Hemophilia A, Hemophilia B
Conditions
Keywords
Hemophilia A, Hemophilia B, Factor VIII, Factor IX, FVIII, FIX, Nonsense mutation, Premature stop codon, HA, HB, PTC124, Ataluren
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.
Interventions
DRUGAtaluren
Oral powder
Sponsors
Genzyme, a Sanofi Company
PTC Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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). |
| 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. |
| 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. |
| 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. |
Countries
Canada, France, Italy, United States
Participant flow
Recruitment details
In this study, participants with HA or HB due to a nonsense mutation were recruited for the study.
Pre-assignment details
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)
Participants by arm
| Arm | Count |
|---|---|
| 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. | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Factor VIII >1% | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Ataluren Overall Study |
|---|---|
| Age, Continuous | 42 years STANDARD_DEVIATION 17.3 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 8 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
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%.
Time frame: Baseline up to Day 14
Population: All enrolled participants who received at least 1 dose of study drug and completed the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Number of Participants With a Plasma FVIII/FIX Activity Response at Day 14 | 0 Participants |
Secondary
Ataluren Plasma Exposure
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)
Population: All enrolled participants who received at least 1 dose of study drug, completed the study, and had evaluable plasma data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Ataluren Plasma Exposure | Pre-Dose | 14.7 microgram/milliliters (μg/mL) |
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Ataluren Plasma Exposure | Post-Dose | 6.66 microgram/milliliters (μg/mL) |
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.
Time frame: Baseline up to Day 28
Population: All enrolled participants who received at least 1 dose of study drug, completed the study, and had evaluable compliance with ataluren administration data.
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).
Time frame: Baseline and Day 14
Population: All enrolled participants who received at least 1 dose of study drug and completed the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Number of Participants With a Change From Baseline in Plasma Anti-FVIII/FIX Inhibitor Titers at Day 14 | 1 Participants |
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.
Time frame: Baseline up to Day 28
Population: All enrolled participants who received at least 1 dose of study drug and had evaluable clinical laboratory data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Hematology, Adrenal Assays, Biochemistry, and Urinalysis) Parameters | Hematology Assays | 0 Participants |
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Hematology, Adrenal Assays, Biochemistry, and Urinalysis) Parameters | Biochemistry Assays | 0 Participants |
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Hematology, Adrenal Assays, Biochemistry, and Urinalysis) Parameters | Adrenal Assays | 0 Participants |
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Number of Participants With a Clinically Meaningful Abnormal Clinical Laboratory (Hematology, Adrenal Assays, Biochemistry, and Urinalysis) Parameters | Urinalysis | 1 Participants |
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.
Time frame: Baseline up to Day 28
Population: All enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) by Severity and Relationship to Study Drug | TEAEs | 8 Participants |
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) by Severity and Relationship to Study Drug | TEAEs Related to Study Drug | 2 Participants |
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) by Severity and Relationship to Study Drug | Severe TEAEs | 0 Participants |
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) by Severity and Relationship to Study Drug | SAEs | 0 Participants |
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.
Time frame: Baseline up to Day 28
Population: All enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Occurrence of Bleeding Episodes | Participants Who Experienced a Bleeding Episode | 3 Participants |
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Occurrence of Bleeding Episodes | Spontaneous Right Hip Bleed | 1 Participants |
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Occurrence of Bleeding Episodes | Soft Tissue Bleed | 1 Participants |
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Occurrence of Bleeding Episodes | Right Knee Bleed | 1 Participants |
| 10 mg/kg, 10 mg/kg, and 20 mg/kg Ataluren | Occurrence of Bleeding Episodes | Upper Shoulder Bleed | 1 Participants |