Micronised Resveratrol as a Treatment for Friedreich Ataxia

• ClinicalTrials.gov Identifier: NCT03933163
• Recruitment Status: Active, not recruiting
• First Posted: May 1, 2019
• Last Update Posted: April 21, 2023
• Sponsor: Murdoch Childrens Research Institute
• Information provided by (Responsible Party): Murdoch Childrens Research Institute

Study Description

Brief Summary:

The aim of this study is to assess the efficacy of micronised resveratrol as a treatment for FRDA, in terms of reducing the severity of ataxia symptoms at 24 weeks, through a randomised blinded, placebo controlled crossover trial.

Condition or disease	Intervention/treatment	Phase
Friedreich Ataxia	Drug: Resveratrol	Phase 2

Detailed Description:

Friedreich ataxia (FRDA) is the most common hereditary ataxia, with an estimated prevalence in Caucasians of 1 in 30,000. Neurological features of FRDA are progressive gait and limb ataxia, absent lower limb reflexes, and loss of position and vibration sense. There are currently no treatments proven to alter the natural history of FRDA. Resveratrol is a naturally occurring compound found in red wine, berries, and nuts. It is postulated to have wide-ranging health benefits, including antioxidant, anticarcinogenic, antidiabetic and neuroprotective properties.

The study will be a double-blinded, placebo-controlled randomised 2-period crossover trial of 2g/day of micronised resveratrol in FRDA over 24 weeks. The study will enrol 40 patients with FRDA from 3 sites. The primary outcome measure is the change in modified Friedreich Ataxia Rating Scale (mFARS) score from baseline to 24 weeks.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Double-blind, randomised, placebo-controlled 2-period crossover trial of 2g/day of micronised resveratrol versus placebo. Participants will be randomised in terms of the order in which they received micronised resveratrol and placebo.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Participants will be randomised between receiving resveratrol in period 1 and placebo in period 2, or placebo in period 1 and resveratrol in period 2.
• Primary Purpose: Treatment
• Official Title: A Randomised Placebo-controlled Crossover Trial of Micronised Resveratrol as a Treatment for Friedreich Ataxia
• Actual Study Start Date: May 23, 2019
• Estimated Primary Completion Date: July 2023
• Estimated Study Completion Date: July 2023

Arms and Interventions

Arm	Intervention/treatment
Resveratrol followed by placebo; 1g micronised resveratrol twice daily for 24 weeks, a wash-out period of 4 weeks, followed by twice daily placebo for 24 weeks.	Drug: Resveratrol; Drug name: Micronised resveratrol. Dosage form: 500mg capsules. Alternate name: 1,3-Benzenediol, 5-[2-(4-hydroxyphenyl)ethenyl]-, (E). Ingredients: 99.50% pure trans-resveratrol. Placebo capsules will be identical in terms of taste, smell, and appearance.
Placebo followed by Resveratrol; Twice daily placebo for 24 weeks, a wash-out period of 4 weeks, followed by 1g micronised resveratrol twice daily for 24 weeks	Drug: Resveratrol; Drug name: Micronised resveratrol. Dosage form: 500mg capsules. Alternate name: 1,3-Benzenediol, 5-[2-(4-hydroxyphenyl)ethenyl]-, (E). Ingredients: 99.50% pure trans-resveratrol. Placebo capsules will be identical in terms of taste, smell, and appearance.

Outcome Measures

Primary Outcome Measures :

1. Modified Friedreich Ataxia Rating Scale [ Time Frame: 24 weeks ]
   Change in the Modified Friedreich Ataxia Rating Scale score (score range 0-99) at 24 weeks compared with baseline. Higher scores are indicative of more severe disease.

Secondary Outcome Measures :

1. Nine-Hole Peg Test [ Time Frame: 24 weeks ]
   Change in the Nine-Hole Peg Test at 24 weeks compared with baseline.
2. Berg Balance Scale [ Time Frame: 24 weeks ]
   Change in the Berg Balance Scale (score range 0-56) at 24 weeks compared with baseline. A higher score indicates lower fall risk.
3. Ataxia Instrumented Measure-Spoon [ Time Frame: 24 weeks ]
   Change in the Ataxia Instrumented Measure-Spoon at 24 weeks compared with baseline.
4. Friedreich Ataxia Impact Scale [ Time Frame: 24 weeks ]
   Change in the Friedreich Ataxia Impact Scale at 24 weeks compared with baseline. The Friedreich Ataxia Impact Scale comprises 8 subscales (score range 0-100) that are scored independently. A higher score indicates greater impact of Friedreich ataxia on health and well-being.
5. Modified Fatigue Impact Scale [ Time Frame: 24 weeks ]
   Change in the Modified Fatigue Impact Scale (score range 0-24) at 24 weeks compared with baseline. Higher scores indicate a greater impact of fatigue on an individual's activities.
6. Measures of speech [ Time Frame: 24 weeks ]
   Change in measures of speech (reading a paragraph, produce a prolonged vowel sound for 5 seconds, count from one to 20, and produce a 1-minute monologue on a pre-specified topic) at 24 weeks compared with baseline.
7. Measures of hearing [ Time Frame: 24 weeks ]
   Change in measures of hearing using the Listening in Spatialized Noise Test (LiSN-S) at 24 weeks compared with baseline.
8. Cardiac parameters measured by echocardiography [ Time Frame: 24 weeks ]
   Change in left ventricular global longitudinal strain at 24 weeks compared to baseline.
9. Cardiac parameters measured by ECG [ Time Frame: 24 weeks ]
   Change in QRS duration at lead V5 at 24 weeks compared to baseline.
10. Frataxin levels [ Time Frame: 24 weeks ]
    Change in frataxin levels at 24 weeks compared to baseline.
11. mRNA levels [ Time Frame: 24 weeks ]
    Change in PGC-1α mRNA levels and Nrf2 mRNA levels at 24 weeks compared to baseline.
12. Plasma F2-isoprostane levels [ Time Frame: 24 weeks ]
    Change in plasma F2-isoprostane levels at 24 weeks compared to baseline.

