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Trial details
A Phase 2a, Randomized, Open-Label Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ISIS 702843 Administered Subcutaneously to Patients with Non-Transfusion Dependent β-Thalassemia Intermedia
Current status:
Approved
|
Date registered:
09/09/2020
Trial version(s)
Current: 03/10/2019
Click here to view the tips and fields' descriptions
Main Information
Primary registry identifying number
LBCTR2020071296
Protocol number
ISIS 702843-CS2
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
Ionis Pharmaceuticals, Inc.
Primary sponsor: Country of origin
USA
Public title
A Phase 2a, Randomized, Open-Label Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ISIS 702843 Administered Subcutaneously to Patients with Non-Transfusion Dependent β-Thalassemia Intermedia
Acronym
Scientific title
A Phase 2a, Randomized, Open-Label Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ISIS 702843 Administered Subcutaneously to Patients with Non-Transfusion Dependent β-Thalassemia Intermedia
Acronym
Brief summary of the study: English
This is a Phase 2a, Randomized, Open-Label Study.The primary objective is to evaluate the Efficacy of antisense inhibitor of TMPRSS6 (ISIS 702843) by demonstrating an improvement in plasma hemoglobin (Hb) concentration at Week 27 of treatment,at Week 53 of treatment.The secondary objectives are to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ISIS 702843 Administered Subcutaneously to Patients with Non-Transfusion Dependent β-Thalassemia Intermedia
Brief summary of the study: Arabic
هذه الدراسة في المرحلة 2 أ ، دراسة عشوائية مفتوحة التسمية. الهدف الرئيسي هو تقييم فعالية مثبط العقاقير من TMPRSS6 (ISIS 702843) من خلال إظهار تحسن في تركيز الهيموغلوبين في البلازما (Hb) في الأسبوع 27 من العلاج ، في الأسبوع 53 من العلاج الأهداف الثانوية هي تقييم السلامة ، التحمل ، الدوائية والديناميكا ISIS 702843 تحت الجلد ل المرضى الذين يعانون من عدم نقل الدم β-الثلاسيميا إنترميديا
Health conditions/problem studied: Specify
Chronic anemia due to ineffective erythropoiesis (IE) in subjects with β thalassemia
Interventions: Specify
The study will comprise 3 cohorts – Cohorts A, B, and C – of approximately 12 eligible patients per cohort:Cohort A (30 mg ISIS 702843), Cohort B (50 mg ISIS 702843), or Cohort C (80 mg ISIS 702843) in a ratio of 1:1:1.Each patient will be treated for up to 2 years, receiving up to 27 doses of ISIS 702843, with a planned 28-day interval between each dose.
Key inclusion and exclusion criteria: Inclusion criteria
1. Patient must have given written informed consent and be able to comply with all study requirements 2. Aged 18-65 years old, inclusive, at the time of informed consent 3. Clinical diagnosis of β-Thalassemia Intermedia with genotypic confirmation of β-globin gene mutations including but not limited to Hemoglobin E (HbE)/β-thalassemia 4. Patient must be non-transfusion dependent as defined by: No more than 6 transfusions in the past 12-month period, and no transfusions in the 8-week period prior to Day 1 5. Mean Hb within the range 6.0-10.0 g/dL, inclusive, with this mean based on all Hb measurements taken in the Screening Period that are at least 6 weeks after the most recent transfusion for that patient. This mean must be based on at least 2 Hb measurements 6. LIC within the range of 3.0-20.0 mg Fe/g dry weight, inclusive 7. Chelators will be permitted provided the patient has been on a stable dose for at least 3 months prior to Day 1, with LIC > 5.0 mg Fe/g dry weight and serum ferritin > 300 ng/mL 8.Females must be non-pregnant and non-lactating, and one of the following: (i) surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), (ii) postmenopausal (defined as 12 months of spontaneous amenorrhea without an alternative medical cause and follicle stimulating hormone [FSH] levels in the postmenopausal range for the laboratory involved), (iii) abstinent, or (iv) if engaged in sexual relations of child-bearing potential, the patient must be using a highly effective contraceptive method from the time of signing the informed consent form until at least 13 weeks after the last dose of ISIS 702843 Males must be one of the following: (i) surgically sterile, (ii) abstinent, or (iii) if engaged in sexual relations with a female of child-bearing potential, the patient must be using a highly effective contraceptive method from the time of signing the informed consent form until at least 13 weeks after the last dose of ISIS 702843.
