APPENDIX 1

Observational or Single-Arm Studies of Hydroxyurea in SCD

Author (Year) and DesignGeneral Study InformationArm, nHbF%aHemoglobin, g/LOther Outcomes
Pediatric Hydroxyurea Safety Trial (HUG-KIDS)
    Kinney et al28 (1999), prospective pre/postInclusion: age 5–15 y, HbSS, pain ≥3 or ACS in last year, 6 heights and weights in 2 yHU, 8417.8 (7.2)b90 (14)bEffects by 6 mo
Follow-up: up to 24 moPre, 847.378
    Ware et al34 (2002), prospective pre/postInclusion: age 5–15 y, HbSS, pain ≥3 or ≥3 pain and ACS episodes in past year, ACS ≥3 in past 2 yHU, 6817.6 [2.9–32]
Follow-up: 11.7 mo (mean)Pre, 686.777
    Zimmerman et al37 (2004), retrospective pre/postInclusion: on HU for ≥6 mo, SCDHU, 12219.7 (8.5)c97 (13)cEfficacy maintained
Follow-up: 45 mo (mean)Pre-HU, 1227.682
HUSOFT trial
    Wang et al33 (2001), cohort with historic comparison armInclusion: infants (age not specified), HbSS, HbSβ 0thalHU, 2120.3 (4.9)88 (12)
Follow-up: 24 moPre-HU, 2821.8 (7.8)85 (12)
Comment: investigators matched 3 patients from the CSSCD to enrolled patients by diagnosis, gender, and ageCSSCD10.9 (7.9)77 (10)
    Hankins et al27 (2005), prospective pre/postInclusion: enrolled in the HUSOFT trialdHU, 1723.7 (7.4)c91 (14)cPain crisis 33.8/100 patient-years
Follow-up: 58.8 mo (25–72)Pre-HU, 2121.8 (7.8)85 (12)
Comment: investigators matched 3 patients from the CSSCD to enrolled patients by diagnosis, gender, and ageCSSCD32.4/100 patient-years
French cluster
    de Montalembert et al24 (1997), prospective pre/postInclusion: age 4–20 y, HbSS, HbSβ +thal, HbSβ 0thal, S α+ thal, SC, pain hospitalization ≥3/yHU, 3513.7 [3.2–27.0]b9 (14)eDecreased painful crises in 32/35
Follow-up: 32 mo (12–59)Pre-HU, 354 [0.85–13.9]84 (12)
    Maier-Redelsperger et al29Inclusion: SCD, pain ≥3/yHU, 2913 (9.4)91 (9)
        (1998), prospective pre/postFollow-up: 22 mo (12–26)Pre-HU, 294 [0.85–13.9]84 (12)
    de Montalembert et al38 (1999), surveyInclusion: 2–20 y when starting HUHU, 101HU stopped in 17
Follow-up: 22 mo (0.5–93)Pre-HU, 101
    de Montalembert et al23 (2006), surveyInclusion: Pain ≥3 hospitalizations, untransfused stroke, ACS, hemoglobin < 6–7, high TCD velocity, cardiac ischemiaHU, 22582 (15)fHU stopped in 82
Follow-up: 46 mo (0–152)Pre-HU, 22566 (5)f
Belgian cluster
    Ferster et al25 (2001), prospective pre/postInclusion: children and young adults, pain ≥2 hospitalizations/y, stroke, TIA, ACS, priapism, or AVNHU, 9316.7 (10.6)g88 (12)gHospitalizations 1.06 (1.9)/patient-year,h ACS 3.5/100 patient-years
Follow-up: 42 moPre-HU, 937.382Hospitalizations 2.76 (2.3)/patient-year
    Gulbis et al26 (2005), prospective pre/post, otherInclusion: children and young adults, pain ≥2 hospitalizations/y, stroke, TIA, ACS, priapism, or AVNHU, 7014 g/L (HbF)c87 [67–120]eHospitalizations 1.38 (2.2)/patient-yeare ACS 3.3/100 patient-years, stroke/TIA 1.3/100 patient-years
Follow-up: 47 mo, 426 patient-yearsPre-HU, 1093 g/L (HbF)82 [67–100]Hospitalizations 3.2 (2.7)/patient-year
Other
    Scott et al21 (1996), prospective pre/postInclusion: age 10–17 y, HbSS, Hb Sβ 0thal, S α+ thal, ≥3 hospitalizations/y for pain, ACS, or priapismHU, 1315.2h (9.8)95g (15)Hospitalizations 3/y (4)
Follow-up: 43.6 mo [24–63]Pre-HU, 156.9 (6.2)82 (10)Hospitalizations 7/y (2.4)
