E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
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). |
|
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 | 100000011951 |
|
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 |
The primary objective is to assess the efficacy of GBT440 in adolescents and adults with Sickle Cell Disease (SCD) as measured by improvement in anemia. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate the effects of GBT440 compared to placebo on SCD symptom exacerbation and TSS from PRO measurement, measures of anemia and hemolysis, and other clinical measures (e.g., VOC, ACS, hospitalization, RBC transfusions, opioid use). |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All participants must meet the following inclusion criteria:
1. Male or female study participants with Sickle Cell Disease:
• Documentation of SCD genotype (HbSS, HbSC, HbSβ thalassemia or other sickle cell syndrome variants) may be based on history of laboratory testing or must be confirmed by
laboratory testing during screening
2. Participants have had at least 1 episode of VOC in the past 12 months. For study eligibility, VOC is defined as a previously documented episode of ACS or acute painful crisis (for which there was no explanation other than VOC) which required prescription or healthcare professional-instructed use of analgesics for moderate to severe pain (documentation must exist in the patient medical record prior to Screening)
3. Age 12 to 65 years
4. Hemoglobin (Hb) ≥6.0 and ≤10.5 g/dL during screening
5. Absolute reticulocyte count and % reticulocyte count must be >1.5 × ULN during Screening
6. For participants taking hydroxyurea (HU), the dose of HU (mg/kg) must be stable for at least 3 months prior to signing the ICF and with no anticipated need for dose adjustments during the study, in the opinion of the Investigator
7. Participants must demonstrate 75% compliance with ePRO measure completion to be enrolled (participants will be given an ePRO device for at least 28 days during Screening; participants who are 60 to 74% compliant can re-screen once with Investigator approval; re-screening is not allowed for participants who are <60% compliant)
8. Participants, who if female and of child bearing potential, are using highly effective methods of contraception from study start to 3 months after the last dose of study drug, and who if male are willing to use barrier methods of contraception, from study start to 3 months after the last dose of study drug
9. Participant has provided documented informed consent or assent (the informed consent form [ICF] must be reviewed and signed by each participant; in the case of pediatric participants, both the consent of the participant’s legal representative or legal guardian, and the participant’s assent must be obtained) |
|
E.4 | Principal exclusion criteria |
Any participant who meets one or more of the following criteria will be excluded from participation:
1. More than 10 VOCs within the past 12 months that required a hospital, emergency room or clinic visit
2. Female who is breast feeding or pregnant
3. Patients who are receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion) or have received a RBC transfusion for any reason within 28 days of signing the ICF
4. Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days of signing the ICF
(i.e., a vaso-occlusive event cannot be within 14 days prior to ICF)
5. Hepatic dysfunction characterized by alanine aminotransferase (ALT) >4 × ULN
6. Participants with clinically significant bacterial, fungal, parasitic or viral infection which require therapy:
• Participants with acute bacterial infection requiring antibiotic use should delay screening/enrollment 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
7. Severe renal dysfunction (estimated glomerular filtration rate at the Screening visit; calculated by the central laboratory) <30mL/min/1.73² or on chronic dialysis
8. 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)
9. History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent including but not limited to the following:
• Unstable angina pectoris or myocardial infarction or elective coronary intervention
• Congestive heart failure requiring hospitalization
• Uncontrolled clinically significant arrhythmias
10. Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable)
11. Participated in another clinical trial of an investigational agent (or medical device) within 30 days or 5 half-lives of date of informed consent, whichever is longer, or is currently participating in another trial of an investigational agent (or medical device)
12. Inadequate venous access as determined by the Investigator/site staff
13. Medical, psychological, or behavioral conditions, which, in the opinion of the Investigator, may confound study interpretation, interfere with compliance, or preclude informed consent |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Increase in Hb >1 g/dL from Baseline to Week 24. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 1, Weeks 2,4,6,8,12,16,20,24,36,48,60,72, EOS(+4weeks) |
|
E.5.2 | Secondary end point(s) |
• Proportion of days with SCD symptom exacerbation during the first 24 weeks of treatment. This is the first-rank secondary endpoint.
• Change from Baseline to Weeks 21–24 in the SCDSM TSS
• Normalization of reticulocyte count at Week 12/24 (% reticulocytes <1.5 × ULN weeks)
• VOC during the treatment period is defined as:
A composite of acute painful crisis or ACS and includes the following:
◦ Moderate to severe pain lasting at least 2 hours
◦ No explanation other than VOC
◦ Requires oral or parenteral opioids, ketorolac, or other analgesics prescribed or directed by a healthcare professional
◦ Must be documented in patient medical record that the patient was seen, or contacted the physician, within 1 day of the event. The event may take place in a medical setting (hospital, clinic, emergency room)
◦ May include episodes of ACS (ACS is defined as an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X ray
• Rate of hospitalization for VOC during the treatment period
• Change from Baseline to 24 weeks in hemolysis and related measures: % reticulocytes, unconjugated bilirubin, Hb, dense RBCs
• Time to first ACS during the treatment period
• Time to first RBC transfusions during the treatment period
• Rate of opioid use, calculated as the proportion days that opioids were used each 4-week period as recorded in an eDiary
• Length of hospitalization for VOC
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day 1, Weeks 2,4,6,8,12,16,20,24,36,48,60,72, EOS(+4weeks) |
|
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 | No |
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 | 3 |
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 | 4 |
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 |
Canada |
Egypt |
France |
Ghana |
Italy |
Jamaica |
Kenya |
Lebanon |
Netherlands |
Nigeria |
Oman |
Qatar |
Turkey |
United Kingdom |
United States |
|
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 | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 15 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |