Safety, Tolerability and Efficacy of ACTIMMUNE® Dose Escalation in Friedreich's Ataxia (STEADFAST)

• Sponsor: Horizon Pharma Ireland, Ltd., Dublin Ireland
• Collaborator: Friedreich's Ataxia Research Alliance
• Information provided by (Responsible Party): Horizon Pharma Ireland, Ltd., Dublin Ireland

Tracking Information

• First Submitted Date: February 12, 2015
• First Posted Date: April 14, 2015
• Results First Submitted Date: November 6, 2017
• Results First Posted Date: December 8, 2017
• Last Update Posted Date: December 8, 2017
• Study Start Date: June 2015
• Actual Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 7, 2017)

Change From Baseline to Week 26 in the Friedreich's Ataxia Rating Scale (FARS)-mNeuro Score [ Time Frame: Baseline, Week 26 ]

The FARS assessment includes neurological signs that specifically reflect neural substrates affected in FA. Based on a neurological examination, bulbar, upper limb, lower limb, peripheral nerve, and upright stability/gait functions were assessed. The FARS-mNeuro score excludes the peripheral nervous system subscale score and the facial and tongue atrophy and fasciculations from the bulbar subscale score. Scores range from 0 (normal) to 93 (most impairment). A negative change from baseline is an improvement.

Original Primary Outcome Measures (submitted: April 8, 2015)

Change in neurological outcome measured by Friedreich's Ataxia Rating Scale (FARS) [ Time Frame: Baseline, Week 13, Week 26 ]

To evaluate the effect of ACTIMMUNE® versus placebo on the change from Baseline to Week 26 in neurological outcome as measured by FARS excluding the peripheral nervous system subscale score and the facial and tongue atrophy and fasciculations from the bulbar subscale score (FARS-mNeuro score).

• Change History: Complete list of historical versions of study NCT02415127 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: December 7, 2017)

• Change From Baseline to Week 26 in Activities of Daily Living (ADL) Score [ Time Frame: Baseline, Week 26 ]
  Participants and/or their caregivers rated 9 areas of daily living skills (speech, swallowing, cutting food and handling utensils, dressing, personal hygiene, falling, walking, quality of sitting position, and bladder function) on a 5-point scale (0=normal, 4=greatest loss of function) with allowable increments of 0.5 if the participant or caregiver strongly felt that a task falls between 2 scores. ADL scores can range from 0 (normal) to 36 (greatest loss of function). A negative change from baseline indicates improvement.
• Change From Baseline at Week 26 in Timed 25-Foot Walk (T25FW) [ Time Frame: Baseline, Week 26 ]
  The T25FW is a quantitative measure of lower extremity function. Participants are directed to 1 end of a clearly marked 25-foot course and instructed to walk 25 feet as quickly as possible, but safely. The task is immediately administered again by having the participant walk back the same distance, and the score for the test is the average of the 2 walks (after reciprocal transformation). Participants may use assistive devices when performing this task, with the same assistive device used at each assessment. A negative change from Baseline indicates improvement.
• Number of FARS-mNeuro Responders and Non-Responders at Week 26 [ Time Frame: Week 26 ]
  A participant was considered a responder if they had an improvement (decrease) of at least 3 points from Baseline at Week 26 for the FARS-mNeuro score. The FARS assessment includes neurological signs that specifically reflect neural substrates affected in FA. Based on a neurological examination, bulbar, upper limb, lower limb, peripheral nerve, and upright stability/gait functions were assessed. The FARS-mNeuro score excludes the peripheral nervous system subscale score and the facial and tongue atrophy and fasciculations from the bulbar subscale score. Scores range from 0 (normal) to 93 (most impairment).
• Change From Baseline to Week 26 in Total Friedreich Ataxia Rating Scale Score (FARStot) [ Time Frame: Baseline, Week 26 ]
  The FARS assessment includes neurological signs that specifically reflect neural substrates affected in FA. Based on a neurological examination, bulbar, upper limb, lower limb, peripheral nerve, and upright stability/gait functions are assessed. FARStot scores range from 0 (normal) to 125 (most impairment). A negative change from baseline indicates improvement.

Original Secondary Outcome Measures (submitted: April 8, 2015)

• The effect of ACTIMMUNE on the timed 25-foot-walk test (T25FW) [ Time Frame: Baseline, Week 13, Week 26 ]
  To evaluate the effect of ACTIMMUNE® versus placebo on change from Baseline to Week 26 in the T25FW.
• The effect of ACTIMMUNE® on the responder rate [ Time Frame: Baseline, Week 13, Week 26 ]
  To evaluate the effect of ACTIMMUNE® versus placebo on the responder rate (≥3 point improvement in the FARS-mNeuro score from Baseline to Week 26).
• The effect of ACTIMMUNE® on the neurological outcome measured by the total FARS score [ Time Frame: Baseline, Week 13, Week 26 ]
  To evaluate the effect of ACTIMMUNE® versus placebo on the change from Baseline to Week 26 in neurological outcome as measured by the total FARS score (FARStot).
• The incidence of treatment emergent adverse events will be summarized by the treatment group [ Time Frame: Baseline, Week 4, Week 13, Week 26, Week 28 ]
• The change from baseline to post-dose values will be summarized by the treatment group for clinical laboratory safety data and vital sign data [ Time Frame: Baseline, Week 4, Week 13, Week 26 ]

