| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054660 |
| E.1.2 | Term | Thalassemia beta |
| E.1.2 | System Organ Class | 100000004850 |
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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 |
| The primary objective of this study in both Population 1 (TDT - transfusion-dependent) and Population 2 (NTDT - non-transfusion-dependent) is to assess the safety and tolerability of IMR-687 in adult subjects with β-thalassemia. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives in Population 1 (TDT) subjects are:
• To evaluate the effect of IMR-687 versus placebo on reduction in red blood cell (RBC) transfusion burden.
• To evaluate the change in transfusional iron load rate of IMR-687 versus placebo.
• To characterize the pharmacokinetic (PK) profile of IMR-687.
The secondary objectives in Population 2 (NTDT) subjects are:
• To evaluate the effect of IMR-687 versus placebo on fetal hemoglobin (HbF).
• To evaluate the effect of IMR-687 versus placebo on anemia.
• To characterize the PK profile of IMR-687.
Please refer to the protocol for the Exploratory objectives. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for the study:
1. Subjects must understand and voluntarily provide informed consent and sign an informed consent form (ICF) prior to any study-related assessments/procedures being conducted. Although RBC transfusions and associated hemoglobine (Hb) laboratory measurements 12 weeks prior to the Screening visit are not study related, the ICF will specifically request subject consent to collect these data.
2. Subjects must be ≥18 to ≤65 years of age at the time of signing the ICF.
3. Subjects must have documented diagnosis of β-thalassemia or HbE/β-thalassemia. Concomitant single alpha gene deletion, duplication, or triplication is allowed.
4. For TDT subjects only: Subjects must be regularly transfused, defined as >3 to 10 RBC units in the 12 weeks prior to screening and no transfusion-free period for ≥35 days during that period.
For NTDT subjects only: Subjects must be transfusion independent, defined as 0 to ≤3 units of RBCs received during the 12-week period prior to randomization, 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 hematopoietic stem cell transplantation within 9 months.
5. Subjects must have documentation of dates of transfusions and the number of all RBC units within the 12 weeks prior to Screening.
6. Subjects must be willing and able to complete all study assessments and procedures, and to communicate effectively with the investigator and site staff.
7. Subjects must have Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1 (Appendix 1 of the protocol).
8. Female subjects must not be pregnant, not be breast feeding, and be highly unlikely to become pregnant. Male subjects must be unlikely to impregnate a partner. Detailed information is available in the protocol.
9. Subjects receiving hydroxyurea 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.
10. For NTDT subjects only: Subjects must have mean baseline Hb ≤10.0 g/dL, based on a minimum of 2 measurements ≥1 week apart within 4 weeks prior to randomization; Hb values within 21 days post-transfusion will be excluded.
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| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must be excluded from the study:
1. Any significant medical condition, lab abnormality, or psychiatric illness that would prevent the subject from participating in the study, including the presence of laboratory abnormalities that may place the subject at unacceptable risk if he/she were to participate in the study.
2. Any situation or condition that confounds the ability to interpret data from the study (e.g., subjects also receiving RBC transfusions at centers not able to obtain laboratory samples for central processing).
3. Diagnosis of α-thalassemia (e.g., HbH) or HbS/ β-thalassemia.
4. BMI <17.0 kg/m2 or a total body weight <45 kg; or BMI >35 kg/m2.
5. Subjects with known active HAV, HBV, or HCV, with active or acute event of malaria, or who are known to be positive for human immunodeficiency virus (HIV).
6. Stroke requiring medical intervention ≤24 weeks prior to randomization.
7. 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 least 28 days prior to randomization (Day 1); other oral anti-coagulants and anti-platelet drugs are permitted. Anti-coagulant therapies for prophylaxis of venous thromboembolism, including pulmonary emboli including when undergoing surgery or high-risk procedures, are allowed if low molecular weight heparins are used in the peri-operative period. Aspirin use is allowed before and during the study.
8. Treatment with an investigational drug or device or participation in an investigational drug or device study ≤28 days prior to randomization.
9. Platelet count >1000 × 10^9/L.
10. Subjects on iron chelation therapy (ICT) at the time of ICF signing must have initiated the treatment with ICT at least 24 weeks before the predicted randomization date. ICT can be initiated at any time during treatment and should be used according to the label.
11. Subjects who have had treatment with erythropoietin-stimulating agents ≤24 weeks prior to randomization.
12. Uncontrolled hypertension as defined by systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg, medical intervention indicated, and more than one drug or more intensive therapy than previously used indicated.
13. Poorly controlled diabetes mellitus as defined by 1) fructosamine levels of >340 μmol/L within 12 weeks prior to randomization; 2) short term hyperglycemia leading to hyperosmolar or ketoacidotic crisis; and/or 3) history of diabetic cardiovascular complications.
