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

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition	Friedreich's Ataxia
Interventions	Drug: Interferon γ-1b; Drug: Placebo
Enrollment	92

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Interferon γ-1b	Placebo
Arm/Group Description	Subcutaneous (SC) doses of ACTIMMUNE® 3 times a week (TIW) for a total of 26 weeks.	SC doses of placebo TIW for a total of 26 weeks.
Period Title: Overall Study
Started	47	45
Completed	46	45
Not Completed	1	0
Reason Not Completed
Adverse Event	1	0

Baseline Characteristics

Arm/Group Title		Interferon γ-1b	Placebo	Total
Arm/Group Description		SC doses of ACTIMMUNE® TIW for a total of 26 weeks.	SC doses of placebo TIW for a total of 26 weeks.	Total of all reporting groups
Overall Number of Baseline Participants		47	45	92
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	47 participants	45 participants	92 participants
		16.5 (4.41)	16.1 (3.75)	16.3 (4.08)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	47 participants	45 participants	92 participants
	Female	26 55.3%	26 57.8%	52 56.5%
	Male	21 44.7%	19 42.2%	40 43.5%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 26 in the Friedreich’s Ataxia Rating Scale (FARS)-mNeuro Score
Description	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.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: All randomized participants with a valid baseline (including Screening) and at least 1 valid post baseline measurement in the primary efficacy outcome (FARS-mNeuro) and at Week 26. A valid FARS-mNeuro score was defined as no missing values in the questionnaire.

Arm/Group Title	Interferon γ-1b	Placebo
Arm/Group Description:	SC doses of ACTIMMUNE® TIW for a total of 26 weeks.	SC doses of placebo TIW for a total of 26 weeks.
Overall Number of Participants Analyzed	46	44
Mean (Standard Deviation); Unit of Measure: units on a scale
	-0.6 (4.61)	-1.0 (4.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Interferon γ-1b, Placebo
	Comments	The primary and secondary efficacy endpoints were tested in a hierarchical manner. Each endpoint was tested in sequential order and the current endpoint must have shown statistical significance (p < 0.05) prior to performing testing the next endpoint. The primary endpoint, FARS-mNeuro, was to be tested first, followed by the key secondary endpoint, ADL, followed by the other secondary endpoints, T25FW, FARS-mNeuro responder rate, and FARStot.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5442
	Comments	From a repeated-measures ANCOVA with fixed effects of treatment, visit, and treatment*visit with baseline score and investigative site as covariates using an unstructured covariance matrix, testing ACTIMMUNE® vs placebo.
	Method	ANCOVA
	Comments	[Not Specified]

2. Secondary Outcome

Title	Change From Baseline to Week 26 in Activities of Daily Living (ADL) Score
Description	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.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

ITT Population: All randomized participants with a valid baseline (including Screening) and at least 1 valid post baseline measurement in the primary efficacy outcome (FARS-mNeuro) and ADL data at Baseline and Week 26. A valid FARS-mNeuro score was defined as no missing values in the questionnaire.

Arm/Group Title	Interferon γ-1b	Placebo
Arm/Group Description:	SC doses of ACTIMMUNE® TIW for a total of 26 weeks.	SC doses of placebo TIW for a total of 26 weeks.
Overall Number of Participants Analyzed	46	45
Mean (Standard Deviation); Unit of Measure: units on a scale
	0.64 (2.938)	0.01 (2.595)

3. Secondary Outcome

Title	Change From Baseline at Week 26 in Timed 25-Foot Walk (T25FW)
Description	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.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

ITT Population: All randomized participants with a valid baseline (including Screening) and at least 1 valid post baseline measurement in the primary efficacy outcome (FARS-mNeuro), and T25FW data at Baseline and Week 26. A valid FARS-mNeuro score was defined as no missing values in the questionnaire.

Arm/Group Title	Interferon γ-1b	Placebo
Arm/Group Description:	SC doses of ACTIMMUNE® TIW for a total of 26 weeks.	SC doses of placebo TIW for a total of 26 weeks.
Overall Number of Participants Analyzed	44	42
Mean (Standard Deviation); Unit of Measure: 1/seconds
	-0.006 (0.0247)	-0.003 (0.0181)

4. Secondary Outcome

Title	Number of FARS-mNeuro Responders and Non-Responders at Week 26
Description	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).
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

ITT Population: All randomized participants with a valid baseline (including Screening) and at least 1 valid post baseline measurement in the primary efficacy outcome (FARS-mNeuro) and data at Week 26. A valid FARS-mNeuro score was defined as no missing values in the questionnaire.

Arm/Group Title	Interferon γ-1b	Placebo
Arm/Group Description:	SC doses of ACTIMMUNE® TIW for a total of 26 weeks.	SC doses of placebo TIW for a total of 26 weeks.
Overall Number of Participants Analyzed	46	44
Measure Type: Count of Participants; Unit of Measure: Participants
Responder	14 30.4%	16 36.4%
Non-responder	32 69.6%	28 63.6%

5. Secondary Outcome

Title	Change From Baseline to Week 26 in Total Friedreich Ataxia Rating Scale Score (FARStot)
Description	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.
Time Frame	Baseline, Week 26

Outcome Measure Data

Analysis Population Description

ITT Population: All randomized participants with a valid baseline (including Screening) and at least 1 valid post baseline measurement in the primary efficacy outcome (FARS-mNeuro) and FARStot data at Baseline and Week 26. A valid FARS-mNeuro score was defined as no missing values in the questionnaire.

