β Thalassemia
Conditions
Keywords
Transfusion, TDT, NTDT
Brief summary
A Study to Evaluate the Safety and Tolerability of IMR-687 in Subjects with Beta Thalassemia
Detailed description
A phase 2, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, PK, and PD of IMR-687 (phosphodiesterase (PDE) 9 inhibitor) administered once daily (qd) orally for 36 weeks in 2 populations of adult subjects with β-thalassemia: Population 1 (Transfusion Dependent Thalassemia (TDT) subjects) and Population 2 (Non-Transfusion Dependent Thalassemia (NTDT) subjects).
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
NONE
Masking description
Double-Blind
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Documented diagnosis of β-thalassemia or HbE/ β-thalassemia in their medical history. Concomitant alpha gene deletion, duplication, or triplication is allowed. 2. Documentation of the dates of transfusion events and the number of all pRBC units per event within the 12 weeks prior to the Baseline (Day 1) visit. . 3. Must be willing and able to complete all study assessments and procedures, and to communicate effectively with the investigator and site staff. 4. TDT Subjects: subjects must be regularly transfused, defined as \>3 to 10 pRBC units in the12 weeks prior to Baseline (Day 1) visit and no transfusion-free period for \>35 days during that period. 5. NTDT subjects: Subjects must be transfusion independent, defined as 0 to ≤3 units of pRBCs received during the 12-week period prior to the Baseline (Day 1) visit, must not be on a regular transfusion program, must be RBC transfusion-free for at least ≥ 4 weeks prior to randomization, and must not be scheduled to start a regular 6. hematopoietic stem cell transplantation within 9 months. 7. NTDT subjects: Subjects must have Hb ≤10.0 g/dL at Screening; the screening Hb sample must be collected 7 to 28 days prior to randomization. Hb values within 21 days post-transfusion will be excluded. 8. ECOG performance score of 0 to 1 9. Female subjects must not be pregnant, or breastfeeding and be highly unlikely to become pregnant. Male subjects must be unlikely to impregnate a partner.
Exclusion criteria
1. Diagnosis of α-thalassemia (e.g., hemoglobin H \[HbH\]) or hemoglobin S (HbS)/ β thalassemia. 2. Body mass index (BMI) \<17.0 kg/m2 or a total body weight \<45 kg; or BMI \>35 kg/m2 3. 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). 4. Stroke requiring medical intervention ≤24 weeks prior to randomization. 5. Platelet count \>1000 × 109/L. 6. Participated in another clinical study of an investigational agent (or device) within 30 days or 5-half-lives of date of informed consent, whichever is longer, or is currently participating in another study. 7. For Subjects on iron chelation therapy (ICT) at the time of ICF signing, initiation of ICT less than 24 weeks before the predicted randomization date. 8. Prior exposure to sotatercept or luspatercept, IMR-687, or gene therapy within 6 months prior to randomization (Day 1). 9. Subjects who have major organ damage
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| IMR-687 Safety and Tolerability | Baseline to Week 40 | Incidence and severity of Adverse Events Incidence and severity of Serious Adverse Events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| NTDT Patients: Proportion of Subjects With an Increase From Baseline of Hb at Week 12 to Week 24 in the Absence of Transfusions. | Baseline to Week 24 | Proportion of subjects with an increase from baseline of ≥1.0 g/dL in mean Hb values at Week 12 to Week 24 in the absence of transfusions. |
| NTDT Patients: Proportion of Subjects With an Increase From Baseline of ≥3% in Mean HbF Values at Week 12 to Week 24 in Absence of Transfusions | Baseline to Week 24 | Proportion of subjects with an increase from baseline of ≥3% in mean HbF values at Week 12 to Week 24 in absence of transfusions |
| TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥33% Hematological Improvement From Week 24 to Week 36 | Baseline to Week 36 | Proportion of patients with ≥33% hematological improvement from Week 24 to Week 36 compared to the 12 weeks prior to Baseline (Day 1) |
| TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥33% Hematological Improvement From Week 12 to Week 24 | Baseline to Week 24 | Proportion of patients with ≥33% hematological improvement (as measured by reduced transfusion burden) from Week 12 to Week 24 compared to the 12 weeks prior to Baseline (Day 1) |
| TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥50% Hematological Improvement From Week 24 to Week 36 | Baseline to Week 36 | Proportion of patients with ≥50% hematological improvement from Week 24 to Week 36 compared to the 12 weeks prior to Baseline (Day 1) |
