Idebenone to Treat Friedreich's Ataxia
| Status: | Completed |
|---|---|
| Conditions: | Neurology |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | 9 - 17 |
| Updated: | 3/20/2019 |
| Start Date: | September 27, 2005 |
| End Date: | December 17, 2007 |
A Six Month Double-Blind, Placebo-Controlled Phase 2 Clinical Trial to Determine the Safety and Efficacy of Idebenone Administered to Patients With Friedreich's Ataxia
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.
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.
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.
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.
- INCLUSION CRITERIA:
Diagnosis of FA with confirmed FRDA mutations.
Age from nine up to but not over eighteen years.
Weight between 30 to 80 kilograms.
Ambulatory (assistance devices permitted).
Willing to participate in all aspects of trial design and follow-up.
All subjects agree and commit to the use of 2 reliable methods of birth control for the
duration of the study if sexually active.
Neurologically symptomatic.
No exposure to idebenone, coenzyme Q10, or other dietary supplements for a period of at
least one month before enrollment in the study.
EXCLUSION CRITERIA:
History of a hypersensitivity reaction to idebenone or coenzyme Q10.
Pregnant or lactating women. All women of child-bearing potential must have negative serum
pregnancy prior to the medication phase of the study. If a minor has a positive pregnancy
test, we will inform her but not inform her parents unless we are asked to by the minor.
Platelet count, white blood cell count or hemoglobin below the lower limit of normal.
Alkaline phosphatase, SGOT, or SGPT greater than 1.5 times the upper limit of normal.
Bilirubin greater than 1.5 g/dl.
Creatinine greater than 1.5 times the upper limit of normal based upon the pediatric
reference range provided by the testing laboratory.
Clinically significant medical disease that, in the judgment of the investigators, would
expose the patient to undue risk of harm or prevent the patient from completing the study.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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