Idebenone to Treat Friedreich's Ataxia
Condition: Friedreich Ataxia
MeSH terms: Ataxia; Cerebellar Ataxia; Friedreich Ataxia
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will determine whether a drug called idebenone is safe and effective in reducing
      the level of oxidants that are believed to damage the nervous system and hearts in patients
      with Friedreich's ataxia. Friedreich's ataxia is caused by an abnormality in the gene that
      makes a protein called frataxin, which is necessary for the proper functioning of
      energy-producing parts of cells called mitrochondria. In Friedreich's ataxia, the
      mitochondria become overloaded with iron, and high levels of harmful compounds called
      oxidants are formed. These oxidants are believed to damage the cells of the nervous system
      and hearts of people with Friedreich's ataxia. Idebenone is a man-made drug similar to a
      naturally occurring compound known as Coenzyme Q10. This study will test whether idebenone
      can alleviate some of the symptoms of Friedreich's ataxia and slow or halt the progression of
      the disease.

      Patients with genetically confirmed Friedreich's ataxia who are between 9 and 18 years of
      age, weigh between 65 and 175 pounds and can walk 25 feet with or without an assistive device
      may be eligible for this study. Candidates are screened with blood tests and a review of
      their medical records.

      Participants undergo the following tests and procedures:

        -  Medical interview and physical examination. Tests include blood and urine tests, an
           electrocardiogram, or EKG (recording of the electrical activity of the heart),
           echocardiogram (ultrasound test showing the pumping action of the heart, thickness of
           the heart walls, and any valve leakage), and a detailed neurological examination,
           including maneuvers such as copying a drawing and putting pegs in a board. Patients'
           parents are asked questions about how they feel their child's disease affects the
           child's quality of life.

        -  Magnetic resonance imaging (MRI) to examine the heart muscle and blood flow to the
           heart. MRI uses a magnetic field and radio waves to produce images of body tissues and
           organs. The patient lies on a table that is moved into the doughnut-shaped MRI scanner,
           wearing earplugs to muffle loud knocking and thumping sounds that occur during the
           scanning process. A catheter (plastic tube) is placed in a vein in the child's arm so
           that a chemical called gadolinium can be injected during the MRI study. Gadolinium
           brightens areas of the heart, improving the ability to see the heart and blood flow.

        -  Physical medicine and rehabilitation evaluations to test the child's physical
           functioning. These tests include gait evaluation, measurements of the ability to exert
           and maintain a constant force, assessment of visual-motor control and fine motor
           control, aerobic exercise endurance testing, and measurement of the ability of the
           child's heart and lungs to increase their effectiveness with exercise.

        -  Idebenone/placebo treatment. Patients are given a 6-month supply of either idebenone
           pills or placebo (pills that look like the study drug but have no active ingredient) to
           take three times a day. Patients are seen by their primary care physician after 1 and 3
           months on the study medication for a brief physical examination. In addition, they have
           blood and urine tests once a month while on medication to check for any abnormalities.

        -  6-month examination. After 6 months on the study drug, patients return to NIH to repeat
           all the tests listed above to determine the effects of idebenone treatment.
    

Detailed description: 
      Background: Friedreich's ataxia (FA) is a progressive, autosomal recessive, multisystem
      degenerative disease for which there is currently no effective treatment. Recent studies have
      suggested that lipid-soluble antioxidants lead to a modest reversal of cardiomyopathy in
      patients with FA. It is possible that antioxidants may also prevent the progression of
      neurodegeneration.

      Objective: This will be a 6 month phase 2 double-blind, placebo-controlled trial to assess
      the safety and efficacy of idebenone administered to adolescents and children with FA.

      Study Population: We aim to enroll 48 subjects composed of children (ages 9-11) and
      adolescents (ages 12-17) with FA divided evenly among 4 treatment arms (placebo, low,
      intermediate, and high dose idebenone).

      Design: Our primary objective is to examine the change in the level of oxidative stress by
      measuring the oxidative marker 8-hydroxy-2-deoxyguanosine from baseline and after 6 months of
      treatment with placebo or varying doses of idebenone. Following informed consent and assent,
      patients will undergo an initial medical history and physical followed by specific
      neurological, functional, and cardiac testing over a two-day outpatient visit. Patients will
      provide blood and urine samples for safety laboratory and biochemical analysis. Each patient
      will be randomized to one of 4 treatment arms and will be provided with a 6 month supply of
      study drug or placebo which will be administered three times a day. Patients will have
      follow-up laboratory monitoring after 1 and 3 months and at the end of the study.
      Additionally, patients will also have an EKG, vital signs, including orthostatics, and a
      physical examination performed after 1 and 3 months by their primary care physician. Patients
      will return after 6 months for follow-up exam, testing, and laboratory monitoring over a
      two-day outpatient visit.

      Outcome Parameters: The primary endpoint in this phase 2 trial is the change in the level of
      the oxidative stress marker 8-hydroxy-2-deoxyguanosine. Secondary endpoints include types and
      frequency of adverse events, if any, compliance with the dosing regimen, and measurements of
      the following: International Cooperative Ataxia Rating Scale (ICARS), Friedreich's ataxia
      Rating Scale (FARS), force control, gait analysis, quantitative sensation testing, fine motor
      control, health related quality of life score (SF-10), functional capacity, aerobic capacity,
      left ventricular wall mass, noninvasive measures of systolic and diastolic ventricular
      function, metabolic markers, markers of mitochondrial DNA damage, and gene expression
      profiling.

      Future Directions: We hope that the results of this phase 2 study will assist us in
      developing a multi-center, double-blinded, placebo-controlled phase III trial.
    

Intervention name(s): Idebenone
Intervention type(s): Drug
Intervention description(s): Idebenone is a short-chain benzoquinone derivative of similar structure to ubiquinone (coenzyme Q10). This compound was synthesized and developed initially by Takeda Chemical Industries, Ltd. (Osaka, Japan) and designated as CV-2619. The chemical name for idebenone is 6-(10-Hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benxoquinone. Santhera Pharmaceuticals (Liestal, Switzerland) LLC, will supply drug for this study as specified by a clinical trial agreement.
Intervention MeSH terms: Idebenone
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Friedreich's Ataxia; Idebenone; Ataxia; Drug Trial; Randomized Trial; Friedreich Ataxia; FA