| 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 |
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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 |
•To evaluate the fetal hemoglobin (HbF) response to IMR-687 versus placebo
•To evaluate the safety of IMR-687 versus placebo
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| E.2.2 | Secondary objectives of the trial |
Secondary Efficacy Objectives
•To evaluate the effect of IMR-687 versus placebo on HbF associated biomarkers
•To evaluate the effect of IMR-687 versus placebo on indices of red cell hemolysis
•To evaluate the effect of IMR-687 versus placebo on indices of white blood cell (WBC) adhesion
•To evaluate the effect of IMR-687 versus placebo on the incidence of vaso-occlusive crises (VOCs)
•To evaluate the effect of IMR-687 versus placebo on quality of life measures
Pharmacokinetic Objectives
•To evaluate the PK of IMR-687 and any major circulating metabolites
Exploratory Efficacy Objectives
•To evaluate the effect of IMR-687 versus placebo on changes in red blood cell (RBC) characteristics and total Hb
•To evaluate the effect of IMR-687 versus placebo on renal function
•To evaluate the effect of IMR-687 versus placebo on indices associated with cardiovascular pathophysiology and ischemic stroke risk
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Male or female aged ≥18 to ≤65 years at the time of informed consent form (ICF) signing.
2.Confirmed diagnosis of SCD (HbSS, HbSB0 thalassemia, or HbSB+ thalassemia) in the medical record; if not available, the diagnosis must be confirmed at the site’s local laboratory instead.
3.Subjects must have had at least 1 and no more than 12 documented episodes of VOC in the past 12 months at the time of ICF signing and at randomization (Day 1).
For study eligibility, VOC is defined as a documented episode of an acute painful crisis (for which there was not an explanation other than VOC) that involved moderate to severe pain lasting for at least 2 hours and at least one of the following:
•Use of escalated analgesia (including healthcare professional-instructed use of an analgesic prescription)
•A hospital, emergency department, or clinic visit and/or healthcare telephone consultation at the time of occurrence
•Diagnosis of acute chest syndrome (ACS) (defined as an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X ray), hepatic sequestration, or splenic sequestration
4.Hemoglobin (Hb) of >5.5 and <10.5 g/dL.
5.Absolute reticulocyte count ≥80 × 10^9/L.
6.Subjects receiving HU must have received it continuously for at least 6 months prior to signing the ICF, and must have been on a stable dose for at least 3 months prior to signing the ICF, with no anticipated need for dose adjustments during the study including the screening period, in the opinion of the investigator.
7.Female subjects must not be pregnant or breastfeeding and be highly unlikely to become pregnant. Male subjects must be unlikely to impregnate a partner.
8.Be capable of giving informed consent and reading and signing the ICF after the nature of the study has been fully explained by the investigator or investigator designee.
9.Be willing and able to complete all study assessments and procedures and to communicate effectively with the investigator and site staff.
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| E.4 | Principal exclusion criteria |
1.Hospital discharge for sickle cell crisis or other vaso occlusive event within the 4 days prior to randomization (Day 1).
2.Red blood cell transfusion within 60 days of signing the ICF or on chronic transfusion therapy regimen. Transfusion status must be reassessed at randomization (Day 1).
Note: If a subject requires a transfusion during the screening period, they may be rescreened up to one time.
3.Subjects with hereditary persistence of HbF (i.e., HbF >25% at screening).
4.Subjects with known active hepatitis A, hepatitis B, or hepatitis C, with active or acute event of malaria, or who are known to be positive for human immunodeficiency virus (HIV).
5.For female subjects of childbearing potential, a positive serum human chorionic gonadotropin (hCG) test (screening) or a positive urine hCG test at randomization (Day 1).
6.Estimated glomerular filtration rate (eGFR) <45 mL/min as calculated by the equation from the Modification of Diet in Renal Disease Study using creatinine, age, sex, and ethnicity.
7.Alanine aminotransferase or aspartate aminotransferase >3 × the upper limit of normal.
8.Body mass index (BMI) <17.0 kg/m2 and a total body weight <45 kg; or a BMI >35 kg/m2.
9.Current or history of malignancies (solid tumors and hematological malignancies), unless the subject has been free of the disease (including completion of any active or adjuvant treatment for prior malignancy) for ≥5 years. However, subjects with the following history/concurrent conditions are allowed if, in the opinion of the investigator, the condition has been adequately diagnosed and is determined to be clinically in remission, and the subject’s participation in the study would not represent a safety concern:
a.Basal or squamous cell carcinoma of the skin
b.Carcinoma in situ of the cervix
c.Carcinoma in situ of the breast
d.Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis clinical staging system)
10.A history of a clinically significant allergic reaction or hypersensitivity, as judged by the investigator, to any drug or any component of the study drug formulations used in the study (see Investigator’s Brochure).
11.History of unstable or deteriorating cardiac or pulmonary disease within 6 months before signing the ICF, including but not limited to the following:
a.Unstable angina pectoris or myocardial infarction or elective coronary intervention
b.Congestive heart failure requiring hospitalization
c.Uncontrolled clinically significant arrhythmias
12.Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable).
