| 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 Disease is a chronic, inherited blood disorder that impacts haemoglobin, a protein found in red blood cells (RBCs) that carries oxygen throughout the body. |
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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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10040644 |
| E.1.2 | Term | Sickle cell disease |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Only Part C and D will be conducted in UK.
Part A: To characterize the pharmacokinetics (PK) of GBT440 in plasma and whole blood following a single dose in pediatric participants with sickle cell disease (SCD)
Part B: The primary objective is to assess the efficacy of GBT440 in pediatric participants with SCD as measured by improvement in anemia
Part C (Relevant to UK):To evaluate the effect of GBT440 on cerebral hemodynamics in pediatric participants with SCD with elevated or conditional TCD flow velocity as assessed by transcranial Doppler (TCD) ultrasonography
Part D (Relevant to UK): To evaluate the safety and tolerability of voxelotor in pediatric participants with SCD aged 9 months to <4 years |
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| E.2.2 | Secondary objectives of the trial |
Only Part C and D relevant for UK
Part C :
• To evaluate the effect of GBT440 on clinical measures of anemia and hemolysis
• To characterize the PK of GBT440 in plasma, whole blood and red blood cells (RBC) following multiple doses in pediatric participants with SCD
• To evaluate the safety and tolerability of GBT440 following multiple doses in pediatric participants with SCD
Part D:
• To characterize the PK of voxelotor in plasma, whole blood, and RBCs in pediatric participants with SCD aged 9 months to <4 years
• To evaluate the effect of voxelotor on clinical measures of anemia and hemolysis in pediatric participants with SCD aged 9 months to <4 years |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants who meet all of the following criteria will be eligible for study enrollment:
1. Male or female participants with homozygous hemoglobin SS (HbSS) or hemoglobin S beta0 thalassemia (HbS β0 thal).
2. Age:
• Part A – 6 to 17 years of age. (Cohort 1 [12 to 17] and Cohort 2 [6 to 11] as defined in the Study Design)
• Part B – 12 to 17 years of age
• Part C – 4 to 17 years of age
• Part D - 9 months to <4 years of age
3. Part A, B, C: A participant taking hydroxyurea (HU) may be enrolled if the dose has been stable for at least 3 months with no anticipated need for dose adjustments during the study and no sign of hematological toxicity. Part D – A participant taking HU may be enrolled if the dose has been stable for at least 1 month. Titration to the maximum tolerated dose (MTD) is allowed during the study
4. Hemoglobin (Hb):
• Part A – No restriction
• Part B – Hb ≤10.5 g/dL
• Part C – Hb ≤10.5 g/dL
• Part D - Hb ≤10.5 g/dL
5. Written informed parental/guardian consent and participant assent has been obtained per institutional review board (IRB)/Ethics Committee (EC) policy and requirements, consistent with ICH guidelines.
6. Participants in Part B (only) of the study must complete a minimum of 14 days with ePRO to be enrolled. Investigator discretion will be used to determine if a participant who has previously been screen failed due to a lack of baseline ePRO data collection can be invited back for re-screening.
7. If sexually active and female, must agree to abstain from sexual intercourse or to use a highly effective method of contraception throughout the study period and for 30 days after discontinuation of study drug. If sexually active and male, must agree to abstain from sexual intercourse or willing to use barrier methods of contraception throughout the study period and for 30 days after discontinuation of study drug.
8. Females of child-bearing potential are required to have a negative pregnancy test before the administration of study drug.
9. Sufficient venous access to permit collection of PK samples and monitoring of laboratory safety variables, in the opinion of the Investigator.
10. For Part C only, participants 12 to 17 years of age must have a TCD velocity ≥140 cm/sec by nonimaging TCD or ≥125 cm/sec by TCDi measured anytime during screening. |
|
| E.4 | Principal exclusion criteria |
Participants meeting any of the following exclusion criteria will not be eligible for study enrollment:
Any one of the following requiring medical attention within 14 days prior to signing the informed consent form (ICF):
• Vaso-occlusive crisis (VOC)
• Acute chest syndrome (ACS)
• Splenic sequestration crisis
• Dactylitis
2. Requires chronic transfusion therapy.
3. History of stroke or meeting criteria for primary stroke prophylaxis (history of two TCD measurements ≥200 cm/sec by nonimaging TCD or ≥185 cm/sec by TCDi).
• For the potential modification, addition of approximately 20 participants enrolled in Part C, TCD ≥170 cm/sec by nonimaging TCD or ≥155 cm/sec by TCDi.
4. Transfusion within 30 days prior to signing the ICF.
5. Renal dysfunction requiring chronic dialysis or creatinine ≥1.5 mg/dL
6. Hepatic dysfunction characterized by alanine aminotransferase (ALT) >4× upper limit of normal (ULN) for age
7. Clinically relevant cardiac abnormality, in the opinion of the Investigator, such as:
• Hemodynamically significant heart disease, e.g., congenital heart defect, uncompensated heart failure, or any unstable cardiac condition
• An arrhythmic heart condition requiring medical therapy
8. QTcF >450 msec, congenital long QT syndrome, second or third degree heart block at rest (with the exception of asymptomatic Mobitz type I second degree heart block)
9. Received an investigational drug within 30 days or 5 half-lives, whichever is longer, of signing the ICF
10. Heavy smoker (defined as smoking more than 10 cigarettes/day or its nicotine equivalent including e-cigarettes)
11. Unlikely to comply with the study procedures
12. Other medical, psychological or addictive condition that, in the opinion of the Investigator, would confound or interfere with evaluation of safety and/or PK of the investigational drug, prevent compliance with the study protocol, or preclude informed consent
13. Participants who do not have a TCD window (Part B and C only) (i.e., participants who are unable to have a TCD due to skull ossification)
14. For Part C only, prior participation in Part B
In addition, for Part D only:
15. Body weight <5 kg for 1 month prior to the screening visit and at the screening visit.
16. Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable).
17. History of malignancy within the past 2 years prior to treatment Day 1 requiring chemotherapy and/or radiation (with the exception of local therapy for non-melanoma skin malignancy).
18. Clinically significant bacterial, fungal, parasitic, or viral infection currently receiving or that will require therapy:
• Participants with acute bacterial infection requiring antibiotic use should delay screening until the course of antibiotic therapy has been completed and the infection has resolved, in the opinion of the investigator.
• Known active hepatitis A, B, or C infection or human immunodeficiency virus (HIV)-positive.
• Known active malaria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Only Part C and D will be conducted in UK sites.
Part A: Cmax, area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC0-last) and AUC0-inf of GBT440 in whole blood
Part B: Change from baseline to Week 24 in Hb.
Part C: Change from baseline to 48 weeks in cerebral blood flow as measured by the TAMM TCD velocity
Part D: TEAEs and SAEs |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part C:
Measured at visits: Screening, Week 24 and Week 48.
Part D: throughout the study |
|
| E.5.2 | Secondary end point(s) |
Only Part C and D will be conducted in UK sites.
Part A:
• Cmax, AUC0-last and AUC0-inf of GBT440 in plasma and RBC
• The time that Cmax was observed (tmax), terminal elimination half-life (t½) in RBC, whole blood and plasma, and percent Hb occupancy
Part B:
• Proportion of days with Sickle Cell Disease (SCD) symptom exacerbation during the first 24 weeks of treatment.
• Change from baseline to Weeks 21–24 in the sickle cell disease severity measure (SCDSM) TSS.
• Change from baseline to 12 and 24 weeks in LDH, indirect bilirubin and reticulocyte count
• GBT440 PK to 24 weeks (Cmax, AUC0-last, AUC0-inf, AUC0-24, T1/2, accumulation ratio, blood/plasma ratio, RBC/plasma ratio, if appropriate) and percent Hb occupancy
• Change from baseline to 12 and 24 weeks in cerebral blood flow as measured by the TAMM TCD velocity.
Part C:
• Change from baseline to weeks 24 and 48 in Hb, LDH, indirect bilirubin and reticulocyte count
• Change from baseline to 24 weeks in cerebral blood flow as measured by the TAMM TCD velocity
• GBT440 PK (Cmax, AUC0-last, AUC0-inf , AUC0-24, T1/2, accumulation ratio, blood/ plasma ratio, RBC/plasma ratio, if appropriate) and percent Hb occupancy
Part D:
• Voxelotor PK (Cmax, AUC0-24, T1/2, if appropriate) and percent Hb occupancy
• Change from baseline to Week 24 in Hb, LDH, indirect bilirubin, and reticulocyte count
• Time to initial Hb response, defined as change from baseline in Hb > 1g/dL |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part C:
First endpoint: From screening through to end of treatment visit
Second endpoint: Measured at visits: screening, WK 24
Third endpoint: Measured at visits: Day 1, week 4,8,12,16,20,24,36 and 48
Part D:
Primary endpoint (safety): From screening through the end of treatment visits - Screening, Day 1, weeks 2,4,8,12,16,20,24,36 and 48
Secondary endpoints:
PK: measured at all study visits with PK collection from screening through the end of treatment visit - Screening, Day 1, weeks 2,8,12,16,24,36 and 48
Change from baseline to week 24 in Hb, LDH, indirect bilirubin and reticulocyte count:Measured at Screening and WK 24
Time to Hb response: measured from screening through the end of treatment visit-screening, Day 1, weeks 2,4,8,12,16,20,24, 36 and 48 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
| Lebanon |
| United States |
| United Kingdom |
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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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 31 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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