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Study to Determine the Safety and Tolerability of Sotatercept (ACE-011) in Adults With Beta( β)- Thalassemia.

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ClinicalTrials.gov Identifier: NCT01571635
Recruitment Status : Active, not recruiting
First Posted : April 5, 2012
Last Update Posted : March 26, 2019
Sponsor:
Information provided by (Responsible Party):
Celgene

Brief Summary:
Dose finding study to determine the safety and tolerability of Sotatercept (ACE-011) in adults with Beta (β)-Thalassemia

Condition or disease Intervention/treatment Phase
Beta Thalassemia Major Beta Thalassemia Intermedia Drug: Sotatercept 0.1mg/kg Drug: Sotatercept 0.3mg/kg Drug: Sotatercept 0.5mg/kg Drug: Sotatercept 0.75mg/kg Drug: Sotatercept 1.0mg/kg Drug: Sotatercept 1.5mg/kg Drug: SOTATERCEPT (ACE-011) Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2a, Open-label, Dose Finding Study to Determine the Safety and Tolerability of SOTATERCEPT (ACE-011) in Adults With Beta (β)-Thalassemia
Actual Study Start Date : October 10, 2012
Actual Primary Completion Date : July 2, 2015
Estimated Study Completion Date : July 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Thalassemia

Arm Intervention/treatment
Experimental: Sotatercept dose level 0.1mg/kg
Experimental 0.1 mg/kg -Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period
Drug: Sotatercept 0.1mg/kg
Drug: SOTATERCEPT (ACE-011)
0.1 mg/kg to 0.5mg/kg Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period.
Other Name: (ACE-011)

Experimental: Sotatercept dose level 0.3mg/ kg
Experimental 0.3 mg/kg - Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period
Drug: Sotatercept 0.3mg/kg
Drug: SOTATERCEPT (ACE-011)
0.1 mg/kg to 0.5mg/kg Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period.
Other Name: (ACE-011)

Experimental: Sotatercept dose level 0.5mg/kg
Experimental 0.5 mg/kg -Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period
Drug: Sotatercept 0.5mg/kg
Drug: SOTATERCEPT (ACE-011)
0.1 mg/kg to 0.5mg/kg Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period.
Other Name: (ACE-011)

Experimental: Sotatercept dose level 0.75mg/kg
Experimental 0.75 mg/kg - Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period
Drug: Sotatercept 0.75mg/kg
Drug: SOTATERCEPT (ACE-011)
0.1 mg/kg to 0.5mg/kg Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period.
Other Name: (ACE-011)

Experimental: Sotatercept dose level 1.0mg/kg
Experimental 1.0 mg/kg -Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period
Drug: Sotatercept 1.0mg/kg
Drug: SOTATERCEPT (ACE-011)
0.1 mg/kg to 0.5mg/kg Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period.
Other Name: (ACE-011)

Experimental: Sotatercept dose level 1.5mg/kg
Experimental 1.5 mg/kg -Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period
Drug: Sotatercept 1.5mg/kg
Drug: SOTATERCEPT (ACE-011)
0.1 mg/kg to 0.5mg/kg Sotatercept will be administered as a subcutaneous injection once every 21 days during the treatment period.
Other Name: (ACE-011)




Primary Outcome Measures :
  1. Potential Recommended Dose (PRD) [ Time Frame: Up to 27 months ]
    The potential recommended dose (PRD) will be determined following the assessment of efficacy and safety parameters based on the first three doses of Sotatercept administered, up to at least 21 days following the first dose, for all doses evaluated. The PRD of Sotatercept will be defined as the highest dose level at which no more than one out of six subjects experiences a dose-limiting toxicity (DLT). The recommended dose of Sotatercept will be defined based on the review of the efficacy and safety parameters as well as dose modification data. The efficacy parameter is defined as: - for transfusion dependent B-Thalassemia major and intermedia : the reduction of transfusion burden by ≥ 20% compared to the calculated baseline transfusion burden to each subject ; - for non-transfusion dependent B-Thalassemia intermedia subjects : increase in Hgb level by ≥ 1 g/dl compared to the baseline Hgb, sustained for 12 weeks.