13.On ECG testing at ICF signing and/or randomization (Day 1), a corrected QT interval, Fridericia’s formula (QTcF) >450 ms in men and >470 ms in women or the presence of clinically significant ECG abnormalities as determined by the investigator.
14.A history of major surgery within 4 weeks or minor surgery within 2 weeks of randomization (Day 1).
15.Stroke requiring medical intervention within 24 weeks prior to randomization (Day 1).
16.Subjects taking direct acting oral anti-coagulants (DOACs) apixaban, dabigatran, rivaroxaban, edoxaban, or ticagrelor, or taking warfarin, are excluded due to the possibility of a cytochrome P450 (CYP)3A-mediated drug interaction, unless they stopped the treatment at least 28 days prior to randomization (Day 1); other oral anti coagulants and anti-platelet drugs are permitted. Anti coagulant therapies for prophylaxis of venous thromboembolism, including pulmonary emboli including when undergoing surgery or high-risk procedures, are allowed if low molecular weight heparins are used in the peri operative period. Aspirin use is allowed before and during the study.
17.Poorly controlled diabetes mellitus as defined by 1) fructosamine levels of >340 µmol/L within 12 weeks prior to randomization (Day 1); 2) short-term hyperglycemia leading to hyperosmolar or ketoacidotic crisis; and/or 3) history of diabetic cardiovascular complications.
18.Subject has received chronic systemic glucocorticoids within 12 weeks prior to randomization (≥5 mg/day). Physiologic replacement therapy for adrenal insufficiency is allowed.
19.Any clinically significant bacterial, fungal, parasitic, or viral infection requiring antibiotic therapy should delay screening/randomization (Day 1) until the course of antibiotic therapy has been completed. This includes, but is not limited to, long-term tuberculosis treatment.
20.Participated in another clinical study 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 study of an investigational agent (or medical device).
Please refer to the protocol for exclusion criteria 21-27. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint: Subject response as defined by an increase of ≥3% in HbF from baseline to Week 24
Primary Safety Endpoints: AEs, SAEs, clinically significant changes in laboratory tests, clinically significant changes in vital signs, and clinically significant changes in ECGs |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Efficacy: An interim analysis (IA) will be performed after 33 subjects have reached Week 24, and a primary analysis will be performed after all subjects have reached Week 24 or terminated early. A final analysis will be conducted at study completion (i.e., when all subjects have reached Week 56 or terminated early).
Primary Safety Endpoints: throughout the study |
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| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
•Change in HbF from baseline to Week 24, Week 36, and Week 52
•Subject response as defined by an increase of ≥3% in HbF from baseline to Week 36 and Week 52
•Change in % F cells from baseline to Week 24, Week 36, and Week 52
•Change in hemolysis markers (% and absolute reticulocytes) and related measures (unconjugated bilirubin and lactate dehydrogenase [LDH]) from baseline to Week 24, Week 36, and Week 52
•Change in soluble E-selectin (E-sel), P-selectin (P-sel), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and myeloperoxidase (MPO) from baseline to Weeks 24, 36, and 52
•Change in the number of VOCs from baseline to Week 24, Week 36, and Week 52
VOC is defined as a documented episode of an acute painful crisis (for which there was not an explanation other than VOC) that involves moderate to severe pain lasting for at least 2 hours and at least one of the following:
- Use of escalated analgesia (including healthcare professional-instructed use of an analgesic prescription).
- A hospital, emergency department, or clinic visit and/or healthcare telephone consultation at the time of occurrence
- Diagnosis of ACS (defined as an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray), hepatic sequestration, or splenic sequestration
•Change in each measured subdomain of the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me®) questionnaire from baseline to Week 24, Week 36, and Week 52
•Change in total preference score and individual domain scores of the Patient-Reported Outcomes Measurements Information System – Preference (PROMIS® 29 + 2 Profile v2.1 [PROPr]) questionnaire from baseline to Week 24, Week 36, and Week 52
•Change in overall score of the Sickle Cell Self-Efficacy Scale (SCSES) from baseline to Week 24, Week 36, and Week 52
Pharmacokinetic endpoints:
•PK profile (concentration-time measurements) of IMR-687 and any major circulating metabolites
Exploratory efficacy endpoints:
• Change in soluble transferrin receptor from baseline to Week 24, Week 36, and Week 52
•Change in RBC characteristics (e.g., mean corpuscular volume [MCV]) and total Hb from baseline to Week 24, Week 36, and Week 52
•Change in renal function as measured by the urine protein-to-creatinine (Pr:Cr) ratio from baseline to Week 24, Week 36, and Week 52
•Change related to index associated with cardiovascular pathophysiology and ischemic stroke risk as measured by N-terminal prohormone of brain natriuretic peptide (NT proBNP) and high-sensitivity C-reactive protein (hsCRP) levels from baseline to Week 24, Week 36, and Week 52 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
secondary Efficacy Endpoints : throughout the study
Pharmacokinetic endpoints: at baseline, Week 4, Week 24 & Week 52 or End of Study visit
Exploratory efficacy endpoints: baseline, Week 24, Week 36, and Week 52 |
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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 | Yes |
| 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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Greece |
| Israel |
| Kenya |
| Lebanon |
| Morocco |
| Netherlands |
| Oman |
| Senegal |
| Tunisia |
| Uganda |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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