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Study of Ataluren (PTC124) in Hemophilia A and B

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00947193
Recruitment Status : Terminated (Study was terminated early due to Sponsor decision and not reflective of adverse safety findings.)
First Posted : July 27, 2009
Results First Posted : June 16, 2020
Last Update Posted : June 16, 2020
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
PTC Therapeutics

Brief Summary:
Hemophilia A (HA) and hemophilia B (HB) are inherited bleeding disorders caused by mutations in the gene for factor VIII (FVIII) and factor IX (FIX), respectively. These proteins are essential for blood clotting. The lack of FVIII/FIX can produce bleeding episodes that cause damage of the bone, muscles, joints, and tissues. A specific type of mutation, called a nonsense (premature stop codon) mutation, is the cause of the disease in approximately 10-30% of participants with hemophilia and results in severe manifestations. Ataluren (PTC124) is an orally delivered, investigational drug that acts to overcome the effects of the premature stop codon, potentially enabling the production of functional FVIII/FIX. This study is a Phase 2a trial evaluating the safety and efficacy of ataluren in participants with HA or HB due to a nonsense mutation. The main purpose of this study is to understand whether ataluren can safely increase FVIII/FIX activity levels.

Condition or disease Intervention/treatment Phase
Hemophilia A Hemophilia B Drug: Ataluren Phase 2

Detailed Description:
In this study, participants with hemophilia A or hemophilia B due to a nonsense mutation were treated with an investigational drug called ataluren (PTC124). Evaluation procedures to determine if a participant qualifies for the study was performed within 14 days prior to the start of treatment. Eligible participants who elected to enroll in the study then participated in a 28-day treatment period. Within the 28-day period, ataluren (PTC124) treatment was to be taken for 2 cycles of 14 days each 3 times per day with meals at a dose level of 5, 5, 10 milligrams/kilograms (mg/kg) in the first cycle and a dose level of 20, 20, 40 mg/kg in the second cycle. After the first 14-day cycle, study doses were changed to 10 mg/kg (morning), 10 mg/kg (midday), and 20 mg/kg (evening) and the doses were administered for 1 cycle only. Then, there was an interval of approximately 14 days without treatment. During the study, ataluren (PTC124) efficacy, safety, and pharmacokinetics were evaluated periodically with measurement of FVIII/FIX activity and inhibitor levels, other blood tests, and urinalysis.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2a Study of Ataluren (PTC124) as an Oral Treatment for Nonsense-Mutation-Mediated Hemophilia A and B
Actual Study Start Date : October 14, 2009
Actual Primary Completion Date : August 30, 2011
Actual Study Completion Date : August 30, 2011

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia

Arm Intervention/treatment
Experimental: Ataluren Overall Study
Ataluren was provided as a vanilla-flavored powder to be mixed with water or milk. Ataluren was taken 3 times per day, with dosing based on the participant's body weight. The dose level for ataluren was 5 mg/kg in the morning, 5 mg/kg at midday, and 10 mg/kg in the evening or 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 14 days, followed by an interval of 14 days without treatment.
Drug: Ataluren
Oral powder
Other Name: PTC124

Primary Outcome Measures :
  1. Number of Participants With a Plasma FVIII/FIX Activity Response at Day 14 [ Time Frame: Baseline up to Day 14 ]
    A plasma FVIII/FIX activity response was defined as an end-of-treatment (Day 14) activity of ≥1%.

Secondary Outcome Measures :
  1. Number of Participants With a Change From Baseline in Plasma Anti-FVIII/FIX Inhibitor Titers at Day 14 [ Time Frame: Baseline and Day 14 ]
    To assess the change from Baseline in plasma anti-FVIII/FIX inhibitor titers, it was determined if any potential antibodies were neutralizing using the Bethesda assay. The Bethesda assay demonstrates antibodies that are neutralizing by quantifying residual FVIII/FIX activity in normal plasma after serial dilutions with participant plasma. For this assay, the neutralizing antibody threshold value was 0.6 Bethesda units (BU).

  2. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) by Severity and Relationship to Study Drug [ Time Frame: Baseline up to Day 28 ]
    The relationship of TEAEs and SAEs to the study drugs was assessed as: probable related, possible related, unlikely related, and unrelated. The severity of TEAEs were graded using the Common Terminology Criteria for Adverse Events, Version 3.0, as: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal). A summary of other non-serious adverse events (AEs) and all serious AEs, regardless of causality is located in Reported AE section.

