| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Sickle cell anaemia is a serious inherited blood disorder where the red blood cells, which carry oxygen around the body, develop abnormally and become rigid and shaped like a crescent (or sickle). |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10040644 |
| E.1.2 | Term | Sickle cell disease |
| E.1.2 | System Organ Class | 100000004850 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
PART A: (placebo-controlled, double-blind, participants 2 to <12 years of age)
The primary objective of Part A of this study is to assess the efficacy of voxelotor with long term, daily dosing compared to placebo in pediatric participants with SCD as measured by improvement in anemia.
PART B: (open-label, participants 9 months to <2 years of age)
The primary objective of Part B is to evaluate the safety and tolerability of voxelotor with long term, daily dosing in infants with SCD.
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| E.2.2 | Secondary objectives of the trial |
PART A:
The secondary objectives of Part A are to evaluate the effects of voxelotor compared to placebo on:
• vaso-occlusive crises (VOC),
• clinical measures of hemolysis,
• analgesic use for SCD,
• sickle cell related clinical events (eg stroke, priapism, gall stones, acute chest syndrome, splenic sequestration, leg ulcers, and dactylitis),
• healthcare resource utilization (incidence of hospitalizations, Emergency Room/clinic visits, RBC transfusions),
• measures related to quality of life (EQ-5DY self-administered and 2 proxyversions, and the PROMIS Pediatric and PROMIS Parent Proxy Scales).
PART B:
The secondary objective of Part B is to evaluate
• clinical measures of hemolysis.
• analgesic use for SCD.
• healthcare resource utilization (incidence of hospitalizations, Emergency Room/clinic visits, RBC transfusions).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
PART A:
1. Age 2 to < 12 years at the time of informed caregiver/legal guardian consent. ·
2. Male or female study participants with SCD. Documentation of SCD genotype (HbSS, HbSC, HbSβ0thal. or other sickle cell syndrome variants) is required and may be based on prior history of laboratory testing or must be confirmed by laboratory testing during screening.
3. Participants must have had at least 1 episode of VOC in the past 12 months. VOC is defined as a previously documented episode of acute painful crisis (for which there was no explanation other than VOC) or Acute Chest Syndrome (ACS) which required prescription or healthcare professional instructed use of analgesics for moderate to severe pain (documentation must exist in the participant’s medical record prior to Screening).
4. For participants taking HU, the dose of HU (mg/kg) must be stable for at least 90 days prior to signing the informed consent form (ICF) and/or assent form, and with no anticipated need for dose adjustments or initiation during the study, in the opinion of the Investigator.
5. Hb ≥ 5.5 g/dL ≤10.5 g/dL.
6. Written informed parental/guardian consent and participant assent (where applicable) has been obtained per IRB/EC policy and requirements, consistent with ICH guidelines.
7. Adequate venous access to permit monitoring of laboratory safety variables and collection of PK samples, in the opinion of the Investigator.
8. Participants, who if female and of child bearing potential, are using highly effective methods of contraception from study start to 30 days after the last dose of study drug, and who if male are willing to use barrier methods of contraception, from study start to 30 days after the last dose of study drug.
9. Females of child-bearing potential are required to have a negative pregnancy test before randomization.
PART B:
Participants who meet all of the following criteria will be eligible for study enrollment in Part B:
1. Age ≥9 months to <24 months of age at the time of informed caregiver/legal guardian consent. ·
2. Male or female study participants with sickle cell disease. Documentation of SCD genotype (HbSS, HbSC, HbSβ thalassemia or other sickle cell syndrome variants) is required and may be based on history of laboratory testing or must be confirmed by laboratory testing duringthe Screening Period.
3. Adequate venous access to permit monitoring of laboratory safety variables and collection of PK samples, in the opinion of the Investigator.
4. . A written informed parental/legal guardian consent has been obtained per institutional review board (IRB)/Ethics Committee (EC) policy and requirements, consistent with ICH guidelines
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| E.4 | Principal exclusion criteria |
PART A and PART B:
1. Body weight < 5kg at the screening visit.
2. VOC:
• Hospitalization for VOC within the 28 days prior to execution of informed consent/assent.
• A VOC in the screening period requiring hospitalization, hospital emergency room visit or a clinic visit resulting in a new prescription of analgesics is an exclusion.