    Olivieri and Vichinsky30 (1998), prospective pre/postInclusion: HbSS, pain ≥3 or ACS in the previous yearHU, 1716.7b (1.8)102b (36)Hospital (d) 8.1/y (2.8),h VOC 1.2/y (0.4),e ACS 0.2/y (0.1),e transfusion 0.4/y (0.2)e
Follow-up: 18 moPre-HU, 157.6 (1.6)89 (43)Hospital (d) 29.1/y (4.8), VOC 3.1/y (0.5), ACS 1.3/y (0.5), transfusion 1.8/y (0.4)
    Ware et al35 (2004), prospective pre/postInclusion: age pediatric, HbSS, transfusion, strokeHU, 3518.6 (6.6)92 (14)Stroke recurrence rate 5.7/100 patient-years
Follow-up: 29 mo [12–49]
    Kratovil et al41 (2006), retrospective case-controlInclusion: HbSS, pain >5/y, stroke and not transfused, severe ACS, TCD examination before and during HUHU, 2411.8b82i [59–106]CBF velocity 111.2 cm/secc
Follow-up: 6–48 moNo HU, 244.678 [52–106]CBF velocity 124 cm/sec
    Svarch et al32 (2006), retrospective pre/postInclusion: age 4–18 y, HbSS, pain ≥3 in past year or sepsis ≥1 in past 2 yHU, 5112.4b (7.9)85b (10)Hospitalizations 0.5/y [0–4], VOC 0.8/y [0–2], transfusions 0/y [0–3]
Follow-up: 24 moPre-HU, 156.4b (5.3)78b (10)Hospitalizations 4/y[0–6], VOC 3/y [0–6] transfusions 3/y, [0–8]
    Zimmerman et al42 (2007), prospective pre/postInclusion: children, HbSS, HbSOHU, 3722.7 (7.9)c94 (10)cCBF velocity 135 cm/sec (27)c
Follow-up: 10 mo (5)
Comment: stroke rate was 0.52/100 patient-yearsPre-HU, 3710.3 (6.6)78 (11)CBF velocity 166 cm/sec (27)
    McKie et al40 (2007), retrospective cohortInclusion: age >2 and <21 y, HbSSHU, albumin + 1911.8 [4–25.4]16/17 without microalbuminuria
HU, albumin + 919.8 (21.5)86 (10)4/9 normalized microalbuminuria
Follow-up: 21.8 moPre-HU, + albumin 98.6 (1.0)80 (14)
Pre-HU, 1548.5 (1.1)
    Harrod et al36 (2007), cross-sectionalInclusion: age <20 yHU/no splenectomy, 46HJB/106 RBC 3533 (2665)
No HU/no splenectomy 581263 (1193)
Follow-up: NRHU/splenectomy 114984 (2037) 2101 (945)
No HU splenectomy 10
    Hankins et al22 (2008), retrospective pre/postInclusion: children, HbSS, HbSβ 0thalHU, 5295 (17)Splenic function increased 6/40, stable brain MRI 24/25
Follow-up: 29 mo (2–103)
Comments: splenic function measured by scintigraphyPre-HU, 5285 (15)
    Santos et al31 (2002), prospective pre/postInclusion: age 3–22, HbSS, HbSβ 0thal, ≥2 episodes of priapism or ACS, ≥6 painful crisesHU, 2120VOC 1.81/y, transfusions 0.43/y, splenic function increased in 10
Follow-up: 12 mo4.8VOC 5/y, transfusions 3.9/y
  • HU indicates hydroxyurea; NR, not reported; HbSβ +thal, sickle β + thalassemia; HbSβ 0thal, sickle β -null thalassemia; HbSC, sickle-hemoglobin C disease; HbSO, hemoglobin SO Arab; CSSCD, Cooperative Study of Sickle Cell Disease; AVN, avascular necrosis; VOC, vasoocclusive crisis; CBF, cerebral blood flow; HJB, Howell-Jolly Body; TIA, transient ischemic attack; RBC, red blood cell; —, data were not reported.

  • a Mean (SD) [range] unless otherwise noted.

  • b P < 0.0001.

  • c P < 0.001.

  • d This is the extension study of the HUSOFT trial; 17 completed 4 years, and 11 completed 6 years from start.

  • e P < 0.05.

  • f Hemoglobin values from 20 patients treated for severe anemia.

  • g P < 0.01.

  • h P < 0.005.

  • i P was not significant.

  • @Uses data from the phase I/II HUG-KIDS study, but analyses only include children who reached the MTD.

  • !Includes patients who were in the HUG-KIDS study (n = 15) and in the HUSOFT trial (n = 7) and 33 patients in stroke study.