Study of Ataluren (PTC124) in Hemophilia A and B

• Sponsor: PTC Therapeutics (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00947193
• Collaborator: Genzyme, a Sanofi Company (Industry)
• Enrollment: 13
• Locations: 13
• Arm: 1
• Actual Duration (Months): 22.5
• Patient Per Site: 1
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Oct 14, 2009
• Actual Primary Completion Date: Aug 30, 2011
• Actual Study Completion Date: Aug 30, 2011

Arms and Interventions

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 Names: PTC124

Outcome Measures

Primary Outcome Measures

1. Number of Participants With a Plasma FVIII/FIX Activity Response at Day 14 [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 [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 [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 [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 [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 [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 [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Bleeding and Clotting Disorders Institute	Peoria	Illinois	United States	61614
2	St. Vincent Indianapolis Hospital	Indianapolis	Indiana	United States	46260
3	New England Hemophilia Center	Worcester	Massachusetts	United States	01605
4	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
5	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
6	Vanderbilt Hemostatis and Thrombosis Clinic	Nashville	Tennessee	United States	37232
7	Puget Sound Blood Center	Seattle	Washington	United States	98104
8	St. Paul's Hospital	Vancouver	British Columbia	Canada	V6Z 1Y6
9	Hôpital Cardiologique	Lille Cedex		France
10	Hôpital Edouard Herriot	Lyon Cedex		France
11	Hôpital Necker Enfants Malades	Paris		France
12	Azienda Ospedaliero-Universitaria Careggi Viale G.B. Morgagni	Firenze		Italy
13	A.Bianchi Bonomi Hemophilia and Thrombosis Center	Milano		Italy

Sponsors and Collaborators

• PTC Therapeutics
• Genzyme, a Sanofi Company

Investigators

• Principal Investigator: Jay Barth, MD, PTC Therapeutics

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• PTC Therapeutics' website

Publications

• 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.
• 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.

• Responsible Party: PTC Therapeutics
• ClinicalTrials.gov Identifier: NCT00947193
• Other Study ID Numbers: PTC124-GD-011-HEM
• First Posted: Jul 27, 2009
• Last Update Posted: Jun 16, 2020
• Last Verified: May 1, 2020

• Keywords provided by PTC Therapeutics: Hemophilia A; Hemophilia B; Factor VIII; Factor IX; FVIII; FIX; Nonsense mutation; Premature stop codon; HA; HB; PTC124; Ataluren
• Additional relevant MeSH terms: Hemophilia A; Hemophilia B

Study Results

Participant Flow

Recruitment Details	In this study, participants with HA or HB due to a nonsense mutation were recruited for the study.
Pre-assignment Detail	Participants requiring treatment with Factor 8 (FVIII)/Factor 9 (FIX) concentrate during 14-day ataluren treatment could continue ataluren treatment for at least 14 days following discontinuing FVIII concentrate treatment for hemophilia type A (HA) and for at least 18 days following discontinuing FIX concentrate treatment for hemophilia type B (HB)

Arm/Group Title	5 mg/kg, 5 mg/kg, and 10 mg/kg Ataluren	10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren
Arm/Group Description	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 milligrams/kilograms (mg/kg) in the morning, 5 mg/kg at midday, and 10 mg/kg in the evening for 14 days, followed by an interval of 14 days without treatment.	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 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.
Period Title: Overall Study
STARTED	3	10
Received at Least 1 Dose of Study Drug	3	10
COMPLETED	0	10
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	Ataluren Overall Study
Arm/Group Description	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.
Overall Participants	13
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42 (17.3)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	13 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of study drug and completed the study.

Arm/Group Title	10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren
Arm/Group Description	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 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.
Measure Participants	10
Count of Participants [Participants]	0 0%

2. Secondary Outcome

Title	Number of Participants With a Change From Baseline in Plasma Anti-FVIII/FIX Inhibitor Titers at Day 14
Description	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).
Time Frame	Baseline and Day 14

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of study drug and completed the study.

Arm/Group Title	10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren
Arm/Group Description	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 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.
Measure Participants	10
Count of Participants [Participants]	1 7.7%

3. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) by Severity and Relationship to Study Drug
Description	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.
Time Frame	Baseline up to Day 28

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of study drug.

Arm/Group Title	Ataluren Overall Study
Arm/Group Description	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.
Measure Participants	13
TEAEs	8 61.5%
TEAEs Related to Study Drug	2 15.4%
Severe TEAEs	0 0%
SAEs	0 0%

4. Secondary Outcome

Title	Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Hematology, Adrenal Assays, Biochemistry, and Urinalysis) Parameters
Description	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.
Time Frame	Baseline up to Day 28

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of study drug and had evaluable clinical laboratory data.

Arm/Group Title	Ataluren Overall Study
Arm/Group Description	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.
Measure Participants	13
Hematology Assays	0 0%
Biochemistry Assays	0 0%
Adrenal Assays	0 0%
Urinalysis	1 7.7%

5. Secondary Outcome

Title	Compliance With Ataluren Administration
Description	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.
Time Frame	Baseline up to Day 28

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of study drug, completed the study, and had evaluable compliance with ataluren administration data.

Arm/Group Title	Ataluren Overall Study
Arm/Group Description	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.
Measure Participants	0

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of study drug, completed the study, and had evaluable plasma data.

Arm/Group Title	10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren
Arm/Group Description	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 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.
Measure Participants	10
Pre-Dose	14.7
Post-Dose	6.66

7. Secondary Outcome

Title	Occurrence of Bleeding Episodes
Description	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.
Time Frame	Baseline up to Day 28

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of study drug.

Arm/Group Title	Ataluren Overall Study
Arm/Group Description	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.
Measure Participants	13
Participants Who Experienced a Bleeding Episode	3 23.1%
Spontaneous Right Hip Bleed	1 7.7%
Soft Tissue Bleed	1 7.7%
Right Knee Bleed	1 7.7%
Upper Shoulder Bleed	1 7.7%

Adverse Events

Time Frame	Baseline up to Day 28
Adverse Event Reporting Description	Adverse event data were collected from all enrolled participants who received at least 1 dose of study drug.
Arm/Group Title	Ataluren Overall Study
Arm/Group Description	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.
All Cause Mortality
	Ataluren Overall Study
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ataluren Overall Study
	Affected / at Risk (%)	# Events
Total	0/13 (0%)
Other (Not Including Serious) Adverse Events
	Ataluren Overall Study
	Affected / at Risk (%)	# Events
Total	8/13 (61.5%)
Cardiac disorders
Conduction disorder	1/13 (7.7%)
Gastrointestinal disorders
Diarrhoea	1/13 (7.7%)
Constipation	1/13 (7.7%)
Dyspepsia	1/13 (7.7%)
Nausea	1/13 (7.7%)
General disorders
Asthenia	1/13 (7.7%)
Renal and urinary disorders
Haematuria	1/13 (7.7%)
Dysuria	1/13 (7.7%)
Vascular disorders
Haemorrhage	3/13 (23.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor can review results and/or communications prior to public release and can embargo communications regarding trial results for a period that is up to 180 days from the time submitted to the sponsor for review. The sponsor may consult with the PI to require changes to the communication or extend the embargo.