| NTDT Patients: Proportion of Subjects With an Increase From Baseline of Hb at Week 24 to Week 36 in the Absence of Transfusions | Baseline to Week 36 | Proportion of subjects with an increase from baseline of ≥1.0 g/dL in mean Hb values at Week 24 to Week 36 in the absence of transfusions. |
| NTDT: Proportion of Subjects With an Increase From Baseline of ≥3% in Mean HbF Values at Week 24 to Week 36 in Absence of Transfusions | Baseline to Week 36 | Proportion of subjects with an increase from baseline of ≥3% in mean HbF values at Week 24 to Week 36 in absence of transfusions |
| TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥50 % Hematological Improvement From Week 12 to Week 24 | Baseline to Week 24 | Proportion of patients with ≥50% hematological improvement from Week 12 to Week 24 compared to the 12 weeks prior to Baseline (Day 1) |
Countries
Denmark, France, Georgia, Greece, Israel, Italy, Lebanon, Malaysia, Morocco, Netherlands, Tunisia, Turkey (Türkiye), United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TDT High Dose TDT High dose | 29 |
| TDT Low Dose TDT Low dose | 25 |
| TDT Placebo TDT Placebo | 20 |
| NTDT High Dose NTDT High dose | 24 |
| NTDT Low Dose NTDT Low dose | 12 |
| NTDT Placebo NTDT Placebo | 12 |
| Total | 122 |
Baseline characteristics
| Characteristic | TDT Low Dose | TDT Placebo | NTDT High Dose | TDT High Dose | NTDT Low Dose | NTDT Placebo | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 30.0 Years STANDARD_DEVIATION 9.95 | 31.3 Years STANDARD_DEVIATION 8.57 | 34.1 Years STANDARD_DEVIATION 12.64 | 31.7 Years STANDARD_DEVIATION 12.06 | 28.5 Years STANDARD_DEVIATION 8.21 | 36.0 Years STANDARD_DEVIATION 9.56 | 31.9 Years STANDARD_DEVIATION 10.69 |
| BMI | 21.252 kg/m2 STANDARD_DEVIATION 2.2874 | 22.699 kg/m2 STANDARD_DEVIATION 2.9968 | 22.031 kg/m2 STANDARD_DEVIATION 3.5415 | 22.900 kg/m2 STANDARD_DEVIATION 3.2252 | 21.1320 kg/m2 STANDARD_DEVIATION 3.5047 | 21.9120 kg/m2 STANDARD_DEVIATION 3.5638 | 22.0873 kg/m2 STANDARD_DEVIATION 3.1573 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 4 Participants | 4 Participants | 5 Participants | 3 Participants | 4 Participants | 27 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants | 4 Participants | 1 Participants | 2 Participants | 13 Participants |
| Race (NIH/OMB) White | 17 Participants | 14 Participants | 17 Participants | 19 Participants | 7 Participants | 6 Participants | 80 Participants |
| Region of Enrollment Denmark | 0 Participants | 2 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 5 Participants |
| Region of Enrollment France | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 2 Participants | 7 Participants |
| Region of Enrollment Georgia | 2 Participants | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants | 8 Participants |
| Region of Enrollment Greece | 2 Participants | 1 Participants | 5 Participants | 9 Participants | 0 Participants | 2 Participants | 19 Participants |
| Region of Enrollment Israel | 2 Participants | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 7 Participants |
| Region of Enrollment Italy | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Lebanon | 4 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 8 Participants |
| Region of Enrollment Malaysia | 6 Participants | 4 Participants | 3 Participants | 4 Participants | 3 Participants | 2 Participants | 22 Participants |
| Region of Enrollment Morocco | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 2 Participants | 6 Participants |
| Region of Enrollment Netherlands | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Region of Enrollment Tunisia | 2 Participants | 0 Participants | 5 Participants | 4 Participants | 4 Participants | 0 Participants | 15 Participants |
| Region of Enrollment Turkey | 5 Participants | 7 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 16 Participants |
| Region of Enrollment United Kingdom | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants |
| Serum Ferritin | 3449.1 micrograms per liter STANDARD_DEVIATION 5093.24 | 1793.3 micrograms per liter STANDARD_DEVIATION 1844.72 | 981.4 micrograms per liter STANDARD_DEVIATION 951.29 | 1724.4 micrograms per liter STANDARD_DEVIATION 1857.66 | 945.8 micrograms per liter STANDARD_DEVIATION 962.09 | 447.8 micrograms per liter STANDARD_DEVIATION 222.32 | 1726.69 micrograms per liter STANDARD_DEVIATION 2740.18 |
| Sex: Female, Male Female | 15 Participants | 9 Participants | 10 Participants | 15 Participants | 6 Participants | 8 Participants | 63 Participants |
| Sex: Female, Male Male | 10 Participants | 11 Participants | 14 Participants | 14 Participants | 6 Participants | 4 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 25 | 0 / 20 | 0 / 24 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 25 / 29 | 22 / 25 | 15 / 20 | 18 / 24 | 12 / 12 | 6 / 12 |
