Friedreich Ataxia
Conditions
Keywords
Friedreich Ataxia
Brief summary
To evaluate the safety, tolerability, and activity of Elamipretide in treating vision loss in Friedreich Ataxia (FRDA).
Detailed description
To evaluate the effect of high dose (40-60mg) versus low dose (20-30mg) Elamipretide on high contrast visual acuity in FRDA compared to baseline at 52 weeks with the option to extend for an additional 52 weeks if there are objective signs of clinical improvement on primary or secondary endpoints. The interim analysis will be based on data from a 36-week visit. For subjects worse than 20/800 at study start, they will be followed using low vision alternatives only.
Interventions
DRUGElamipretide
Elamipretide is a tetra peptide with limited blood brain barrier penetration being developed for use in a variety of mitochondrial disorders, including FRDA, mitochondrial myopathy and Barth Syndrome.
Sponsors
Friedreich's Ataxia Research Alliance
Stealth BioTherapeutics Inc.
Children's Hospital of Philadelphia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Genetically confirmed FRDA (point mutations allowed). 2. Age \>16 years. 3. Disease onset before 18 years of age. 4. If female, the subject is not pregnant or lactating or intending to become pregnant before, during, 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. 5. All subjects must agree to use a reliable method of contraception throughout the study and for 30 days after the last dose of study drug. Male subjects should not father a baby during the study or for at least 30 days after the last dose of study drug. 6. All concomitant medications (including over-the-counter medications), vitamins, and supplements must be at stable doses for 30 days prior to study entry and kept stable throughout the study to the best of their ability. 7. Visual acuity (VA) worse than 20/40 (binocular) on the basis of FRDA. Must not be correctable by refraction, or subjects must have sufficient physical exam findings of optic neuropathy (funduscopic, visual fields, or retinal ganglion cell loss) to justify the primary diagnosis of FRDA related optic neuropathy Or 8. Ejection Fraction (EF) less than 50% at last evaluation (within 1 year before screening), with a history consistent with cardiomyopathy from FRDA, and VA 20/25- 20/40.
Exclusion criteria
1. Any unstable illness that in the investigator's opinion precludes participation in the study. 2. Use of any investigational product within 30 days prior to Screening. 3. A history of substance abuse. 4. Diagnosis of active HIV or Hepatitis B or C infection. 5. Presence of severe renal disease (eGFR \<30 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. 6. Clinically significant abnormal white blood cell count (ANC \<1500), hemoglobin (\< 9.0 gm/dL), or platelet count (100 K or \>500 K) as evidenced by laboratory test results at Screening. 7. Any other active cause of optic neuropathy (Vitamin B12 deficiency, Vitamin E deficiency, etc.) or cardiac disease 8. EF less than 35% at last echocardiographic evaluation 9. Uncontrolled arrhythmia 10. Current use of any systemic chronic immunosuppressive drugs 11. Current use of Metformin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in High Contrast Visual Acuity | Baseline to 52 weeks | Change in High Contrast Visual Acuity will be measured by assessing the differences in the number of letters read (binocular) on the ETDRS High Contrast Visual Acuity Chart between groups (low dose and high dose). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Low Luminescence Visual Activity | Baseline to 52 weeks | Change in Low Luminescence Visual Acuity will be measured by assessing the difference in the number of letters read (binocular) on the ETDRS High Contrast Visual Acuity Chart with Low Luminescence Filter between groups (low dose and high dose). |
| Change in Retinal Nerve Fiber Layer by Optical Coherence Tomography (OCT) | Baseline to 52 weeks | The change in thickness of the retinal nerve fiber layer between groups (low dose and high dose) will be measured using the OCT, a non-invasive imaging test that uses light waves to take cross-section pictures of the retina. |
