Sickle Cell Disease
Conditions
Keywords
Sickle Cell Disease
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.
Interventions
DRUGIMR-687
Oral administration of once daily IMR-687
DRUGPlacebo
Oral administration of once daily Placebo
Sponsors
Imara, Inc.
Cardurion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double-Blind
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Confirmed diagnosis of SCD (HbSS, HbSB0 thalassemia, or HbSB+ thalassemia) 2. Hemoglobin of \>5.5 and \<10.5 g/dL; Hb values within 21 days post-transfusion will be excluded. 3. 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). 4. 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. 5. Female subjects must not be pregnant or breastfeeding and be highly unlikely to become pregnant. Male subjects must be unlikely to impregnate a partner. 6. Must be willing and able to complete all study assessments and procedures, and to communicate effectively with the investigator and site staff.
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 measurements 3. Subjects with HbF \>25% at screening. 4. Significant kidney disease (eGFR \<45mL/min) and liver dysfunction: alanine aminotransferase or aspartate aminotransferase \>3x upper limit of normal. 5. Body mass index (BMI) \<17.0 kg/m2 and a total body weight \<45 kg; or a BMI \>35 kg/m2. 6. 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). 7. Stroke requiring medical intervention within 24 weeks prior to randomization (Day 1). 8. Prior exposure to IMR-687. 9. 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). 10. A history of use of crizanlizumab (Adakveo®) or voxelotor (Oxbryta®) within 6 months prior to signing the informed consent. 11. 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. 12. Prior gene therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect on the Incidence of Vaso-occlusive Crises (VOCs) | Baseline to Week 52 | 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. |
| Proportion of Patients With Adverse Events and Serious Adverse Events | Baseline to Week 56 | Incidence of Adverse Events Incidence of Serious Adverse Events |
Countries
Ghana, Greece, Italy, Kenya, Lebanon, Morocco, Netherlands, Oman, Senegal, Tunisia, Uganda, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Higher Dose IMR-687 Oral administration of once daily IMR-687
IMR-687: Oral administration of once daily IMR-687 | 49 |
| Lower Dose IMR-687 Oral administration of once daily IMR-687
IMR-687: Oral administration of once daily IMR-687 | 34 |
| Placebo Oral administration of once daily Placebo
Placebo: Oral administration of once daily Placebo | 32 |
| Total | 115 |
Baseline characteristics
| Characteristic | Higher Dose IMR-687 | Total | Placebo | Lower Dose IMR-687 |
|---|---|---|---|---|
| Age, Continuous | 25.0 years STANDARD_DEVIATION 7.91 | 26.2 years STANDARD_DEVIATION 8.47 | 26.2 years STANDARD_DEVIATION 9.27 | 27.9 years STANDARD_DEVIATION 8.44 |
| BMI | 21.04 kg/m^2 STANDARD_DEVIATION 3.571 | 21.06 kg/m^2 STANDARD_DEVIATION 3.308 | 21.10 kg/m^2 STANDARD_DEVIATION 2.794 | 21.03 kg/m^2 STANDARD_DEVIATION 3.451 |
| HbF | 11.51 % of HbF STANDARD_DEVIATION 7.775 | 11.01 % of HbF STANDARD_DEVIATION 6.384 | 11.16 % of HbF STANDARD_DEVIATION 4.903 | 10.16 % of HbF STANDARD_DEVIATION 5.453 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 34 Participants | 69 Participants | 20 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants | 20 Participants | 2 Participants | 9 Participants |
| Race (NIH/OMB) White | 6 Participants | 26 Participants | 10 Participants | 10 Participants |
| Region of Enrollment Ghana | 11 Participants | 21 Participants | 8 Participants | 2 Participants |
| Region of Enrollment Greece | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Kenya | 5 Participants | 13 Participants | 4 Participants | 4 Participants |
| Region of Enrollment Lebanon | 0 Participants | 7 Participants | 3 Participants | 4 Participants |
| Region of Enrollment Morocco | 5 Participants | 10 Participants | 3 Participants | 2 Participants |
| Region of Enrollment Oman | 1 Participants | 5 Participants | 0 Participants | 4 Participants |
| Region of Enrollment Senegal | 4 Participants | 7 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Tunisia | 1 Participants | 8 Participants | 4 Participants | 3 Participants |
| Region of Enrollment Uganda | 16 Participants | 29 Participants | 5 Participants | 8 Participants |
| Region of Enrollment United Kingdom | 3 Participants | 5 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 3 Participants | 7 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Female | 36 Participants | 64 Participants | 14 Participants | 14 Participants |
| Sex: Female, Male Male | 13 Participants | 51 Participants | 18 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 47 | 0 / 33 | 0 / 32 |
| other Total, other adverse events | 38 / 47 | 29 / 33 | 24 / 32 |
| serious Total, serious adverse events | 17 / 47 | 12 / 33 | 12 / 32 |
Outcome results
Primary
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.
Time frame: Baseline to Week 52
Population: ITT Analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Higher Dose IMR-687 | Effect on the Incidence of Vaso-occlusive Crises (VOCs) | 2.32 VOCs/weeks/52 |
| Lower Dose IMR-687 | Effect on the Incidence of Vaso-occlusive Crises (VOCs) | 1.20 VOCs/weeks/52 |
| Placebo | Effect on the Incidence of Vaso-occlusive Crises (VOCs) | 2.48 VOCs/weeks/52 |
Primary
Proportion of Patients With Adverse Events and Serious Adverse Events
Incidence of Adverse Events Incidence of Serious Adverse Events
Time frame: Baseline to Week 56
Population: Safety Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Higher Dose IMR-687 | Proportion of Patients With Adverse Events and Serious Adverse Events | Number of participants with Treatment-Emergent Adverse Events | 40 Participants |
| Higher Dose IMR-687 | Proportion of Patients With Adverse Events and Serious Adverse Events | Number of participants with Treatment Emergent Serious Adverse Events | 17 Participants |
| Lower Dose IMR-687 | Proportion of Patients With Adverse Events and Serious Adverse Events | Number of participants with Treatment-Emergent Adverse Events | 29 Participants |
| Lower Dose IMR-687 | Proportion of Patients With Adverse Events and Serious Adverse Events | Number of participants with Treatment Emergent Serious Adverse Events | 12 Participants |
| Placebo | Proportion of Patients With Adverse Events and Serious Adverse Events | Number of participants with Treatment-Emergent Adverse Events | 28 Participants |
| Placebo | Proportion of Patients With Adverse Events and Serious Adverse Events | Number of participants with Treatment Emergent Serious Adverse Events | 12 Participants |