Eligibility Criteria

• Ages Eligible for Study: 16 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age ≥16 years.
2. Diagnosis of FRDA, genetically documented to be due to homozygosity for a GAA repeat expansion in intron 1 of FXN.
3. Functional stage on the Ataxia subscale of the full FARS of 1 or higher (a score of 1 is assigned if the subject has "Minimal signs detected by the physician during screening. Can run or jump without loss of balance. No disability."), and total mFARS score of ≤ 65.
4. Adequate end organ function defined as follows: (i) total bilirubin <2x upper limit of normal unless attributable to Gilbert disease, (ii) ALT and AST <1.5x upper limit of normal, (iii) Creatinine <2x upper limit of normal, (iv) neutrophils >1.5x10^9/L, (v) platelets >10^6/μL.
5. Written informed consent provided.

Exclusion Criteria:

1. Non-elective hospitalisation within the past 60 days that could be of concern in the investigator's judgment. Any hospitalisation in the previous 60 days will be assessed and if in the investigator's judgement it could compromise the individual or the study, that person will not be recruited. Examples include if the individual is hospitalised for management of cardiac morbidity such as uncontrolled arrhythmia or angina or for orthopaedic surgery for a lower limb fracture.
2. Women who are pregnant or lactating or men and women of childbearing potential who are unwilling to use contraception for the duration of the study.
3. FRDA due to compound heterozygosity for an expanded GAA repeat and a point mutation/ deletion in the FXN gene.
4. Current or recent (in last 12 months) arrhythmias including: atrial fibrillation, atrial flutter, sinus tachycardia >120/min, sinus bradycardia <50/min. Symptomatic paroxysmal arrhythmia which is recurring frequently. Cardiac insufficiency (by New York Heart Association >2). Reduced LV ejection fraction (<50%) in the last six months.
5. Medical illness that in the judgment of the investigator would jeopardise the safe completion of the study. Examples include cancer, chronic inflammatory disease, severe diabetes (type I or II, HbA1c >8%), chronic liver insufficiency, epilepsy, thrombocytosis.
6. Evidence of end organ dysfunction through failure to meet one or more parameters in inclusion criterion number 4.
7. Prior invasive cancer (excluding localised basal cell or squamous cell skin cancer).
8. Known hypersensitivity to resveratrol.
9. Use of any investigational agent within 30 days of enrolment.
10. Use of antioxidants such as vitamin E, coenzyme Q10 or idebenone within 30 days prior to enrolment.
11. Concomitant use of medications with potential for clinically relevant drug interactions. This includes medications with a narrow therapeutic range that are metabolised by the cytochrome P450 3A4, 2D6 or 2C9 systems e.g. warfarin, amiodarone.

Contacts and Locations

Locations

Australia, New South Wales

Royal North Shore Hospital

St Leonards, New South Wales, Australia, 2065

Australia, Queensland

University of Queensland Centre for Clinical Research

Herston, Queensland, Australia, 4029

Australia, Victoria

Murdoch Children's Research Institute

Parkville, Victoria, Australia, 3052

Australia, Western Australia

Royal Perth Hospital

Perth, Western Australia, Australia, 6000

Sponsors and Collaborators

Murdoch Childrens Research Institute

Investigators

• Principal Investigator: Martin B Delatycki, PhD, MBBS; Murdoch Children's Research Institute

More Information

• Responsible Party: Murdoch Childrens Research Institute
• ClinicalTrials.gov Identifier: NCT03933163
• Other Study ID Numbers: 36007
• First Posted: May 1, 2019
• Last Update Posted: April 21, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

The de-identified data set collected for analysis of the study will be available six months after publication of the primary outcome.

The study protocol, analysis plan and consent forms will also be available. The data may be obtained from the Murdoch Children's Research Institute by contacting martin.delatycki@vcgs.org.au.

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: 6 months after publication of primary outcome
• Access Criteria: Prior to releasing any data the following are required: a data access agreement must be signed between relevant parties and there must be an agreement around appropriate acknowledgement and any additional costs involved must be covered. Data will only be shared with a recognised research institution which has approved the proposed analysis plan.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Murdoch Childrens Research Institute:

Resveratrol; Frataxin

Additional relevant MeSH terms:

Ataxia; Cerebellar Ataxia; Friedreich Ataxia; Dyskinesias; Neurologic Manifestations; Nervous System Diseases; Cerebellar Diseases; Brain Diseases; Central Nervous System Diseases; Spinocerebellar Degenerations; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Mitochondrial Diseases; Metabolic Diseases; Resveratrol; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs; Enzyme Inhibitors; Platelet Aggregation Inhibitors