LBCTR : Trial details

A Phase 2 Study to Evaluate the Safety and Tolerability of IMR-687 in Subjects with Beta Thalassemia

Current status: Approved | Date registered: 02/10/2020

Trial version(s)

Current: 24/02/2020

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Main Information

Primary registry identifying number

LBCTR2020093402

Protocol number

IMR-BTL-201

MOH registration number

Trial already registered with the MoPH

Study registered at the country of origin

Type of registration

Prospective

Date of registration in national regulatory agency

Primary sponsor

IMARA, Inc.

Primary sponsor: Country of origin

116 Huntington Avenue, 6th Floor Boston, MA 02116

Public title

A Phase 2 Study to Evaluate the Safety and Tolerability of IMR-687 in Subjects with Beta Thalassemia

Acronym

Scientific title

A Phase 2 Study to Evaluate the Safety and Tolerability of IMR-687 in Subjects with Beta Thalassemia

Acronym

Brief summary of the study: English

This is a phase 2 study intended to explore the potential use of IMR-687 to treat subjects with β-thalassemia. This is the first study of IMR-687 in a β-thalassemia population, and, as such, is designed to examine the safety, tolerability, and PK, as well as the potential PD effects, of IMR-687 administered once daily for 36 weeks in adult subjects with β-thalassemia.

Brief summary of the study: Arabic

هذه دراسة مرحلة 2 تهدف إلى استكشاف الاستخدام المحتمل لـ IMR-687 لعلاج الأشخاص المصابين به β-الثلاسيميا. هذه هي الدراسة الأولى من IMR-687 في عدد سكان β الثلاسيمية ، وعلى هذا النحو ، هي مصمم لدراسة السلامة والتسامح والحرائك الدوائية ، فضلاً عن الآثار المحتملة للديناميكا الدوائية ، الخاصة بـ IMR-687 تدار مرة واحدة يوميًا لمدة 36 أسبوعًا في الأشخاص البالغين المصابين بالثلاسيمية بيتا.

Health conditions/problem studied: Specify

Reduced Hb in red blood cells (RBCs), decreased RBC production, and anemia due to reduced or absent synthesis of the β chain of hemoglobin (Hb) and mutations in the hemoglobin beta (HBB) gene in subjects with β-thalassemia.

Interventions: Specify

This study will enroll approximately 120 subjects with β-thalassemia (60 subjects with TDT and 60 subjects with NTDT), aged 18 through 65 years.Subjects will receive either IMR-687 (lower dose [≥3.0 to ≤4.5 mg/kg] or higher dose [>4.5 to ≤6.7 mg/kg]) or placebo in a blinded fashion. Subjects will be randomly assigned in a 2:1 ratio to receive either IMR-687 lower dose or placebo. Prior to the introduction of IMR-687 higher dose, the DMC will review safety data for at least 5 subjects who received IMR-687. If the DMC recommends inclusion of the higher dose, randomization will then proceed in a 1:2:1 ratio (IMR- 687 lower dose, IMR-687 higher dose, or placebo). The DMC may request additional data and/or meeting(s) in order to make the recommendation on whether to move forward with inclusion of the higher dose.

Key inclusion and exclusion criteria: 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 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 units1 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 units1 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). 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. 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 spontaneousamenorrhea 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 consent through 3 months after the completion of study therapy. True abstinence is defined as abstinence that is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of the study, and withdrawal are not acceptable methods of contraception. Acceptable methods of highly effective birth control are combined or progestogen-only hormonal contraception that is associated with inhibition of ovulation, intrauterine device, and intrauterin hormone-releasing system. 9. Subjects receiving hydroxyurea musthave 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.

Key inclusion and exclusion criteria: Gender

Both

Key inclusion and exclusion criteria: Age minimum

Key inclusion and exclusion criteria: Age maximum

Key inclusion and exclusion criteria: Exclusion criteria

Subjects meeting any of the following criteria must be excluded from the study: 1. Any significant medical condition, laboratory 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., hemoglobin H [HbH]) or hemoglobin S (HbS)/ β-thalassemia. 4. Body mass index (BMI) <17.0 kg/m² or a total body weight <45 kg; or BMI >35 kg/m². 5. 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). 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 × 10⁹/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 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) 19. Screening or Baseline (Day 1) electrocardiogram (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. 20. Consumption/use of the following drugs or other substances within the specified time periods before randomization or plans to consume/use at any time during the study. If there is any question as to whether a substance is permitted, please review the product labelling (if applicable) and consult the medical monitor and/or sponsor. a. PDE type 5 inhibitors (including but not limited to sildenafil, tadalafil, and vardenafil) within 7 days prior to randomization (Day 1) or plans to use during the study. b. Grapefruit, grapefruit juice, grapefruit products, or herbal supplements with CYP-altering abilities within 1 week prior to randomization (Day 1) or plans to consume during the study. c. CYP3A-sensitive substrates, including the synthetic opioid fentanyl and alfentanil, or moderate to strong CYP3A inhibitors or inducers within 28 days prior to randomization (Day 1) or plans to use during the study. d. Any drugs or substances known to be substrates or inhibitors of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) within 28 days prior to randomization (Day 1) or plans to use during the study. 21. Other prior or ongoing medical condition, physical findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the subject, make it unlikely that the course of treatment or follow-up would be completed, or impair the assessment of study results (e.g., a history of drug or alcohol abuse as judged by the investigator within the past 1 year). 22. Any clinically significant bacterial, fungal, parasitic, or viral infection requiring antibiotictherapy should delay screening/randomization (Day 1) until the course of antibiotic therapy has been completed. This includes but is not limited to long-term tuberculosis treatment. 23. Prior exposure to sotatercept, luspatercept, IMR-687, or gene therapy. 24. In the opinion of the investigator, the subject is unable to meet the requirements of the study.

