of sickle cell diseases causes megaloblastic transformation of the bone marrow that is responsible for the increase of the mean corpuscular volume. Haematologica 2007;Suppl 1:298. [CFGD REGISTER: SC201]
Silva‐Pinto 2014 {published data only}
    1. Silva-Pinto AC, Dias-Carlos C, Saldanha-Araujo F, Ferreira FI, Palma PV, Araujo AG, et al. Hydroxycarbamide modulates components involved in the regulation of adenosine levels in blood cells from sickle-cell anemia patients. Annals of Hematology 2014;93(9):1457-65. [CENTRAL: 1000846] [CFGDREGISTER: SC259] [JID:: 9107334] [PMID: ] - PubMed
Smith 2022 {published data only}
    1. McClish DK, Smith WR, Okhomiuna V, Mouaffo DS, Lottenberg R, Chen I, et al. The association of painful crises with patient reported outcomes in sickle cell disease: the SHIP-HU study. Blood 2018;132(Suppl 1):3509. [CFGD REGISTER: SC413a] [DOI: 10.1182/blood-2018-99-114869] - DOI
    1. Smith WR, McClish DK, Johnson S, Lottenberg R, Sisler I, Sop D, et al. The effect of patient navigators on health-related quality of life in sickle cell anemia: the SHIP-HU study. Blood 2019;134 Suppl 1:2168. [CFGD REGISTER: SC413c]
    1. Smith WR, McClish DK, Lottenberg R, Sisler I, Sop D, Johnson S, et al. The effect of patient navigators on laboratory parameters of hydroxyurea adherence in sickle cell anemia: the ship-hu study. Blood 2019;134 Suppl 1:2309. [CFGD REGISTER: SC413b]
    1. Smith WR, McClish DK, Lottenberg R, Sisler IY, Sop D, Johnson S, et al. A randomised controlled provider-blinded trial of community health workers in sickle cell anaemia: effects on haematologic variables and hydroxyurea adherence. British Journal of Haematology 2022;196(1):193-203. [CFGD REGISTER: SC413d] - PubMed
STAND 2019 {published data only}
    1. Abboud MR, Howard J, Cancado R, Smith WR, Guvenc B, Espurz N, et al. Crizanlizumab versus placebo, with or without hydroxyurea/hydroxycarbamide, in adolescent and adult patients with sickle cell disease and vaso-occlusive crises: a randomized, double-blind, phase III study (STAND). Blood 2019;134:998. [CENTRAL: CN-02048780] [CFGD REGISTER: SC392] [EMBASE: 630316641]
STEADFAST 2019 {published data only}
    1. Ataga KI, Saraf SL, Derebail VK, Sharpe CC, Inati A, Lebensburger JD, et al. The effect of crizanlizumab plus standard of care (Soc) versus soc alone on renal function in patients with sickle cell disease and chronic kidney disease: a randomized, multicenter, open-label, phase ii study (Steadfast). Blood 2019;134:1018. [CENTRAL: CN-02050662] [CFGD REGISTER: SC391a] [EMBASE: 630319168]
    1. EUCTR2018-003608-38-GR. Study exploring the effect of crizanlizumab on kidney function in patients with chronic kidney disease caused by sickle cell disease [A phase II, multicenter, randomized, open label two arm study comparing the effect of crizanlizumab + standard of care to standard of care alone on renal function in sickle cell disease patients = 16 years with chronic kidney disease due to sickle cell nephropathy (STEADFAST) - STEADFAST]. www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2018-003608-38-GR (first received 2019). [CENTRAL: CN-02068279] [CFGD REGISTER: SC391b]
SUSTAIN 2019 {published data only}
    1. Ataga KI, Kutlar A, Cancado R, Liles D, Velez-Nandayapa L, Lincy J, et al. Crizanlizumab treatment is not associated with the development of proteinuria and hematuria in patients with sickle cell disease: a safety analysis from the sustain study. Hemasphere 2018;2(S1):305-6. [CFGD REGISTER: SC287h]
    1. Ataga KI, Kutlar A, DeBonnett L, Lincy J, Kanter J. Crizanlizumab treatment is associated with clinically significant reductions in hospitalization in patients with sickle cell disease: results from the sustain study. Blood 2019;134:2289. [CENTRAL: CN-02052376] [CFGD REGISTER: SC287j] [EMBASE: 630317661]
    1. Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. New England Journal of Medicine 2017;376(5):429-39. [CFGD REGISTER: SC287a] [DOI: 10.1056/NEJMoa1611770] - DOI - PMC - PubMed
    1. Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, et al. SUSTAIN: a multicenter, randomized, placebo-controlled, double-blind, 12-month study to assess safety and efficacy of selg1 with or without hydroxyurea therapy in sickle cell disease patients with sickle cell-related pain crises. Blood 2016;128(22):1. [CFGD REGISTER: SC287f]
    1. Kanter J, Kutlar A, Liles D, Cancado R, Bruederle A, Shi M, et al. Crizanlizumab 5.0 mg/kg increased the time to first on-treatment sickle cell pain crisis: a subgroup analysis of the phase II sustain study. Blood 2017;130(Suppl 1):613. [CFGD REGISTER: SC287c]
Vichinsky 2013 {published data only}
    1. Vichinsky E, Torres M, Glass J, Minniti CP, Barrette S, Habr D, et al. A randomized phase II study evaluating the efficacy and safety of deferasirox versus deferoxamine in patients with sickle cell disease (SCD): 2-year results including pharmacokinetics (PK) and safety of deferasirox with concomitant hydroxyurea therapy. Blood 2011;118(21):1082. [ABSTRACT NO: 1082] [CFGD REGISTER: SC233a]
    1. Vichinsky E, Torres M, Minniti CP, Barrette S, Habr D, Zhang Y, et al. Efficacy and safety of deferasirox compared with deferoxamine in sickle cell disease: two-year results including pharmacokinetics and concomitant hydroxyurea. American Journal of Hematology 2013;88(12):1068-73. [CFGD REGISTER: SC233b] [PMID: ] - PubMed
Voskaridou 2005 {published data only}
    1. Voskaridou E, Terpos E, Margeli A, Hantzi E, Meletis J, Papassotiriou I, et al. Renal dysfunction and osteodystrophy in patients with sickle cell thalassaemia under long-term treatment with hydroxyurea. In: 10th Congress of the European Hematology Association; 2005 June 2-5; Stockholm International Fairs, Sweden. 2005. [ABSTRACT NO: 0174] [CFGD REGISTER: SC168]

References to ongoing studies

NCT01389024 {published data only}
    1. NCT01389024. Hydroxyurea to prevent brain injury in sickle cell disease (HUPrevent). www.clinicaltrials.gov/ct2/show/NCT01389024 (first received 30 June 2011).
NCT03806452 {published data only}
    1. NCT03806452. SIKAMIC (SIklos on Kidney Function and AlbuMInuria Clinical Trial). www.clinicaltrials.gov/ct2/show/NCT03806452 (first received 16 January 2019).

Additional references

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Aumont 2015
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Ballas 1996
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References to other published versions of this review

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