A Study of IMR-687 in Subjects With Sickle Cell Disease

Study Overview
=================
Brief Summary
-----------------
A Study to Evaluate the Safety and Efficacy of IMR-687 in Subjects with Sickle Cell Disease

Detailed Description
-----------------
A phase 2b, randomized, double-blind, placebo-controlled, multicenter study of subjects with sickle cell disease (SCD; homozygous sickle hemoglobin [HbSS], sickle-β0 [HbSβ0] thalassemia, or sickle-β+ [HbSβ+] thalassemia) to evaluate the safety and efficacy of the phosphodiesterase type 9 (PDE9) inhibitor, IMR-687, administered once daily (qd) for 52 weeks.

Official Title
-----------------
A Phase 2b Study to Evaluate the Safety and Efficacy of IMR-687 in Subjects With Sickle Cell Disease

Conditions
-----------------
Sickle Cell Disease

Intervention / Treatment
-----------------
* Drug: IMR-687
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of SCD (HbSS, HbSB0 thalassemia, or HbSB+ thalassemia) Hemoglobin of >5.5 and <10.5 g/dL; Hb values within 21 days post-transfusion will be excluded. Subjects must have had at least 2 and no more than 12 documented episodes of VOCs in the past 12 months at the time of informed consent signing and at randomization (Day 1). Subjects receiving HU must have received it continuously for at least 6 months prior to signing informed consent, and must have been on a stable dose for at least 3 months prior to signing the informed consent, with no anticipated need for dose adjustments during the study including the screening period, in the opinion of the investigator. Female subjects must not be pregnant or breastfeeding and be highly unlikely to become pregnant. Male subjects must be unlikely to impregnate a partner. Must be willing and able to complete all study assessments and procedures, and to communicate effectively with the investigator and site staff. Exclusion Criteria: Hospital discharge for sickle cell crisis or other vaso-occlusive event within the 4 days prior to randomization (Day 1). 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 measurements Subjects with HbF >25% at screening. Significant kidney disease (eGFR <45mL/min) and liver dysfunction: alanine aminotransferase or aspartate aminotransferase >3x upper limit of normal. Body mass index (BMI) <17.0 kg/m2 and a total body weight <45 kg; or a BMI >35 kg/m2. 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). Stroke requiring medical intervention within 24 weeks prior to randomization (Day 1). Prior exposure to IMR-687. 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). A history of use of crizanlizumab (Adakveo®) or voxelotor (Oxbryta®) within 6 months prior to signing the informed consent. Receipt of erythropoietin, luspatercept (Reblozyl®)or other hematopoietic growth factor treatment within 3 months of signing the ICF or anticipated need for such agents during the study. Prior gene therapy.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Higher dose IMR-687<br>Oral administration of once daily IMR-687 | Drug: IMR-687<br>* Oral administration of once daily IMR-687<br>|
| Experimental: Lower Dose IMR-687<br>Oral administration of once daily IMR-687 | Drug: IMR-687<br>* Oral administration of once daily IMR-687<br>|
| Placebo Comparator: Placebo<br>Oral administration of once daily Placebo | Drug: Placebo<br>* Oral administration of once daily Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect on the Incidence of Vaso-occlusive Crises (VOCs) | Annualized rate of VOCs. For each subject, the total number of VOCs on treatment were divided by the time on treatment divided by 52 weeks. The median was then summarized. | Baseline to Week 52 | 
| Proportion of Patients With Adverse Events and Serious Adverse Events | Incidence of Adverse Events Incidence of Serious Adverse Events | Baseline to Week 56 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sickle Cell Disease