Type of Study

Type

Interventional

Type of intervention

Pharmaceutical

Trial scope

Therapy

Trial scope: Specify scope

Study design: Allocation

Randomized controlled trial

Study design: Masking

Blinded (masking used)

Study design: Control

Placebo

Study phase

Study design: Purpose

Other

Study design: Specify purpose

safety and tolerability

Study design: Assignment

Parallel

IMP has market authorization

Name of IMP

IMR-687

Type of IMP

Cell therapy

Pharmaceutical class

IMR-687 is a potent, specific, and highly selective small molecule inhibitor of phosphodiesterase (PDE) 9; PDE9 mediates cellular signaling pathways by degrading cyclic guanosine monophosphate (cGMP) to its inactive or monophosphate form.

Therapeutic indication

Treatment of adults with either transfusion dependent or non-transfusion dependent β-thalassemia

Therapeutic benefit

This is the first study of IMR-687 in β-thalassemia subjects; therefore, the primary objective of this study is to determine the safety and tolerability of qd oral doses of IMR-687 across several doses anticipated to be pharmacologically active.Potential benefits of IMR-687 include addressing the missing or decreased presence of the beta globin subunit by pharmacologic induction of HbF production. In addition to resolving persistent anemia, HbF induction rectifies the missing or mutated beta globin subunit and thereby reduces the overabundance of free-floating alpha globin subunits. These benefits have the potential to result in increased functional RBC production, higher Hb levels, reduced hemolysis and the reduction of adhesion and inflammation.

Biospecimen retention

Samples without DNA

Biospecimen description

Blood samples will be collected for serum virology (screening assessment) only if clinically indicated. Testing will be performed through a central laboratory and may include hepatitis B surface antigen (HBsAg), hepatitis A immunoglobulin M (IgM), and hepatitis C virus (HCV) antibody, as well as HIV testing also for hematology,PD, PK, clinical chemistry and coagulation. Urine will be assessed for appearance, color, pH, specific gravity, ketone, protein, glucose,bilirubin, and urobilinogen, including occult blood and microscopic examination of sediment(only if occult blood is detected).

Target sample size

120

Actual enrollment target size

Date of first enrollment: Type

Anticipated

Date of first enrollment: Date

01/10/2020

Date of study closure: Type

Anticipated

Date of study closure: Date

01/10/2021

Recruitment status

Pending

Date of completion

IPD sharing statement plan

Yes

IPD sharing statement description

The sponsor assures that the key design elements of this protocol will be posted in a publicly accessible database such as ClinicalTrials.gov. The clinical study report will be submitted to the IRBs/IECs and regulatory authorities within one year of the end of the study (worldwide). The detailed obligations regarding the publication of any data, material results, or other information generated or created in relation to the study shall be set out in the agreement between each investigator and the sponsor.

Additional data URL

Summary Results

Secondary Identifying Numbers

Full name of issuing authority	Secondary identifying number
FDA US IND	130549
EMA	2019-002989-12

Sources of Monetary or Material Support

Name
IMARA Inc.

Secondary Sponsors

Name

Contact for Public/Scientific Queries

Contact type	First name	Last name	Address	Country	Telephone	Email	Affiliation
Public	Aziz	Zoghbi	MCT-CRO, Berytech Technology and Health, 5th Floor Damascus Road, Beirut, Lebanon	Lebanon	009611612 500	zog_az@mctcro. com	Regional Manager
Scientific	Ali	Taher	Chronic Care Center, Hazmieh, Lebanon	Lebanon	009613755 669	ataher@aub.edu. lb	Principal Investigator

Centers/Hospitals Involved in the Study

Center/Hospital name	Name of principles investigator	Principles investigator speciality	Ethical approval
Chronic Care Center	Dr.Ali Taher	Professor of Medicine, Hematology & Oncology	Approved

Ethics Review

Ethics approval obtained	Approval date	Contact name	Contact email	Contact phone
Chronic Care Center	24/06/2020	Michelle Abi Saad	cccmas@chroniccare.org.lb	9615455101
American University of Beirut Medical Center	28/07/2020	Dr Deborah Mukherji	irb@aub.edu.lb	961350000 ext 5445

