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 |
Primary Efficacy Objective: • To evaluate the effect of IMR-687 versus placebo on the annualized rate of vaso-occlusive crises (VOCs)
Primary Safety Objective: • To evaluate the safety and tolerability of IMR-687 versus placebo
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E.2.2 | Secondary objectives of the trial |
Key Secondary Efficacy Objectives • To evaluate the effect of IMR-687 versus placebo on the time to the first occurrence of a VOC • To evaluate the fetal hemoglobin (HbF) response to IMR-687 versus placebo
Other Secondary Efficacy Objectives • To evaluate the effect of IMR-687 versus placebo on other measures of VOCs • To evaluate the effect of IMR-687 versus placebo on percentage of cells positive for fetal hemoglobin (HbF) (% F-cells) and total hemoglobin (Hb) • To evaluate the effect of IMR-687 versus placebo on biomarkers of red blood cell (RBC) hemolysis • To evaluate the effect of IMR-687 versus placebo on quality of life (QoL) measures • To evaluate the effect of IMR-687 versus placebo on biomarkers of adhesion, inflammation, and cardiac stress and on RBC indices
Secondary Pharmacokinetic Objective • To evaluate the pharmacokinetic (PK) exposure of IMR-687
Exploratory Objective • To evaluate the effect of IMR-687 versus placebo on renal function
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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, HbSβ0 thalassemia, or HbSβ+ 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 2 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, splenic sequestration, or priapism (in males) 4.Hb of >5.5 and <10.5 g/dL; Hb values within 21 days post-transfusion will be excluded. 5.This inclusion criterion has been removed. 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. Subjects participating in a chronic/prophylactic RBC transfusion program (i.e., regularly scheduled RBC transfusions); any transfusions within 21 days of screening or Baseline Hb measurement. 3.Subjects with 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.Significant kidney disease as indicated by, for example, Estimated glomerular filtration rate (eGFR) <45 mL/min as calculated by the equation from the Modification of Diet in Renal Disease (MDRD) Study using creatinine, age, sex, and ethnicity (modified MDRD formula). 7.Alanine aminotransferase or aspartate aminotransferase >3 × the upper limit of normal. 8.Body mass index (BMI) <17.0 kg/m2 or >35 kg/m2; or total body weight <45 kg. 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 of/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.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 the 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 on 2 or more of the triplicate ECGs, or the presence of clinically significant ECG abnormalities as determined by the investigator. 14.Major surgery within 8 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 (apixaban, dabigatran, rivaroxaban, edoxaban, or ticagrelor) or taking warfarin, unless they stopped the treatment at least 28 days prior to randomization (Day 1); low molecular weight heparins are allowed in the peri operative period; Aspirin use (<100 mg per day) is allowed before and during the study. 17.Poorly controlled diabetes mellitus in the opinion of the investigator, for example 1)Hb A1c >9.0% within 12 weeks prior to randomization (in the medical history); 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 prednisone or equivalent). 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 • Annualized rate of VOCs 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, splenic sequestration, or priapism (in males)
Safety Endpoints • AEs, serious adverse events (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 |
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E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoints • Time to first VOC • Proportion of HbF responders (defined as the proportion of subjects with an absolute increase of ≥3% in HbF from baseline) at Week 24
Other Secondary Efficacy Endpoints • Proportion of VOC-free subjects • Annualized rate of hospitalizations for VOCs • Time to second VOC • Proportion of HbF responders (defined as the proportion of subjects with an absolute increase of ≥3% in HbF from baseline) at Week 52 • Change from baseline in HbF (%) and F-cells (%) at Week 24 and Week 52 • Proportion of Hb responders (defined as the proportion of subjects with an increase of ≥1.0 g/dL in total Hb from baseline) at Week 24 and Week 52 • Change from baseline in total Hb (g/dL) at Week 24 and Week 52 • Change from baseline in biomarkers of RBC hemolysis (% and absolute reticulocytes, unconjugated [indirect] bilirubin, and lactate dehydrogenase [LDH]) at Week 24 and Week 52 • Change from baseline in each measured subdomain of the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me®) questionnaire at Week 24 and Week 52 • Change from baseline 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 at Week 24 and Week 52 • Change from baseline in overall score of the Sickle Cell Self-Efficacy Scale (SCSES) at Week 24 and Week 52 • Change from baseline in biomarkers of adhesion such as soluble E-selectin (E-sel), P-selectin (P-sel), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) at Week 24 and Week 52 • Change from baseline in biomarkers of inflammation such as high-sensitivity C-reactive protein (hsCRP) and myeloperoxidase (MPO) at Week 24 and Week 52 • Change from baseline in biomarkers of cardiac stress such as N-terminal prohormone of brain natriuretic peptide (NT-proBNP) at Week 24 and Week 52 • Change from baseline in RBC indices, such as mean corpuscular volume (MCV), at Week 24 and Week 52
Pharmacokinetic endpoints: •PK profile (concentration-time measurements) and population PK of IMR-687
Exploratory efficacy endpoints: •Change from baseline in renal function as measured by the urine protein-to-creatinine (Pr:Cr) ratio and microalbumin at Week 24 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, 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
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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 | 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 |
Ghana |
Kenya |
Lebanon |
Morocco |
Oman |
Senegal |
Tunisia |
Uganda |
United States |
Greece |
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
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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 | 4 |
E.8.9.1 | In the Member State concerned days | 6 |
E.8.9.2 | In all countries concerned by the trial years | 2 |