| Change in Visual Quality of Life by Visual Functioning Questionnaire (VFQ) | Baseline to 52 weeks | The VFQ is a 25-item patient reported outcome on visual symptomology to assess change in patient self-report of visual ability over time compared to baseline between groups (low dose and high dose). The VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. Each item is then converted to a 0 to 100 scale. The summary statistic is the difference in mean values from Baseline to Week 52. A negative value represents a worsening over time and a positive value represents improvement. |
| Change in Low Contrast Visual Acuity | Baseline to 52 weeks | Change in Low Contrast Visual Acuity will be measured by assessing the differences in the number of letters read (binocular) on the ETDRS Low Contrast Visual Acuity Chart between groups (low dose and high dose). |
| Change in Cardiac Fibrosis | Baseline to 36 weeks | The change in cardiac fibrosis over time by T1 mapping using late gadolinium enhancement between groups (low dose and high dose). |
| Change Cardiac Stroke Volume | Baseline to 36 weeks | The change in stroke volume will be calculated by Ejection Fraction x Ventricular Volume x Pulse Rate, over time between groups (low dose and high dose). |
| Change in Cardiac Strain | Baseline to 36 weeks | The change in cardiac strain (dL/L) in each dimension per cardiac cycle between groups (low dose and high dose) is measured by speckle tracking on imaging. |
Countries
United States
Participant flow
Pre-assignment details
Of the 20 enrolled participants, 4 subjects screen failed and did not meet the study inclusion criteria. Of the 16 subjects who received treatment and 8 subjects withdrew after consenting and starting treatment from the study. 8 subjects completed all study visits.
Participants by arm
| Arm | Count |
|---|---|
| Low Dose (20-30mg) Subjects will receive daily subcutaneous (SC) dosing of Elamipretide (20-30 mg) for 52 weeks
Elamipretide: Elamipretide is a tetra peptide with limited blood brain barrier penetration being developed for use in a variety of mitochondrial disorders, including FRDA, mitochondrial myopathy and Barth Syndrome. | 8 |
| High Dose (40-60 mg) Subjects will receive daily subcutaneous (SC) dosing of Elamipretide (40-60 mg) for 52 weeks
Elamipretide: Elamipretide is a tetra peptide with limited blood brain barrier penetration being developed for use in a variety of mitochondrial disorders, including FRDA, mitochondrial myopathy and Barth Syndrome. | 8 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Lack of Efficacy | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Low Dose (20-30mg) | High Dose (40-60 mg) | Total |
|---|---|---|---|
| Age, Customized 18-24 (years) | 3 Participants | 2 Participants | 5 Participants |
| Age, Customized 25-34 (years) | 2 Participants | 2 Participants | 4 Participants |
| Age, Customized 35-44 (years) | 2 Participants | 2 Participants | 4 Participants |
| Age, Customized 45-54 (years) | 0 Participants | 2 Participants | 2 Participants |
| Age, Customized 55-64 (years) | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 7 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 8 Participants | 14 Participants |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 8 Participants |
| Sex: Female, Male Male | 2 Participants | 6 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 8 / 8 | 8 / 8 |
| serious Total, serious adverse events | 2 / 8 | 2 / 8 |
Outcome results
Primary
Change in High Contrast Visual Acuity
Change in High Contrast Visual Acuity will be measured by assessing the differences in the number of letters read (binocular) on the ETDRS High Contrast Visual Acuity Chart between groups (low dose and high dose).
Time frame: Baseline to 52 weeks
Population: 2 subjects in low dose and 1 subject in the high dose did not complete Week 52 study visit
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose (20-30mg) | Change in High Contrast Visual Acuity | 5.5 Number of Letters Read on a Vision Board |
| High Dose (40-60 mg) | Change in High Contrast Visual Acuity | 0 Number of Letters Read on a Vision Board |
Secondary
Change Cardiac Stroke Volume
The change in stroke volume will be calculated by Ejection Fraction x Ventricular Volume x Pulse Rate, over time between groups (low dose and high dose).
Time frame: Baseline to 36 weeks
Population: 2 subjects in low dose and 2 subject in the high dose did not complete cardiac testing at the Week 36 study visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose (20-30mg) | Change Cardiac Stroke Volume | 0.12 percentage of change in stroke volume | Standard Deviation 0.16 |
| High Dose (40-60 mg) | Change Cardiac Stroke Volume | -0.02 percentage of change in stroke volume | Standard Deviation 0.29 |
Secondary
Change in Cardiac Fibrosis
The change in cardiac fibrosis over time by T1 mapping using late gadolinium enhancement between groups (low dose and high dose).
Time frame: Baseline to 36 weeks
Population: Due to insufficient number of high quality reproducible scans we were unable to conduct a systematic analysis. The T1 mapping using late gadolinium enhancement needed for this analysis was not done because reproducible scans were unobtainable in individuals with advanced FA due to inability to lie still for sufficient amounts of time and will never be analyzed in the future.
Secondary
Change in Cardiac Strain
The change in cardiac strain (dL/L) in each dimension per cardiac cycle between groups (low dose and high dose) is measured by speckle tracking on imaging.
Time frame: Baseline to 36 weeks
Population: Due to insufficient number of high quality reproducible scans we were unable to conduct a systematic analysis. The speckle tracking needed for this analysis was not done because reproducible scans were unobtainable in individuals with advanced FA due to inability to lie still for sufficient amounts of time and will never be analyzed in the future.
Secondary
Change in Low Contrast Visual Acuity
Change in Low Contrast Visual Acuity will be measured by assessing the differences in the number of letters read (binocular) on the ETDRS Low Contrast Visual Acuity Chart between groups (low dose and high dose).
Time frame: Baseline to 52 weeks
Population: All subjects in both low dose and high dose were unable to read a single letter on the low contrast vision board
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose (20-30mg) | Change in Low Contrast Visual Acuity | 0 Number of Letters Read on a Vision Board |
| High Dose (40-60 mg) | Change in Low Contrast Visual Acuity | 0 Number of Letters Read on a Vision Board |
Secondary
Change in Low Luminescence Visual Activity
Change in Low Luminescence Visual Acuity will be measured by assessing the difference in the number of letters read (binocular) on the ETDRS High Contrast Visual Acuity Chart with Low Luminescence Filter between groups (low dose and high dose).
Time frame: Baseline to 52 weeks
Population: 2 subjects in low dose and 1 subject in the high dose did not complete Week 52 study visit
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose (20-30mg) | Change in Low Luminescence Visual Activity | 0.5 Number of Letters Read on a Vision Board |
| High Dose (40-60 mg) | Change in Low Luminescence Visual Activity | 0 Number of Letters Read on a Vision Board |
Secondary
Change in Retinal Nerve Fiber Layer by Optical Coherence Tomography (OCT)
The change in thickness of the retinal nerve fiber layer between groups (low dose and high dose) will be measured using the OCT, a non-invasive imaging test that uses light waves to take cross-section pictures of the retina.
Time frame: Baseline to 52 weeks
Population: 6 low-dose and 7 high-dose subjects attempted to complete this procedure. However, due to disease progression (abnormal eye movements) and visual impairment (unable to focus on visual target) subjects were unable to perform the OCT exam in both low dose and high dose, thus resulting in poor quality images that were unable to be analyzed and will never be analyzed in the future.
Secondary
Change in Visual Quality of Life by Visual Functioning Questionnaire (VFQ)
The VFQ is a 25-item patient reported outcome on visual symptomology to assess change in patient self-report of visual ability over time compared to baseline between groups (low dose and high dose). The VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. Each item is then converted to a 0 to 100 scale. The summary statistic is the difference in mean values from Baseline to Week 52. A negative value represents a worsening over time and a positive value represents improvement.
Time frame: Baseline to 52 weeks
Population: 2 subjects in low dose and 1 subject in the high dose did not complete Week 52 study visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose (20-30mg) | Change in Visual Quality of Life by Visual Functioning Questionnaire (VFQ) | -2.42 Units on a scale | Standard Deviation 3.85 |
| High Dose (40-60 mg) | Change in Visual Quality of Life by Visual Functioning Questionnaire (VFQ) | 2.08 Units on a scale | Standard Deviation 5.77 |