Countries of Recruitment

Name
Italy
France
Greece
Denmark
Turkey
Tunisia
Egypt
Morocco
Lebanon
Georgia
Malaysia
United Kingdom
Netherlands
United States of America

Health Conditions or Problems Studied

Condition	Code	Keyword
TDT and NTDT Thalassemia	Thalassaemia (D56)	Thalassemia

Interventions

Intervention	Description	Keyword
100, 150, or 200 mg white tablets of IMR-687	Subjects will be advised to take two IMR-687 tablets orally with food qd for 36 weeks. In order to maintain an exposure of ≥3.0 to ≤4.5 mg/kg, subjects in the lower dose group weighing <67 kg will be dispensed 100 mg tablets and those weighing ≥67 kg will be dispensed 150 mg tablets. In order to maintain an exposure of >4.5 to ≤6.7 mg/kg, subjects in the higher dose group weighing <67 kg will be dispensed 150 mg tablets and those weighing ≥ 67 kg will be dispensed 200 mg tablets. The different doses of IMR-687 are visually identical in tablet form. Placebo will consist of tablets containing matrix absent IMR-687 and will be identical in appearance to the IMR-687 tablets. Subjects will be advised to take two placebo tablets orally with food qd for 36 weeks.	IMR-687

Primary Outcomes

Name	Time points	Measure
Changes in Vital Signs	Vital signs will be taken predose and 12 hours (±20 minutes) postdose on Day 1 and Week 3 for TDT subjects and on Day 1 and Week 4 for NTDT subjects (during PK assessments). At all other timepoints, vital signs can be taken irrespective of taking study drug.	heart rate, respiratory rate, blood pressure, and body temperature
Changes from baseline in 12-Lead-ECG	ECGs to be performed in triplicate. At Baseline and at Weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36, ECGs will be obtained at predose and 2 hours (±30 minutes) postdose. At all other timepoints, ECGs can be taken irrespective of taking study drug.	heart rate, PR interval, QRS duration, QT interval, and QTcF interval
Incidence and severity of Adverse Event and Serious Adverse Event.	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 (Week 40).	AEs will be coded using MedDRA: Abnormal test findings ,Clinically significant symptoms and signs, Changes in physical examination findings, Hypersensitivity ,Drug abuse ,Drug dependency, Drug overdose , Drug withdrawal , Drug misuse, Drug interactions, Extravasation , Exposure during pregnancy , Exposure via breastfeeding , Medication error
Physical Examinations findings	Complete PEs will be performed at Screening, Week 24, and Week 36 and will include a general examination 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.	general examination of the body, including the abdomen, heart, lungs, lymph nodes, back/neck, neurological system, skin, extremities, head, eyes, nose, and throat.
Changes in Clinical laboratory variables	over 36 week treatment	hematology,coagulation,serum chemistry, urinalysis and pregnancy test.

Key Secondary Outcomes

Name	Time points	Measure
Quality of life	at Baseline and at Weeks 12, 24, and 36.	TranQOL and SF-36 QoL tools in the TDT population and the NTDT-PRO and SF-36 QoL tools in the NTDT population
Pharmacokinetic Analyses	At Baseline (all subjects) and either Week 3 (TDT) or Week 4 (NTDT), serial blood samples will be drawn pre-dose (within 30 minutes) and at 30 minutes (±5 minutes), 1.5 hours (±15 minutes), 4 hours (±15 minutes), 6 hours (±1 hour) and 24 hours (±2 hours) after administration of study drug. A trough blood sample will be drawn pre-dose at Week 1, Week 24, and Week 36.	Maximum concentration (Cmax); Time to maximum concentration (tmax); Apparent terminal half-life (t½); and • AUC from time 0 to 24 hours (AUC(0-24)), 0 to the last measurable timepoint (AUClast), and extrapolated to infinity (AUC(0-∞)).
Pharmacodynamic markers	Blood samples should be obtained prior to administration of study drug. PD markers will need to be collected prior to each RBC transfusion (if applicable)	1) serum ferritin, soluble transferrin receptor, hepcidin-25, and haptoglobin levels; 2) WBC adhesion markers: sE-sel, sP-sel, sICAM-1; VCAM-1, hsCRP; 3) cardiovascular marker: serum NT-proBNP.

Trial Results

Summary results in Lebanon

Study results globally

Date of posting of results summaries

Date of first journal publication of results

Results URL link

Baseline characteristics

Participant flow

Adverse events

Outcome measures

URL to protocol files

Link(s) to publications related to the study

Changes History

Change	Date

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Trial details

A Phase 2 Study to Evaluate the Safety and Tolerability of IMR-687 in Subjects with Beta Thalassemia

Current status: Approved | Date registered: 02/10/2020

Main Information

Secondary Identifying Numbers

Sources of Monetary or Material Support

Secondary Sponsors

Contact for Public/Scientific Queries

Centers/Hospitals Involved in the Study

Ethics Review

Countries of Recruitment

Health Conditions or Problems Studied

Interventions

Primary Outcomes

Key Secondary Outcomes

Trial Results

Changes History

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