| serious Total, serious adverse events | 1 / 29 | 3 / 25 | 1 / 20 | 3 / 24 | 0 / 12 | 0 / 12 |
Outcome results
Primary
IMR-687 Safety and Tolerability
Incidence and severity of Adverse Events Incidence and severity of Serious Adverse Events
Time frame: Baseline to Week 40
Population: Safety Analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TDT High Dose | IMR-687 Safety and Tolerability | Treatment emergent Adverse Event related to study drug | 19 Participants |
| TDT High Dose | IMR-687 Safety and Tolerability | Treatment emergent Adverse Events | 25 Participants |
| TDT High Dose | IMR-687 Safety and Tolerability | Grade 3 or greater treatment emergent Adverse Event | 4 Participants |
| TDT Low Dose | IMR-687 Safety and Tolerability | Treatment emergent Adverse Event related to study drug | 15 Participants |
| TDT Low Dose | IMR-687 Safety and Tolerability | Treatment emergent Adverse Events | 22 Participants |
| TDT Low Dose | IMR-687 Safety and Tolerability | Grade 3 or greater treatment emergent Adverse Event | 9 Participants |
| TDT Placebo | IMR-687 Safety and Tolerability | Treatment emergent Adverse Event related to study drug | 8 Participants |
| TDT Placebo | IMR-687 Safety and Tolerability | Treatment emergent Adverse Events | 15 Participants |
| TDT Placebo | IMR-687 Safety and Tolerability | Grade 3 or greater treatment emergent Adverse Event | 2 Participants |
| NTDT High Dose | IMR-687 Safety and Tolerability | Treatment emergent Adverse Event related to study drug | 11 Participants |
| NTDT High Dose | IMR-687 Safety and Tolerability | Treatment emergent Adverse Events | 18 Participants |
| NTDT High Dose | IMR-687 Safety and Tolerability | Grade 3 or greater treatment emergent Adverse Event | 4 Participants |
| NTDT Low Dose | IMR-687 Safety and Tolerability | Treatment emergent Adverse Event related to study drug | 7 Participants |
| NTDT Low Dose | IMR-687 Safety and Tolerability | Treatment emergent Adverse Events | 12 Participants |
| NTDT Low Dose | IMR-687 Safety and Tolerability | Grade 3 or greater treatment emergent Adverse Event | 1 Participants |
| NTDT Placebo | IMR-687 Safety and Tolerability | Treatment emergent Adverse Events | 6 Participants |
| NTDT Placebo | IMR-687 Safety and Tolerability | Grade 3 or greater treatment emergent Adverse Event | 1 Participants |
| NTDT Placebo | IMR-687 Safety and Tolerability | Treatment emergent Adverse Event related to study drug | 4 Participants |
Secondary
NTDT Patients: Proportion of Subjects With an Increase From Baseline of ≥3% in Mean HbF Values at Week 12 to Week 24 in Absence of Transfusions
Proportion of subjects with an increase from baseline of ≥3% in mean HbF values at Week 12 to Week 24 in absence of transfusions
Time frame: Baseline to Week 24
Population: Per Protocol Analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TDT High Dose | NTDT Patients: Proportion of Subjects With an Increase From Baseline of ≥3% in Mean HbF Values at Week 12 to Week 24 in Absence of Transfusions | 1 Participants |
| TDT Low Dose | NTDT Patients: Proportion of Subjects With an Increase From Baseline of ≥3% in Mean HbF Values at Week 12 to Week 24 in Absence of Transfusions | 1 Participants |
| TDT Placebo | NTDT Patients: Proportion of Subjects With an Increase From Baseline of ≥3% in Mean HbF Values at Week 12 to Week 24 in Absence of Transfusions | 0 Participants |
p-value: >0.99Fisher Exact
Secondary
NTDT Patients: Proportion of Subjects With an Increase From Baseline of Hb at Week 12 to Week 24 in the Absence of Transfusions.
Proportion of subjects with an increase from baseline of ≥1.0 g/dL in mean Hb values at Week 12 to Week 24 in the absence of transfusions.
Time frame: Baseline to Week 24
Population: Per protocol analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TDT High Dose | NTDT Patients: Proportion of Subjects With an Increase From Baseline of Hb at Week 12 to Week 24 in the Absence of Transfusions. | 0 Participants |
| TDT Low Dose | NTDT Patients: Proportion of Subjects With an Increase From Baseline of Hb at Week 12 to Week 24 in the Absence of Transfusions. | 0 Participants |
| TDT Placebo | NTDT Patients: Proportion of Subjects With an Increase From Baseline of Hb at Week 12 to Week 24 in the Absence of Transfusions. | 0 Participants |
p-value: >0.99Fisher Exact
Secondary
NTDT Patients: Proportion of Subjects With an Increase From Baseline of Hb at Week 24 to Week 36 in the Absence of Transfusions
Proportion of subjects with an increase from baseline of ≥1.0 g/dL in mean Hb values at Week 24 to Week 36 in the absence of transfusions.