Key inclusion and exclusion criteria: Gender
Both
Key inclusion and exclusion criteria: Age minimum
18
Key inclusion and exclusion criteria: Age maximum
65
Key inclusion and exclusion criteria: Exclusion criteria
1. Genotypic confirmation of either α-globin gene triplication or sickle hemoglobin (HbS)/β-thalassemia, as determined by genetic assessment of blood-related disorders 2. Clinically significant abnormalities in medical history or physical examination, which at the discretion of the PI will pose significant additional risk to the patient in participating in the study 3. Clinically significant abnormalities in Screening laboratory values that would render a patient unsuitable for inclusion, at the discretion of the PI 4. Current use of iron-chelation therapy if LIC is 3.0–5.0 mg Fe/g dry weight, inclusive, or if serum ferritin ≤ 300 ng/mL 5. Symptomatic splenomegaly, including abdominal pain or organ obstruction, or evidence of hypersplenism, such as low white blood cell (WBC) count and/or low platelets 6. Platelet count < LLN, or platelet count > 1,000 x 109/L 7. Significant concurrent/recent coagulopathy; history of non-traumatic significant bleeding; history of immune thrombocytopenic purpura (ITP); current use of SC anti-coagulants; history of thrombotic events, including stroke or deep vein thrombosis (DVT) 8. Clinically significant renal dysfunction which at the discretion of the PI will pose significant additional risk to the patient in participating in the study 9. Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2, using CKD-EPI 10. Clinically significant liver function test (LFT) abnormalities 11. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)> 3.0 × ULN 12. Historical diagnosis of cirrhosis, or current signs and symptoms of cirrhosis 13. Fasting blood glucose > 2.0 × ULN 14. Significant pulmonary hypertension (PHT) defined as tricuspid regurgitation > 3.0 meters per second (m/s) on echocardiography and/or requiring treatment 15. Uncontrolled hypertension (which for this protocol is considered > 140 mm Hg systolic or > 90 mm Hg diastolic) 16. Heart failure class 3 or higher (New York Heart Association, NYHA) 17. Ejection fraction < 50% by echocardiogram, multigated acquisition (MUGA), or cardiac magnetic resonance imaging (MRI) 18. Patients unable to have MRI performed, for example, because of a pacemaker or implantable cardioverter-defibrillator (MRI is being used to measure LIC) 19. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Day 1 20. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C (unless treatment has caused the patient to test negative for hepatitis C), or chronic hepatitis B 21. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator 22. Recent introduction of hydroxyurea (within 6 months prior to Day 1) 23. Treatment with or exposure to another investigational drug, biological agent, ASO, small interfering ribonucleic acid (siRNA), or device within one month of Screening, or 5 half-lives of investigational agent, whichever is longer; or: -Treatment with or exposure to sotatercept (ACE-011), luspatercept (ACE-536), or ruxolitinib within 4 months of Screening -Treatment with or exposure to hematopoietic stimulating agents (e.g., EPOs) or any hypoxia-inducible factor prolyl hydroxylase inhibitors -Prior bone marrow transplant, stem cell transplant, or gene therapy 24. Regular use of alcohol within 6 months prior to Screening (> 7 drinks/wk for females, > 14 drinks/wk for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) 25. Surgery associated with significant blood loss within 4 months of Screening, splenectomy within 12 months of Screening, or splenectomy scheduled during the Treatment Period 26. Use of iron supplements, including iron-containing vitamins, within 4 months of Screening 27. Pregnant or lactating 28. Have any other conditions which, in the opinion of the PI, would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing 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
Open (masking not used)
Study design: Control
N/A
Study phase
2
Study design: Purpose
Treatment
Study design: Assignment
Single
IMP has market authorization
No
Name of IMP
ISIS 702843
Type of IMP
Others
Type of IMP: Specify
Antisense Oligonucleotide
Pharmaceutical class
ISIS 702843 is an antisense inhibitor of transmembrane protease, serine 6 (TMPRSS6)
Therapeutic indication
Anemia and Iron overload in patients with Non-Transfusion Dependent β-Thalassemia Intermedia
Therapeutic benefit
Administration of PTG-300 may result in iron redistribution in β-thalassemia subjects with potentially beneficial effects on erythropoiesis and consequently improvements in chronic anemia. This improvement in ineffective erythropoiesis may result in a clinical benefit for NTD β-thalassemia intermedia subjects, by improving the symptomatology of the chronic anemia and the complications of the extramedullary hematopoiesis in the first group and by decreasing the need for transfusions in the latter.
