The population for this study includes subjects with the following forms of SCD: homozygous sickle hemoglobin (HbSS), sickle-ß° (HbSB°) thalassemia, and sickle-ß? (HbSB?) thalassemia. Sickle cell
Conditions
Interventions
This study will enroll approximately 99 adult (18-65 years) subjects with Sickle Cell Disease. Initially, subjects will be randomly assigned in a 2:1 ratio
to receive either IMR-687 lower dose or plac
IMR-687 will be supplied as 100, 150, or 200 mg white tablets. Subjects will be advised to take 2 tablets orally, qd. The different doses of IMR-687 are visually identical. Subjects will be directed t
Sponsors
IMARA, Inc.
Eligibility
Sex/Gender
All
Age
18 Years to 65 Years
Inclusion criteria
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, HbSB° 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?/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. Male or female subjects must meet at least one of the following criteria: • A female subject who is not of reproductive potential is eligible without requiring the use of contraception. A female subject who is not of reproductive potential is defined as one who: (1) has reached natural menopause (defined as 12 months of spontaneous amenorrhea without an alternative medical cause, and can be confirmed with serum follicle-stimulating hormone levels in the postmenopausal range as determined by the central laboratory); (2) is 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy; or(3) has undergone bilateral tubal ligation. Spontaneous amenorrhea does not include cases for which there is an underlying disease that causes amenorrhea (e.g., anorexia nervosa). • A female of reproductive potential must have 2 negative pregnancy tests as verified by the investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, at the end of treatment visit, and at the end of study visit. This applies even if the subject practices true abstinence from heterosexual contact. • A male subject who is not of reproductive potential is eligible without requiring the use of contraception. A male subject who is not of reproductive potential is defined as one who has undergone a successful vasectomy. A successful vasectomy is defined as (1) microscopic documentation of azoospermia or (2) a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity post-vasectomy. • A male or female subject who is of reproductive potential agrees to remain truly abstinent or use (or have their partner use) acceptable methods of highly effective contraception starting from the time of
Exclusion criteria
Exclusion criteria: Subjects who meet any of the following criteria will be excluded from the study: 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) 3 × the upper limit of normal. 8. Body mass index (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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Name: Changes in vital signs;Timepoints: Vital signs will be collected at every on-site visit .At the Day 1 and Week 4 visits, vital signs will be taken predose and 2 hours (±20 minutes) postdose, during the PK assessments. At all other timepoints, vital signs can be taken irrespective of taking study drug.;Measure: heart rate, respiratory rate, blood pressure, and body temperature;Name: Changes in 12-Lead ECG;Timepoints: All ECGs to be performed in triplicate. From Baseline (Day 1 visit) through EOT (Week 52 visit), ECGs will be obtained at both pre-dose and 2 hours (±30 minutes) post-dose. During the screening, ET, and EOS (Week 56) visits, ECG will be obtained irrespective of taking study drug.;Measure: heart rate, PR interval, QRS duration, QT interval, and QTcF interval;Name: Incidence of Adverse Event AEs and Serious Adverse Event.;Timepoints: All AEs and SAEs, related and unrelated, will be recorded from the signing of informed consent through the end-of-study safety follow-up visit.;Measure: All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA);Name: Physical Examination;Timepoints: Complete PEs will be performed at Screening and at Weeks 12, 24, 36, 52, and 56; these consist of a general examination of the body, including the abdomen, heart, lungs, lymph nodes, back/neck, neurological system, skin, extremities, head, eyes, nose, and throat. At all other visits, symptom-directed PEs will be obtained after identification of AEs deemed by the investigator to be of significant clinical concern.;Measure: abdomen, heart, lungs, lymph nodes, back/neck, neurological system, skin, extremities, head, eyes, nose, and throat.;Name: Clinical Laboratory Variables;Timepoints: over 52 weeks of treatment;Measure: hematology,coagulation,serum chemistry,urinalysis and pregnancy test | — |
Secondary
| Measure | Time frame |
|---|---|
| Name: Quality of life;Timepoints: at Baseline and weeks 4,12,24,36 and 52;Measure: ASCQ-Me®, PROPr, SCSES;Name: Pharmacokinetic Assessment;Timepoints: At the Day 1 and Week 4 visits, serial blood samples for IMR-687 (including metabolites and HU, if applicable) plasma concentrations will be drawn pre-dose (within 30 minutes) and at 30 minutes (±5 minutes), 1.5 hours (±15 minutes), 6 hours (±1 hour), and 24 hours (±2 hours) after administration of study drug. On these full profile PK days, food details will also be recorded at the study sites. A trough blood sample will be drawn pre-dose at Week 24 and on the last day of dosing (Week 52).;Measure: Cmax, tmax, and AUC(0-24), 0 to the last measurable timepoint (AUC(last)), and extrapolated to infinity (AUC(0-infinity);Name: Pharmacodynamic Assessment;Timepoints: Screening,baseline and throughout treatment period;Measure: E-selectin, P-selectin, ICAM-1, VCAM-1, MPO, and transferrin receptor. | — |
Countries
Egypt, Ghana, Greece, Italy, Kenya, Lebanon, Morocco, Netherlands, Oman, Senegal, Tunisia, Uganda, United Kingdom, United States of America
Contacts
Public ContactAziz Zoghbi
Regional Manager
Outcome results
None listed