Clinical trial NCT00947193: Study of Ataluren (PTC124) in Hemophilia A and B
Official title: A Phase 2a Study of Ataluren (PTC124) as an Oral Treatment for Nonsense-Mutation-Mediated Hemophilia A and B
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Hemophilia A
Hemophilia B
Keywords: Hemophilia A
Hemophilia B
Factor VIII
Factor IX
FVIII
FIX
Nonsense mutation
Premature stop codon
HA
HB
PTC124
Ataluren
Lead sponsor: PTC Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Genzyme, a Sanofi Company
First posted: 2009-07-27
Enrollment: 13
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Number of Participants With a Plasma FVIII/FIX Activity Response at Day 14
timeFrame: Baseline up to Day 14
Secondary outcomes:
measure: Number of Participants With a Change From Baseline in Plasma Anti-FVIII/FIX Inhibitor Titers at Day 14
timeFrame: Baseline and Day 14
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) by Severity and Relationship to Study Drug
timeFrame: Baseline up to Day 28
measure: Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Hematology, Adrenal Assays, Biochemistry, and Urinalysis) Parameters
timeFrame: Baseline up to Day 28
measure: Compliance With Ataluren Administration
timeFrame: Baseline up to Day 28
measure: Ataluren Plasma Exposure
timeFrame: Day 10 (pre-dose) and Day 14 (post-dose)
measure: Occurrence of Bleeding Episodes
timeFrame: Baseline up to Day 28
Other outcomes:
Locations:
city: Peoria
country: United States
facility: The Bleeding and Clotting Disorders Institute
state: Illinois
city: Indianapolis
country: United States
facility: St. Vincent Indianapolis Hospital
state: Indiana
city: Worcester
country: United States
facility: New England Hemophilia Center
state: Massachusetts
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Hemostatis and Thrombosis Clinic
state: Tennessee
city: Seattle
country: United States
facility: Puget Sound Blood Center
state: Washington
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Lille Cedex
country: France
facility: Hôpital Cardiologique
city: Lyon Cedex
country: France
facility: Hôpital Edouard Herriot
city: Paris
country: France
facility: Hôpital Necker Enfants Malades
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria Careggi Viale G.B. Morgagni
city: Milano
country: Italy
facility: A.Bianchi Bonomi Hemophilia and Thrombosis Center
Study officials:
affiliation: PTC Therapeutics
name: Jay Barth, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. doi: 10.1177/0091270006297140.
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. doi: 10.1038/nature05756. Epub 2007 Apr 22.