  3. Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Hematology, Adrenal Assays, Biochemistry, and Urinalysis) Parameters [ Time Frame: Baseline up to Day 28 ]
    The Investigator used his/her judgment in determining whether an abnormality was clinically significant, diagnostic evaluation was warranted, and potential interruption of ataluren was appropriate. Life-threatening (Grade 4) or severe (Grade 3) laboratory abnormalities were considered dose-limiting, although recurrent or persistent moderate (Grade 2) events were also considered dose-limiting in certain circumstances. Values considered abnormal included -Hematology: Serum total bilirubin Grade 2 (>1.5-3.0*upper limit of normal [ULN]) and Serum alanine aminotransferase, Serum aspartate aminotransferase, and Serum gamma glutamyl transferase Grade 2 (>2.5-3.0*ULN); -Adrenal: Plasma adrenocorticotropic hormone >ULN (and cortisol within normal limits); and -Renal: serum creatinine Grade 1 (>ULN-1.5*ULN) and Serum blood urea nitrogen ≥1.5-3.0*ULN. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

  4. Compliance With Ataluren Administration [ Time Frame: Baseline up to Day 28 ]
    Ataluren compliance as assessed by quantification of used and unused drug. Data were not collected or analyzed for this measure because participants were terminated early from the study.

  5. Ataluren Plasma Exposure [ Time Frame: Day 10 (pre-dose) and Day 14 (post-dose) ]
    The ataluren plasma concentrations before and 2 hours after the first morning dose at end of treatment was measured.

  6. Occurrence of Bleeding Episodes [ Time Frame: Baseline up to Day 28 ]
    Frequency, timing, anatomic location, and severity of any bleeding episodes were recorded. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

Inclusion Criteria:

  • Ability to provide written informed consent
  • Age ≥18 years
  • Presence of a nonsense mutation as the sole disease-causing mutation in the FVIII or FIX gene
  • At least 20 prior treatments with FVIII or FIX concentrates
  • Willingness and ability to comply with scheduled visits, drug administration plan, study restrictions, and study procedures

Exclusion Criteria:

  • Known hypersensitivity to any of the ingredients or excipients of the study drug
  • Any history of prior anti-FVIII/FIX inhibitors
  • Unable or unwilling to forego prophylactic FVIII/FIX concentrate use during the screening and on-study periods (Note: Participants were allowed use of FVIII/FIX concentrates for treatment of bleeding episodes while on study)

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 identifier (NCT number): NCT00947193

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United States, Illinois
The Bleeding and Clotting Disorders Institute
Peoria, Illinois, United States, 61614
United States, Indiana
St. Vincent Indianapolis Hospital
Indianapolis, Indiana, United States, 46260
United States, Massachusetts
New England Hemophilia Center
Worcester, Massachusetts, United States, 01605
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Vanderbilt Hemostatis and Thrombosis Clinic
Nashville, Tennessee, United States, 37232
United States, Washington
Puget Sound Blood Center
Seattle, Washington, United States, 98104
Canada, British Columbia
St. Paul's Hospital
Vancouver, British Columbia, Canada, V6Z 1Y6
Hôpital Cardiologique
Lille Cedex, France
Hôpital Edouard Herriot
Lyon Cedex, France
Hôpital Necker Enfants Malades
Paris, France
Azienda Ospedaliero-Universitaria Careggi Viale G.B. Morgagni
Firenze, Italy
A.Bianchi Bonomi Hemophilia and Thrombosis Center
Milano, Italy
Sponsors and Collaborators
PTC Therapeutics
Genzyme, a Sanofi Company
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Principal Investigator: Jay Barth, MD PTC Therapeutics
Additional Information:
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Responsible Party: PTC Therapeutics Identifier: NCT00947193    
Other Study ID Numbers: PTC124-GD-011-HEM
First Posted: July 27, 2009    Key Record Dates
Results First Posted: June 16, 2020
Last Update Posted: June 16, 2020
Last Verified: May 2020
Keywords provided by PTC Therapeutics:
Hemophilia A
Hemophilia B
Factor VIII
Factor IX
Nonsense mutation
Premature stop codon
Additional relevant MeSH terms:
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Hemophilia A
Hemophilia B
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Genetic Diseases, X-Linked