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: April 8, 2015)

Pharmacokinetic profile analysis of ACTIMMUNE [ Time Frame: Week 4, Week 13, and Week 26 ]

PK profile will be characterized. Approximately 40 patients will remain confined overnight at week 4 for serial blood collections. All patients will contribute a single blood sample at weeks 13 and 26 for PK analysis.

Descriptive Information

• Brief Title: Safety, Tolerability and Efficacy of ACTIMMUNE® Dose Escalation in Friedreich's Ataxia
• Official Title: Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy, Safety, and Pharmacokinetic Study of ACTIMMUNE® (Interferon γ-1b) in Children and Young Adults With Friedreich's Ataxia
• Brief Summary: The purpose of this phase 3 randomized, multi-center, double-blind, placebo-controlled study is to evaluate the efficacy and safety of ACTIMMUNE® (interferon-γ 1b) in the treatment of Friedreich's Ataxia (FA) and to evaluate the pharmacokinetic (PK) characteristics of ACTIMMUNE® in FA patients.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Friedreich's Ataxia

Intervention

• Drug: Interferon γ-1b
  The study drug dose is planned to be escalated on a weekly basis over the first 4 weeks of treatment (from 10 µg/m² to 25, 50, and 100 µg/m²). The dose may be reduced, interrupted, or held based on tolerability. By Week 13, all participants are to be on a stable tolerated dose of study drug in order to continue study participation; the dose may not be further increased after week 13, however, it may be reduced on a case-by-case basis to manage drug-related adverse events (AEs).
  Other Name: ACTIMMUNE®
• Drug: Placebo
  The volume of placebo is planned to correspond with volume of study drug that would be given to the participant if the participant was randomized to the study drug arm.

Study Arms

• Experimental: Interferon γ-1b
  Approximately 45 participants will receive subcutaneous (SC) doses of ACTIMMUNE® 3 times a week (TIW) for a total of 26 weeks.
  Intervention: Drug: Interferon γ-1b
• Placebo Comparator: Placebo
  Approximately 45 participants will receive SC doses of placebo TIW for a total of 26 weeks.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 18, 2016): 92
• Original Estimated Enrollment (submitted: April 8, 2015): 90
• Actual Study Completion Date: November 2016
• Actual Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Written informed consent and child assent, if applicable.
• FA confirmed by genetic testing with two expanded guanine-adenine-adenine (GAA) repeats.
• FA functional stage of >1 to <5 and ability to walk 25 feet with or without an assistive device.
• Male or female subject between the ages of 10 and 25 years, inclusive.
• If female, the subject is not pregnant or lactating or intending to become pregnant during the study, or within 30 days after the last dose of study drug. Female subjects of child-bearing potential must have a negative serum pregnancy test result at Screening, a negative urine pregnancy test result at Baseline, and agree to use a reliable method of contraception throughout the study and for 30 days after the last dose of study drug.

Exclusion Criteria:

• Any unstable illness that in the investigator's opinion precludes participation in the study.
• Use of any investigational product within 30 days prior to randomization.
• A history of substance abuse.
• Presence of clinically significant cardiac disease (as determined by the investigator based on electrocardiogram [ECG] and echocardiogram results at Screening). Specifically, an ejection fraction of <40% or a prolonged QT interval (>50% of cycle duration) will result in exclusion. If the investigator notes any other clinically significant abnormalities on the ECG or echocardiogram, the subject may be eligible if they are provided clearance from a cardiologist.
• History of hypersensitivity to interferon (IFN)-ɣ or E. coli-derived products.
• Presence of moderate or severe renal disease (estimated creatinine clearance <50 mL/min) or hepatic disease (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] >2x the upper limit of normal) as evidenced by laboratory results at Screening.
• Clinically significant abnormal white blood cell count, hemoglobin, or platelet count as evidenced by laboratory test results at Screening.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 10 Years to 25 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02415127
• Other Study ID Numbers: HZNP-ACT-301
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes

• IPD Sharing Statement: Not Provided
• Responsible Party: Horizon Pharma Ireland, Ltd., Dublin Ireland
• Study Sponsor: Horizon Pharma Ireland, Ltd., Dublin Ireland
• Collaborators: Friedreich's Ataxia Research Alliance

Investigators

• Principal Investigator: David Lynch, MD, PhD; Children's Hospital of Philadelphia

• PRS Account: Horizon Pharma Ireland, Ltd., Dublin Ireland
• Verification Date: December 2017