Study of Ataluren (PTC124) in Hemophilia A and B

Hemophilia A Clinical Trial

Official title:

A Phase 2a Study of Ataluren (PTC124) as an Oral Treatment for Nonsense-Mutation-Mediated Hemophilia A and B

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00947193
• Other study ID #: PTC124-GD-011-HEM
• Status: Terminated
• Phase: Phase 2
• Start date: October 14, 2009
• Est. completion date: August 30, 2011

Study information

• Verified date: May 2020
• Source: PTC Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 13
• Est. completion date: August 30, 2011
• Est. primary completion date: August 30, 2011
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Hemophilia A
• Hemophilia B

Intervention

Drug:
• Ataluren
Oral powder

Locations

Country	Name	City	State
Canada	St. Paul's Hospital	Vancouver	British Columbia
France	Hôpital Cardiologique	Lille Cedex
France	Hôpital Edouard Herriot	Lyon Cedex
France	Hôpital Necker Enfants Malades	Paris
Italy	Azienda Ospedaliero-Universitaria Careggi Viale G.B. Morgagni	Firenze
Italy	A.Bianchi Bonomi Hemophilia and Thrombosis Center	Milano
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	St. Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	Vanderbilt Hemostatis and Thrombosis Clinic	Nashville	Tennessee
United States	The Bleeding and Clotting Disorders Institute	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Puget Sound Blood Center	Seattle	Washington
United States	New England Hemophilia Center	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
PTC Therapeutics	Genzyme, a Sanofi Company

Countries where clinical trial is conducted

United States,  Canada,  France,  Italy, 

References & Publications (2)

Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol. 2007 Apr;47(4):430-44. — View Citation

Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007 May 3;447(7140):87-91. Epub 2007 Apr 22. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With a Plasma FVIII/FIX Activity Response at Day 14	A plasma FVIII/FIX activity response was defined as an end-of-treatment (Day 14) activity of =1%.	Baseline up to Day 14
Secondary	Number of Participants With a Change From Baseline in Plasma Anti-FVIII/FIX Inhibitor Titers at 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).	Baseline and Day 14
Secondary	Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) by Severity and Relationship to Study Drug	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.	Baseline up to Day 28
Secondary	Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Hematology, Adrenal Assays, Biochemistry, and Urinalysis) Parameters	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.	Baseline up to Day 28
Secondary	Compliance With Ataluren Administration	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.	Baseline up to Day 28
Secondary	Ataluren Plasma Exposure	The ataluren plasma concentrations before and 2 hours after the first morning dose at end of treatment was measured.	Day 10 (pre-dose) and Day 14 (post-dose)
Secondary	Occurrence of Bleeding Episodes	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.	Baseline up to Day 28

External Links

•   PTC Therapeutics' website