• A VOC that does not require hospitalization during the screening period is not an exclusion provided that the hemoglobin level prior to randomization is within 1 g/dL of the screening value.
• More than 10 VOCs within the past 12 months that required hospitalization, or Emergency Room or clinic visit.
3. Severe renal dysfunction (<60 mL/min/1.73 m2 by Schwartz formula).
4. Hepatic dysfunction characterized by ALT > 4x ULN for age.
5. Clinically relevant cardiac abnormality, in the opinion of the Investigator, such as: ·
• Hemodynamically significant heart disease, eg congenital heart disease with left to right shunt or cyanosis, congestive heart failure, or an unstable cardiac condition. ·
• An arrhythmic heart condition requiring medical therapy. ·
• History of clinically significant abnormal electrocardiogram (ECG), congenital long QT syndrome, second or third-degree heart block at rest (except for asymptomatic Mobitz type I second degree heart block).
6. Participants with clinically significant bacterial, fungal, parasitic, or viral infection which requires therapy:
• Participants with acute bacterial infection requiring antibiotic use should delay screening until the course of antibiotic therapy has been completed.
• Participants with known active hepatitis A, B, or C or who are known to be human immunodeficiency virus (HIV)-positive.
• Participants who have tested positive for malaria at screening.
• Participants with acute malaria infection should delay screening until infection has been resolved and their hemoglobin level has, in the opinion of the Investigator, returned to the participant’s pre-infection level.
7. Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable).
8. Received an investigational drug within 30 days or 5 half-lives, whichever is longer, of the parent/legal guardian signing the ICF.
9. Parent or legal guardian/participants are unlikely to comply with the study procedures.
10. Other medical, psychological or addictive condition that, in the opinion of the Investigator, would confound or interfere with evaluation of safety, efficacy and/or PK of the investigational drug, prevent compliance with the study protocol, or preclude informed consent.
Additionally, for PART A only:
1. Meets the criteria for primary stroke prophylaxis.
2. Has been treated with erythropoietin or other hematopoietic growth factors within 28 days of signing informed consent/assent or if, in the opinion of the Investigator, there is an anticipated need for such agents during the study.
3. RBC transfusion therapy (also termed chronic, prophylactic, or preventative transfusion) or has received a RBC transfusion or exchange transfusion for any reason within 90 days of signing the informed consent/assent.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
PART A:
The primary efficacy endpoint is the increase in Hb >1 g/dL from Baseline (the average of Hb results from screening and Day 1) to Week 24. A participant is a responder if the Hb is >1 g/dL compared to Baseline.
PART B:
The safety endpoints are: AEs, clinical laboratory assessments (including assessing blood chemistry, liver function test, and hematology), SCD related AEs (including dactylitis, splenic sequestration, hepatic sequestration, acute painful crisis, priapism, ACS, transient ischemic attack, stroke, sepsis), vital signs, and ECGs. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PART A:
Hb >1 g/dL from Baseline (the average of Hb results from screening and Day 1) to Week 24.
PART B:
From screening through to EOS visit. |
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| E.5.2 | Secondary end point(s) |
PART A:
• Rate of VOC (combined secondary endpoint analysis with main population from Phase 3 Study GBT440-031).
• Change from Baseline to Week 24 in clinical measures of hemolysis (Hb, % reticulocytes, LDH, and unconjugated bilirubin).
• Time to first VOC.
• Rate of analgesic use, defined as proportion of days participants are on analgesics during the treatment period.
• Time to first sickle cell related clinical event (eg, stroke, priapism, gall stones, acute chest syndrome, splenic sequestration, leg ulcers, and dactylitis) and rate of SCD related clinical events.
• Time to first RBC transfusion and rate of RBC transfusion.
• Change from Baseline to Week 48 using quality of life assessments (EQ-5DY self-administered and 2 proxy versions and the PROMIS Pediatric and PROMIS Parent Proxy Scales)
PART B:
• The secondary endpoint is the mean change from Baseline to Week 12 and Week 24 in clinical measures of hemolysis (Hb, % reticulocytes, LDH, and unconjugated bilirubin).
• Rate of analgesic use, defined as proportion of days participants are on analgesics during the treatment period.
• Rate of RBC transfusion.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Measured at visits: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 36, 48 and EOS (last doe plus 4 weeks).
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Egypt |
| France |
| Ghana |
| Kenya |
| Lebanon |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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