Friedreich Ataxia
Conditions
Keywords
Friedreich ataxia, Interferon gamma-1b, FRDA
Brief summary
Friedreich ataxia (FRDA) is a progressive neurodegenerative disease of children and adults for which there is presently no therapy. Recently, a study reported that interferon gamma (IFN-g) could raise frataxin protein levels in both cell lines derived from patients with Friedreich ataxia and in a mouse model with Friedreich ataxia. The present study will test whether IFN-g is safe, tolerated and potentially efficacious in a heterogeneous cohort of children with FRDA.
Detailed description
Study Objectives: Primary: • To assess the effect of Interferon Gamma-1b (IFN-g) on increasing frataxin expression and protein in children with FRDA. Secondary: * To assess the effect of IFN-g on neurological outcomes (FARS, performance measures, and hearing) in subjects with FRDA. * To assess the effectiveness of IFN-g on quality of life in subjects with FRDA. * To assess the safety and tolerability of IFN-g at the currently approved dose in the FRDA population. Study Phases: Screening - During screening, subjects will be assessed for inclusion and exclusion criteria. Intervention - Subjects will begin treatment at baseline visit and the dose of study medication will be increased to the maximum dose over four weeks. The subjects will be maintained at the maximum dose for 8 weeks. After 12 weeks, treatment will stop. Study medication will be administered via subcutaneous injections three times per week for 12 weeks. Follow-up - Follow-up visits will occur at 7 and 28 days after the subject has completed the 12 weeks of active treatment.
Interventions
DRUGInterferon Gamma-1b
Subjects will begin by taking 10 mcg/m2 of IFN-g-1b for the first two weeks of the study. Dose will be escalated to 25 mcg/m2 of IFN-g-1b for weeks three and four of the study. Finally, the dose will be escalated to 50 mcg/m2 of IFN-g-1b for the last eight weeks of the study, which is the current dose approved by the FDA for children. All doses will be administered via subcutaneous injection.
Sponsors
Friedreich's Ataxia Research Alliance
Vidara Therapeutics Research Ltd
Children's Hospital of Philadelphia
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with FRDA confirmed by genetic testing with 2 expanded Guanine-adenine-adenine repeats * Females who are not pregnant or breast feeding, and who do not intend to become pregnant. Females of child-bearing potential must use a reliable method of contraception and must provide a negative urine pregnancy test at screening * Stable doses of all medications, vitamins and supplements for 30 days prior to study entry and for the duration of the study * Parent/guardian permission (informed consent) and child assent
Exclusion criteria
* Any unstable illness that in the investigator's opinion precludes participation in this study * Use of any investigational product within 30 days prior to enrollment * Subjects with a history of substance abuse * Presence of clinically significant cardiac disease * History of hypersensitivity to IFN-g or E. coli derived products * Presence of severe renal disease or hepatic disease * Clinically significant abnormal White blood cell count, hemoglobin or platelet count * Any subject planning a scheduled surgical procedure during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Whole Blood Frataxin Levels | Frataxin levels were measured at the beginning and conclusion of treatment (baseline and 12 weeks) | Assessment of the change in whole blood frataxin levels as assessed by lateral flow assay using an immunoassay for frataxin. Frataxin levels in the blood were measured at each study visit. Change in frataxin level at the end of treatment (week 12) relative to frataxin level at baseline was analyzed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Friedreich Ataxia Rating Scale (FARS) Score | FARS score was calculated at the beginning and conclusion of treatment (baseline and 12 weeks) | The Friedreich Ataxia Rating Scale (FARS) is neurological rating scale specifically developed and validated for FRDA. The FARS includes assessments of stance, gait, upper and lower limb coordination, speech, proprioception and strength. In addition to the standard neurological examination, the FARS contains three quantitative performance measures and a component that assesses activities of daily living (ADL). Quantitative performance measures include the nine-hole peg test, and a timed 25-foot walk. FARS scores correlate significantly with functional disability, activities of daily living scores and disease duration. The scores from the three subscales are added to generate a total score ranging from 0 to 159, with a higher score indicating a greater level of disability. |
Countries
United States
Participant flow
Recruitment details
12 subjects were screened and all were enrolled in the study between September - December 2013.
Participants by arm
| Arm | Count |
|---|---|
| Interferon Gamma-1b (ACTIMMUNE) All individuals in this study were treated with interferon gamma-1b (ACTIMMUNE). Doses were administered via subcutaneous injections three times per week for 12 weeks. Dose-escalation schedule was completed by all subjects as follows: For the first two weeks subjects took10 mcg/m2 of interferon gamma-1b (IFN-g-1b), then the dose was escalated to 25 mcg/m2 of IFN-g-1b for weeks three and four of the study, finally, the dose was escalated to 50 mcg/m2 of IFN-gamma-1b for the last eight weeks of the study, which is the current dose approved by the FDA for children. | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 2 |
Baseline characteristics
| Characteristic | Interferon Gamma-1b (ACTIMMUNE) |
|---|---|
| Age, Categorical <=18 years | 12 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 12 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 11 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Change in Whole Blood Frataxin Levels
Assessment of the change in whole blood frataxin levels as assessed by lateral flow assay using an immunoassay for frataxin. Frataxin levels in the blood were measured at each study visit. Change in frataxin level at the end of treatment (week 12) relative to frataxin level at baseline was analyzed.
Time frame: Frataxin levels were measured at the beginning and conclusion of treatment (baseline and 12 weeks)
Population: The primary analysis was based on an intent-to-treat approach including all subjects who had baseline frataxin blood levels collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Interferon Gamma-1b (ACTIMMUNE) | Change in Whole Blood Frataxin Levels | -1.5 percentage of baseline frataxin level | Standard Deviation 1.9 |
p-value: 0.027t-test, 2 sided
Secondary
Change in Total Friedreich Ataxia Rating Scale (FARS) Score
The Friedreich Ataxia Rating Scale (FARS) is neurological rating scale specifically developed and validated for FRDA. The FARS includes assessments of stance, gait, upper and lower limb coordination, speech, proprioception and strength. In addition to the standard neurological examination, the FARS contains three quantitative performance measures and a component that assesses activities of daily living (ADL). Quantitative performance measures include the nine-hole peg test, and a timed 25-foot walk. FARS scores correlate significantly with functional disability, activities of daily living scores and disease duration. The scores from the three subscales are added to generate a total score ranging from 0 to 159, with a higher score indicating a greater level of disability.
Time frame: FARS score was calculated at the beginning and conclusion of treatment (baseline and 12 weeks)
Population: The analysis was based on an intent-to-treat approach and included all subjects with baseline FARS assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Interferon Gamma-1b (ACTIMMUNE) | Change in Total Friedreich Ataxia Rating Scale (FARS) Score | -4.98 units on a scale | Standard Deviation 3.6 |
p-value: 0.0078t-test, 2 sided