Biospecimen retention
Samples with DNA**
Biospecimen description
blood sample will be taken for genotyping of B-globin variants and a genetic assessment of blood-related disorders that will include determination of α-globin copy number and whether the patient has exclusionary sickle hemoglobin (HbS)/B-thalassemia. Blood and urine samples will be collected regularly throughout the study for efficacy, safety, PK, and PD analyses.
Target sample size
36
Actual enrollment target size
Date of first enrollment: Type
Anticipated
Date of first enrollment: Date
17/02/2020
Date of study closure: Type
Anticipated
Date of study closure: Date
31/12/2022
Recruitment status
Pending
Date of completion
IPD sharing statement plan
Yes
IPD sharing statement description
Medical records of study subjects are stored and treated as confidential. The study site will record basic personal details including name, contact details, gender, height, weight, year of birth, age, ethnicity, and racial origin (to be used only for clinical purposes), as well as information on medical history, and clinical data collected about participation in the study. Medical records and other personal information will be treated as confidential.
Additional data URL
None
Summary Results
Secondary Identifying Numbers
Full name of issuing authority
Secondary identifying number
Food and Drug Administration
EudraCT #: 2019-003505-96
Sources of Monetary or Material Support
Name
Ionis Pharmaceuticals, Inc.
Secondary Sponsors
Name
Not Applicable
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
009611612500
zog_az@mctcro. com
Regional Manager
Scientific
Ali
Taher
Chronic Care Center, Hazmieh, Lebanon
Lebanon
009613755 669
ataher@aub.edu. lb
PI
Centers/Hospitals Involved in the Study
Center/Hospital name
Name of principles investigator
Principles investigator speciality
Ethical approval
Chronic Care Center
Dr. Ali Taher
Hematology/Oncology
Approved
Ethics Review
Ethics approval obtained
Approval date
Contact name
Contact email
Contact phone
American University of Beirut Medical Center
05/05/2020
Dr Deborah Mukherji
irb@aub.edu.lb
01-350000 ext 5445
Chronic Care Center
24/06/2020
Michele Abi Saad
cccmas@chroniccare.org.lb
05-455101
Countries of Recruitment
Name
Canada
Australia
Greece
Turkey
Thailand
Lebanon
Health Conditions or Problems Studied
Condition
Code
Keyword
Thalassemia
Thalassaemia (D56)
thalassemia
Interventions
Intervention
Description
Keyword
ISIS 702843
27 doses of 30 mg/0.3 mL
Cohort A
ISIS 702843
27 doses of 50 mg/0.5 mL
Cohort B
ISIS 702843
27 doses of 80 mg/0.8 mL
Cohort C
Primary Outcomes
Name
Time points
Measure
HB ≥ 1.0 g/dL
Week 27 of treatment
Hemoglobin test
Key Secondary Outcomes
Name
Time points
Measure
HB ≥ 1.5 g/dL increase from Baseline
Week 53 of treatment
Hemoglobin test
LIC ≥ 1.0 mg Fe/g dry weight decrease from Baseline
Week 53 of treatment
LIC measured by MRI
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
Download as PDF
Save a PDF copy of the summary of the trial