14. Subjects who have major organ damage, including:
a. Liver disease with ALT or AST >3× ULN, direct bilirubin >2× ULN, or history/evidence of cirrhosis, as well as presence of masses/tumor.
b. Heart disease, heart failure as classified by the New York Heart Association classification 3 or higher, or significant arrhythmia requiring treatment, or recent myocardial infarction within 6 months of randomization, or significant cardiac iron T2* <15 ms, or left ventricular ejection fraction <56%.
c. Severe lung disease, including pulmonary fibrosis or pulmonary hypertension, i.e., ≥Grade 3 NCI CTCAE version 5.0.
d. Estimated glomerular filtration rate <45 mL/min/1.73 m2 (per Modification of Diet in Renal Disease formula).
e. Nephrotic range proteinuria (>3 g/L).
15. Subjects who have received chronic systemic glucocorticoids ≤12 weeks prior to randomization (≥5 mg/day). Physiologic replacement therapy for adrenal insufficiency is allowed.
16. Major surgery ≤12 weeks prior to randomization (subjects must have completely recovered from any previous surgery prior to randomization).
17. 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).
18. History or current 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 yrs. 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)
19. Screening or Baseline (Day 1) ECG, demonstrating a QTcF >450 ms in men and >470 ms in women, or the presence of clinically significant ECG abnormalities as determined by the investigator.
Please refer to the protocol for exclusion criteria 20-24 |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
IMR-687 safety and tolerability as measured by:
• Incidence and severity of adverse events and serious adverse events
• Observed values and changes from baseline in 12-lead ECG parameters, clinical laboratory tests (chemistry, hematology, coagulation, urinalysis), and vital signs for any timepoint
• Physical examination findings
• Use of concomitant medications and therapies |
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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) |
Population 1:
* Proportion of subjects with a ≥20% hematological improvement from Week 12 to Week 24 and Week 24 to Week 36, compared to the 12- week prescreening timeframe.
* Proportion of subjects with a ≥20% hematological improvement from Week 12 to Week 36, compared to the 12-week prescreening timeframe.
* Proportion of subjects with a ≥33% hematological improvement from Week 12 to Week 24 and Week 24 to Week 36, compared to the 12- week prescreening timeframe.
* Proportion of subjects with a ≥33% hematological improvement from Week 12 to Week 36, compared to the 12-week prescreening timeframe.
* Mean number of transfusion events from baseline to Week 36 compared to placebo.
* The plasma PK profile of IMR-687 (and metabolites) after administration to subjects will be evaluated by determination of PK parameters (e.g., Cmax, tmax, t½, AUC0-24, AUClast, and AUC0-∞) based on drug concentration levels in plasma obtained over time.
* Mean change from baseline to Week 36, and proportion of subjects with improvement for iron chelation therapy daily dose and serum ferritin.
Population 2:
* The plasma PK profile of IMR-687 (and metabolites) after administration to subjects will be evaluated by determination of PK parameters (e.g., Cmax, tmax, t½, AUC0-24, AUClast, and AUC0-∞) based on drug concentration levels in plasma obtained over time.
* Mean change from baseline to Week 36, and proportion of subjects with improvement for iron chelation therapy daily dose and serum ferritin.
* Mean change in Hb and HbF concentrations from baseline to Week 24 and Week 36 in the IMR-687 group compared with the placebo group.
* Mean change in percent HbF at Week 24 and Week 36 compared to HbF at baseline in the IMR-687 group versus the placebo group.
* Subject response in HbF, where a responder has an increase of ≥3% at Week 24 compared to HbF at baseline in the IMR-687 group compared to the placebo group.
* Mean change in Hb and HbF concentrations over a continuous 12-week interval from Week 12 to Week 24 and Week 24 to Week 36 in the absence of transfusions in IMR-687 group compared with the placebo group.
Please refer to the protocol for the Exploratory Endpoints. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
In 12week intervals from Week 12 to Week 24 and Week 24 to Week 36 and troughout the study.
PK: Population 1 at Baseline, week 1, week 3, 24 and 36 (or End of Treatment visit); population 2 at Baseline, week 1, week 4, 24 and 36 (or End of Treatment visit) |
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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 | Yes |
| 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
| No |
| 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 |
| Australia |
| Denmark |
| Egypt |
| France |
| Georgia |
| Greece |
| India |
| Israel |
| Italy |
| Lebanon |
| Malaysia |
| Morocco |
| Netherlands |
| Tunisia |
| Turkey |
| United Kingdom |
| United States |
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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 | 0 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 11 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 5 |
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