  2. Actual Recommended Dose (RD) [ Time Frame: Up to 27 months ]
    The RD of Sotatercept will be defined based on the review of the efficacy and safety parameters as well as dose modification data. The efficacy parameter is defined as: - for transfusion dependent B-Thalassemia major and intermedia : the reduction of transfusion burden by ≥ 20% compared to the calculated baseline transfusion burden to each subject ; - for non-transfusion dependent B-Thalassemia intermedia subjects : increase in Hgb level by ≥ 1 g/dl compared to the baseline Hgb, sustained for 12 weeks.


Secondary Outcome Measures :
  1. Reduction of Transfusion Burden [ Time Frame: Up to 27 months ]
    Assess the reduction of transfusion burden in transfusion dependent Beta-Thalassemia major and Intermedia subjects.

  2. Number of Participants with Adverse Events [ Time Frame: Up to 27 months ]
    Number of participants with adverse events

  3. PK-Observed Maximum Concentration (Cmax) [ Time Frame: Up to 16 samples over 27 months ]
    PK-observed maximum concentration (Cmax)

  4. PK-Time to Maximum Concentration (Tmax) [ Time Frame: Up to 16 samples over 27 months ]
    PK-Time to maximum concentration (Tmax)

  5. PK-Area Under the Concentration-Time Curve (AUC) [ Time Frame: Up to 16 samples over 27 months ]
    PK-Area under the concentration-time curve (AUC)

  6. PK-Concentration of Anti-Sotatercept Antibody in Serum [ Time Frame: Up to 16 samples over 27 months ]
    PK-Concentration of anti-sotatercept antibody in serum

  7. Hgb Level Increase [ Time Frame: Up to 27 months ]
    Hgb level increase during the study treatment compared to the baseline Hgb level in non-transfusion dependent Beta Thalassemia intermedia subjects.

  8. RBC Transfusion Burden [ Time Frame: Up to 27 months ]
    Reduction of transfusion burden by ≥ 20% compared to the calculated baseline transfusion burden for transfusion dependent Beta Thalassemia major and Beta Thalassemia Intermedia subjects.

  9. PK-Serum Concentration of Sotatercept [ Time Frame: Up to 16 samples over 27 months ]
    PK-Serum concentration of sotatercept



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men and women 18 years of age at the time of signing the informed consent document with a diagnosis of β-thalassemia major (including all subtypes) or β-thalassemia intermedia.
  • For transfusion dependent subjects: permanent transfusion dependency is defined as requiring packed red blood cells (pRBCs) and iron chelation therapy:

    • Average transfusion requirement of at least 2 units/30 days of pRBCs (Gale, 2011) confirmed for a minimum of 168 days (six months) immediately preceding enrollment (study Day 1, first Dose);
    • No transfusion-free period of more than 45 consecutive days during the 168 days immediately preceding enrollment (study Day 1, first Dose);
    • Prior transfusion hemoglobin levels ≤ 10.5 g/dL.
  • For non-transfusion dependent subjects: non-transfusion dependency is defined as a transfusion free for a minimum of 168 days immediately preceding enrollment (study Day 1, first Dose), with the exception of ≤ to one episode of transfusion in the period of a minimum of 168 days immediately preceding enrollment (study Day 1, first Dose) (One episode of transfusion is defined as ≤ 4 transfusion units administered, occurred within 42 days [first transfusion is counted as day 1] due to concurrent illness [e.g. infection], [Guidelines Clin Management of Thalassaemia, 2008]). (This inclusion criteria is not valid for France).
  • Performance status: Eastern Cooperative Oncology Group (ECOG) score of 0 to 1
  • No concurrent severe hepatic disease:

    • Aspartate Aminotransferase (AST) or Alanine Transaminase (ALT) no greater than 3 x upper limit of normal (ULN);
    • Albumin ≥ 3 g/dL.
  • Serum creatinine ≤ 1.5 x ULN.
  • Females of childbearing potential participating in the study are to use highly effective methods of birth control during study participation and for 112 days (approximately five times the mean terminal half-life of sotatercept [23 days] based on multiple-dose PK data) following the last dose of sotatercept. FCBP must have a negative serum beta Human Chorionic Gonadotropin (β-HCG) pregnancy test within three days of Sotatercept dosing (Day 1). Subjects must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of sotatercept. A FCBP is a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy or who has not been postmenopausal for at least 24 consecutive months (i.e., who has had menses at some time in the preceding 24 months).
  • Males must agree to use a latex condom during any sexual contact with FCBSs while participating in the study and for 112 days following the last dose of Sotatercept, even if he has undergone a successful vasectomy. Subjects must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of sotatercept.
  • Agreement to adhere to the study visit schedule, understand and comply with all protocol requirements.
  • Understand and provide written informed consent.