Time frame: Baseline to Week 36
Population: Per Protocol Analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TDT High Dose | NTDT Patients: Proportion of Subjects With an Increase From Baseline of Hb at Week 24 to Week 36 in the Absence of Transfusions | 1 Participants |
| TDT Low Dose | NTDT Patients: Proportion of Subjects With an Increase From Baseline of Hb at Week 24 to Week 36 in the Absence of Transfusions | 1 Participants |
| TDT Placebo | NTDT Patients: Proportion of Subjects With an Increase From Baseline of Hb at Week 24 to Week 36 in the Absence of Transfusions | 0 Participants |
p-value: >0.99Fisher Exact
Secondary
NTDT: Proportion of Subjects With an Increase From Baseline of ≥3% in Mean HbF Values at Week 24 to Week 36 in Absence of Transfusions
Proportion of subjects with an increase from baseline of ≥3% in mean HbF values at Week 24 to Week 36 in absence of transfusions
Time frame: Baseline to Week 36
Population: Per Protocol Analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TDT High Dose | NTDT: Proportion of Subjects With an Increase From Baseline of ≥3% in Mean HbF Values at Week 24 to Week 36 in Absence of Transfusions | 1 Participants |
| TDT Low Dose | NTDT: Proportion of Subjects With an Increase From Baseline of ≥3% in Mean HbF Values at Week 24 to Week 36 in Absence of Transfusions | 0 Participants |
| TDT Placebo | NTDT: Proportion of Subjects With an Increase From Baseline of ≥3% in Mean HbF Values at Week 24 to Week 36 in Absence of Transfusions | 0 Participants |
p-value: >0.99Fisher Exact
Secondary
TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥33% Hematological Improvement From Week 12 to Week 24
Proportion of patients with ≥33% hematological improvement (as measured by reduced transfusion burden) from Week 12 to Week 24 compared to the 12 weeks prior to Baseline (Day 1)
Time frame: Baseline to Week 24
Population: Per Protocol Analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TDT High Dose | TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥33% Hematological Improvement From Week 12 to Week 24 | 2 Participants |
| TDT Low Dose | TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥33% Hematological Improvement From Week 12 to Week 24 | 1 Participants |
| TDT Placebo | TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥33% Hematological Improvement From Week 12 to Week 24 | 2 Participants |
p-value: >0.99Fisher Exact
Secondary
TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥33% Hematological Improvement From Week 24 to Week 36
Proportion of patients with ≥33% hematological improvement from Week 24 to Week 36 compared to the 12 weeks prior to Baseline (Day 1)
Time frame: Baseline to Week 36
Population: Per Protocol Analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TDT High Dose | TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥33% Hematological Improvement From Week 24 to Week 36 | 0 Participants |
| TDT Low Dose | TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥33% Hematological Improvement From Week 24 to Week 36 | 1 Participants |
| TDT Placebo | TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥33% Hematological Improvement From Week 24 to Week 36 | 1 Participants |
p-value: >0.4839Fisher Exact
Secondary
TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥50 % Hematological Improvement From Week 12 to Week 24
Proportion of patients with ≥50% hematological improvement from Week 12 to Week 24 compared to the 12 weeks prior to Baseline (Day 1)
Time frame: Baseline to Week 24
Population: Per Protocol Analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TDT High Dose | TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥50 % Hematological Improvement From Week 12 to Week 24 | 0 Participants |
| TDT Low Dose | TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥50 % Hematological Improvement From Week 12 to Week 24 | 0 Participants |
| TDT Placebo | TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥50 % Hematological Improvement From Week 12 to Week 24 | 2 Participants |
p-value: 0.2065Fisher Exact
Secondary
TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥50% Hematological Improvement From Week 24 to Week 36
Proportion of patients with ≥50% hematological improvement from Week 24 to Week 36 compared to the 12 weeks prior to Baseline (Day 1)
Time frame: Baseline to Week 36
Population: Per Protocol Analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TDT High Dose | TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥50% Hematological Improvement From Week 24 to Week 36 | 0 Participants |
| TDT Low Dose | TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥50% Hematological Improvement From Week 24 to Week 36 | 1 Participants |
| TDT Placebo | TDT Patients: Reduction in Red Blood Cell (RBC) Transfusion Burden With ≥50% Hematological Improvement From Week 24 to Week 36 | 1 Participants |
p-value: 0.4839Fisher Exact