Arm/Group Title	Interferon γ-1b	Placebo
Arm/Group Description:	SC doses of ACTIMMUNE® TIW for a total of 26 weeks.	SC doses of placebo TIW for a total of 26 weeks.
Overall Number of Participants Analyzed	46	44
Mean (Standard Deviation); Unit of Measure: units on a scale
	-0.2 (5.53)	-0.6 (5.19)

Adverse Events

Time Frame	Treatment emergent adverse events (TEAEs) are presented. Adverse events (AEs) occurring or worsening after the dose on Day 1 through the end of the study (Week 26) were considered TEAEs. Serious TEAEs were collected through 2 weeks after study discontinuation (Week 28).
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Interferon γ-1b	Placebo
Arm/Group Description	SC doses of ACTIMMUNE® TIW for a total of 26 weeks.	SC doses of placebo TIW for a total of 26 weeks.
All-Cause Mortality
	Interferon γ-1b	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Interferon γ-1b	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/47 (2.13%)	2/45 (4.44%)
General disorders
Chest pain † 1	1/47 (2.13%)	0/45 (0.00%)
Infections and infestations
Pneumonia † 1	1/47 (2.13%)	1/45 (2.22%)
Metabolism and nutrition disorders
Dehydration † 1	0/47 (0.00%)	1/45 (2.22%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 16.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Interferon γ-1b	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	45/47 (95.74%)	37/45 (82.22%)
Blood and lymphatic system disorders
Neutropenia † 1	7/47 (14.89%)	1/45 (2.22%)
Gastrointestinal disorders
Abdominal pain upper † 1	3/47 (6.38%)	5/45 (11.11%)
Constipation † 1	1/47 (2.13%)	3/45 (6.67%)
Diarrhoea † 1	3/47 (6.38%)	2/45 (4.44%)
Nausea † 1	18/47 (38.30%)	11/45 (24.44%)
Vomiting † 1	3/47 (6.38%)	4/45 (8.89%)
General disorders
Chills † 1	6/47 (12.77%)	2/45 (4.44%)
Fatigue † 1	4/47 (8.51%)	8/45 (17.78%)
Injection site bruising † 1	5/47 (10.64%)	5/45 (11.11%)
Injection site erythema † 1	7/47 (14.89%)	1/45 (2.22%)
Injection site pain † 1	5/47 (10.64%)	3/45 (6.67%)
Injection site pruritus † 1	4/47 (8.51%)	1/45 (2.22%)
Pain † 1	4/47 (8.51%)	2/45 (4.44%)
Pyrexia † 1	7/47 (14.89%)	8/45 (17.78%)
Infections and infestations
Nasopharyngitis † 1	6/47 (12.77%)	5/45 (11.11%)
Upper respiratory tract infection † 1	3/47 (6.38%)	2/45 (4.44%)
Urinary tract infection † 1	5/47 (10.64%)	4/45 (8.89%)
Injury, poisoning and procedural complications
Excoriation † 1	3/47 (6.38%)	3/45 (6.67%)
Fall † 1	3/47 (6.38%)	3/45 (6.67%)
Joint injury † 1	3/47 (6.38%)	0/45 (0.00%)
Laceration † 1	2/47 (4.26%)	5/45 (11.11%)
Ligament sprain † 1	1/47 (2.13%)	4/45 (8.89%)
Investigations
Neutrophil count decreased † 1	4/47 (8.51%)	0/45 (0.00%)
White blood cell count decreased † 1	4/47 (8.51%)	0/45 (0.00%)
Musculoskeletal and connective tissue disorders
Back pain † 1	4/47 (8.51%)	5/45 (11.11%)
Muscle spasms † 1	4/47 (8.51%)	1/45 (2.22%)
Myalgia † 1	8/47 (17.02%)	2/45 (4.44%)
Pain in extremity † 1	0/47 (0.00%)	3/45 (6.67%)
Nervous system disorders
Dizziness † 1	6/47 (12.77%)	4/45 (8.89%)
Headache † 1	24/47 (51.06%)	15/45 (33.33%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	5/47 (10.64%)	6/45 (13.33%)
Nasal congestion † 1	8/47 (17.02%)	7/45 (15.56%)
Oropharyngeal pain † 1	6/47 (12.77%)	8/45 (17.78%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 16.1

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Horizon requests that any Investigator/institution that plans on presenting or publishing results provide written notification of their request a minimum of 60 days prior to presentation or publication. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsors’ Intellectual Property rights .

Results Point of Contact

Name/Title: Julie Ball, Executive Director Clinical Development & Operations

Organization: Horizon Pharma Ireland, Ltd. Dublin, Ireland

EMail: clinicaltrials@horizonpharma.com

Responsible Party:	Horizon Pharma Ireland, Ltd., Dublin Ireland
ClinicalTrials.gov Identifier:	NCT02415127 History of Changes
Other Study ID Numbers:	HZNP-ACT-301
First Submitted:	February 12, 2015
First Posted:	April 14, 2015
Results First Submitted:	November 6, 2017
Results First Posted:	December 8, 2017
Last Update Posted:	December 8, 2017