Exclusion Criteria:

  • Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing participating in the study.
  • Evidence of active Hepatitis C antibody (HCV), Hepatitis B surface antigen (HBsAg and HB core Ab), or Human Immunodeficiency Virus (HIV) antibody.
  • Known history of thromboembolic events ≥ Grade 3 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 (current active minor version).
  • Subjects with insulin dependent diabetes.
  • Subjects with major cardiac problems such as:

    • Major risk of heart failure, confirmed with myocardiac T2* ≤ 10 ms. Myocardiac T2* performed in the last one and a half years prior to subject enrollment (study Day 1, first Dose) will be considered valid.
    • Cardiac arrhythmia which requires treatment (i.e. atrial fibrillation).
  • Treatment with another investigational drug or device < 28 days prior to study entry.
  • Use of an Erythropoiesis Stimulating Agent (ESA) within the 28 days prior to enrollment (study Day 1, first Dose).
  • Subjects on hydroxyurea treatment for which the dose was changed in the last one year prior to subject enrollment (study Day 1, first Dose).
  • Subjects on anticoagulant therapy, such as warfarin.
  • Subjects who started bisphosphonates within the last three months prior to subject enrollment (study Day 1, first Dose).
  • Pregnant or lactating females.
  • Uncontrolled hypertension. Controlled hypertension for this protocol is considered ≤ Grade 1 according to NCI CTCAE version 4.0 (current active minor version) (Appendix B).
  • A history of major organ damage including:

    • Liver disease with ALT > 3x ULN or histopathological evidence of liver cirrhosis on liver biopsy;
    • Heart disease with ejection fraction ≥ Grade 2 according to NCI CTCAE version 4.0 (current active minor version);
    • Kidney disease with a calculated creatinine clearance < 40 mL/min (Cockcroft-Gault formula);
    • Pulmonary fibrosis or pulmonary hypertension as confirmed by a specialist.
  • Adrenal insufficiency.
  • Heart failure as classified by the New York Heart Association (NYHA) classification of 3 or higher (Appendix C).
  • Major surgery within 30 days prior to study Day 1 (subjects must have completely recovered from any previous surgery prior to study Day 1).
  • History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the Investigational Product (see Investigator Brochure).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01571635


Locations
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France
Hopital Henri Mondor
Créteil, France, 94010
Groupe Hospitalier Henri Mondor
Créteil, France
Hospital of Necker
Paris, France, 75015
Hôpital Necker-Enfants Malades
Paris, France
Greece
Laiko General Hospital
Ampelokipi - Athens, Greece, 11526
Italy
Universita degli Studi di Cagliari - ASL8
Cagliari, Italy, 09121
Universita Degli Studi Di Cagliari
Cagliari, Italy, 09121
Ospedale Galliera
Genoa, Italy, 16128
Ente Ospedaliero Ospedali Galliera
Genova, Italy, 16128
Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
Milano, Italy, 20122
Fondazione IRCCS Ospedale Maggiore
Milano, Italy, 20122
United Kingdom
UCL Cancer Institute
London, United Kingdom, WC1E 6BT
UCL Cancer Institue
London, United Kingdom, WC1E6BT
Sponsors and Collaborators
Celgene
Investigators
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Study Director: Abderrahmanne Laadem, CRP Celgene

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT01571635     History of Changes
Other Study ID Numbers: ACE-011-B-THAL-001
2011-005659-15 ( EudraCT Number )
First Posted: April 5, 2012    Key Record Dates
Last Update Posted: March 26, 2019
Last Verified: March 2019
Keywords provided by Celgene:
Beta-Thalassaemia
Additional relevant MeSH terms:
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Thalassemia
beta-Thalassemia
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn