Retinitis Pigmentosa
Conditions
Keywords
retinitis pigmentosa, valproic acid, visual field
Brief summary
The objectives of this study are to evaluate the efficacy of Valproic Acid (VPA) to both slow the progression of visual function loss and/or to restore visual function in patients with Autosomal Dominant Retinitis Pigmentosa (RP) and to collect safety and tolerability information.
Detailed description
Retinitis Pigmentosa (RP) is an incurable and untreatable group of heterogeneous retinal degenerative diseases that cause severe visual loss. There is currently no therapeutic that substantially slows the progression of this disease, and certainly none that can restore vision in RP patients. The Valproic Acid (VPA) study is designed as a six-site, interventional, prospective, randomized, placebo controlled, double-blinded study of 90 participants to evaluate the efficacy of oral Valproic Acid to both slow the progression of visual function loss and/or to restore visual function in patients with an Autosomal Dominant RP genetic mutation and to collect safety and tolerability information. Patients that participate in the study will be randomized to either placebo or VPA in a 1:1 ratio.
Interventions
DRUGValproic Acid
One to four 250mg softgels by mouth daily (dose determined by body weight)
DRUGPlacebo
Dosage per subject weight- same schedule as the active comparator
Sponsors
United States Department of Defense
Foundation Fighting Blindness
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Understand/sign the IRB-approved study informed consent document. 2. Age greater than or equal to 18 years, no upper age limit 3. Males and non-child bearing females must weigh ≥40 Kg and ≤158.9 Kg; Females of child bearing potential must weigh ≥40 Kg and ≤74.9 Kg. 4. Diagnosis of Retinitis Pigmentosa (RP). 5. Visual acuity of greater than or equal to 35 letters in at least one eye as measured by the EVA-ETDRS (equivalent to 20/200 on a Snellen chart). 6. Genotyped as autosomal dominant form of RP. 7. Female subjects of childbearing potential and male subjects able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse or must commit to practice at least two acceptable methods of contraception to minimize the chance of pregnancy during the study and for the 13 week period after stopping the study drug. 8. Female subjects of childbearing potential must have a negative urine pregnancy test at study entry and throughout the duration of the study. 9. Willingness to comply with the protocol.
Exclusion criteria
1. Medical problems that make consistent follow-up over the treatment period unlikely (e.g. stroke, severe MI, end stage malignancy), or in general a poor medical risk because of other systemic diseases or active uncontrolled infections. 2. Other retinal diseases: Glaucoma, retinal inflammatory disease (CME is allowable), cataract worse than +2 NS, or herpes simplex virus of the eye. 3. Intact visual field of 5⁰ or less. 4. Subject unable to provide reliable perimetry measurements in both eyes for both static and kinetic visual field, as determined by the Reading Center. 5. Diabetes. 6. History of cancer (other than non-melanoma skin cancer) diagnosed, or requiring treatment within the past 2 years. 7. A hemoglobin concentration, a platelet count or an absolute neutrophil count below the lower limit of normal at study entry. 8. Suspected liver dysfunction determined by having liver function values elevated above the upper limit of normal. 9. History of pancreatitis by clinical features and/or laboratory abnormalities in the last 12 months. 10. Renal dysfunction based on serum creatinine,(MDRD) equation. 11. Urea cycle disorders. 12. History of neurological conditions including epilepsy, history of brain injury, encephalitis, or any organic brain syndrome. 13. History of schizophrenia, schizoaffective disorder, bipolar disorder, suicidality or organic mental disorders. 14. Currently receiving valproic acid or other anti-convulsants. 15. Sensitive to or have ever had an allergic reaction to valproic Acid. 16. Sensitive to or have ever had an allergic reaction to peanuts as peanut oil is an inactive ingredient in valproic acid capsules and the placebo. 17. Has taken one of the disallowed drugs at least 2 weeks prior to randomization. 18. Pregnant women. 19. Lactating mothers who are breast feeding their babies. 20. RP patients involved in other clinical trials within the last 3 months. 21. Require enrollment by consent of a legally authorized representative. 22. Persons who are unable to read are not allowed to consent for themselves or others to participate in this study. 23. The potential participant lives in the same household as a current participant in this protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Visual Field Area From Baseline to 52 Weeks--III4e Isopter | baseline to week 52 | Mean change in visual field area from baseline to 52 weeks. Visual field area is measured with semi-automated kinetic perimetry (SKP) using the Octopus 900 (Haag-Streit) with the III4e target size for each eye and done at least twice to ensure reliable sessions; the visual field area measurements are averaged over the two sessions. Analysis performed with linear mixed model |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Visual Field Area From Baseline to 52 Weeks--I4e Isopter | baseline to week 52 | Mean change in visual field area from baseline to 52 weeks. Visual field area is measured with semi-automated kinetic perimetry (SKP) using the Octopus 900 (Haag-Streit) with the I4e target size for each eye and done at least twice to ensure reliable sessions; the visual field area measurements are averaged over the two sessions. Analysis performed with linear mixed model |
| Static Perimetry by Treatment Arm--Full Field Hill of Vision | baseline to week 52 | Mean change from baseline at week 52 for Full field Hill of Vision (Static perimetry) |
| Static Perimetry Volume--30 Degree Hill of Vision | baseline to week 52 | Mean Change from baseline to week 52 for Static Perimetry Volume --30 Degree Hill of Vision. Full field static perimetry protocol was followed using the Octopus 900 (Haag-Streit) for a single session for each eye. |
| Mean Change From Baseline in Best Corrected Visual Acuity | baseline to week 52 | Mean change in best corrected visual acuity as assessed by ETDRS (Early Treatment Diabetic Retinopathy Study) method from baseline to week 52 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Subjects who receive placebo
Placebo: Dosage per subject weight- same schedule as the active comparator | 44 |
| Valproic Acid Subjects who receive valproic acid
Valproic Acid: One to four 250mg softgels by mouth daily (dose determined by body weight) | 46 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Placebo | Valproic Acid | Total |
|---|---|---|---|
| Age, Continuous | 51.6 years STANDARD_DEVIATION 10.9 | 49.3 years STANDARD_DEVIATION 12.3 | 50.4 years STANDARD_DEVIATION 11.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 5 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 41 Participants | 79 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Genetic Mutations IMPDH1 | 1 Participants | 0 Participants | 1 Participants |
| Genetic Mutations KLHL7 | 1 Participants | 0 Participants | 1 Participants |
| Genetic Mutations NR2E3 | 0 Participants | 2 Participants | 2 Participants |
| Genetic Mutations NR2E3 and TOPORS | 0 Participants | 1 Participants | 1 Participants |
| Genetic Mutations PRPF31 | 5 Participants | 9 Participants | 14 Participants |
| Genetic Mutations PRPF8 | 3 Participants | 1 Participants | 4 Participants |
| Genetic Mutations PRPH2 | 2 Participants | 2 Participants | 4 Participants |
| Genetic Mutations RHO | 22 Participants | 19 Participants | 41 Participants |
| Genetic Mutations RHO and PRPH2 | 2 Participants | 0 Participants | 2 Participants |
| Genetic Mutations RHO and ROM1 | 0 Participants | 1 Participants | 1 Participants |
| Genetic Mutations RP1 | 4 Participants | 9 Participants | 13 Participants |
| Genetic Mutations SNRNP200/ASCC3L1 | 2 Participants | 0 Participants | 2 Participants |
| Genetic Mutations TOPORS | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 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 | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 43 Participants | 44 Participants | 87 Participants |
| Sex: Female, Male Female | 20 Participants | 24 Participants | 44 Participants |
| Sex: Female, Male Male | 24 Participants | 22 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 1 / 46 |
| other Total, other adverse events | 41 / 44 | 45 / 46 |
| serious Total, serious adverse events | 2 / 44 | 3 / 46 |
Outcome results
Primary
Mean Change in Visual Field Area From Baseline to 52 Weeks--III4e Isopter
Mean change in visual field area from baseline to 52 weeks. Visual field area is measured with semi-automated kinetic perimetry (SKP) using the Octopus 900 (Haag-Streit) with the III4e target size for each eye and done at least twice to ensure reliable sessions; the visual field area measurements are averaged over the two sessions. Analysis performed with linear mixed model
Time frame: baseline to week 52
Population: The analysis followed the intent-to-treat principle in that all randomized participants were included and analyzed according to their treatment assignment regardless of amount or type of treatment received. Only observed data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo--Right Eye | Mean Change in Visual Field Area From Baseline to 52 Weeks--III4e Isopter | -122.9 Visual field area (degrees squared) | Standard Deviation 543.6 |
| Placebo--Left Eye | Mean Change in Visual Field Area From Baseline to 52 Weeks--III4e Isopter | -112.0 Visual field area (degrees squared) | Standard Deviation 584.63 |
| Valproic Acid--Right Eye | Mean Change in Visual Field Area From Baseline to 52 Weeks--III4e Isopter | -293.7 Visual field area (degrees squared) | Standard Deviation 736.56 |
| Valproic Acid--Left Eye | Mean Change in Visual Field Area From Baseline to 52 Weeks--III4e Isopter | -237.1 Visual field area (degrees squared) | Standard Deviation 691.76 |
p-value: 0.035Mixed Models Analysis
Secondary
Mean Change From Baseline in Best Corrected Visual Acuity
Mean change in best corrected visual acuity as assessed by ETDRS (Early Treatment Diabetic Retinopathy Study) method from baseline to week 52
Time frame: baseline to week 52
Population: The analysis followed the intent-to-treat principle in that all randomized participants were included and analyzed according to their treatment assignment regardless of amount or type of treatment received. Only observed data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo--Right Eye | Mean Change From Baseline in Best Corrected Visual Acuity | -1.4 letters read correctly | Standard Deviation 5.21 |
| Placebo--Left Eye | Mean Change From Baseline in Best Corrected Visual Acuity | 0.0 letters read correctly | Standard Deviation 3.41 |
| Valproic Acid--Right Eye | Mean Change From Baseline in Best Corrected Visual Acuity | 0.2 letters read correctly | Standard Deviation 4.41 |
| Valproic Acid--Left Eye | Mean Change From Baseline in Best Corrected Visual Acuity | 1.3 letters read correctly | Standard Deviation 5.05 |
Secondary
Mean Change in Visual Field Area From Baseline to 52 Weeks--I4e Isopter
Mean change in visual field area from baseline to 52 weeks. Visual field area is measured with semi-automated kinetic perimetry (SKP) using the Octopus 900 (Haag-Streit) with the I4e target size for each eye and done at least twice to ensure reliable sessions; the visual field area measurements are averaged over the two sessions. Analysis performed with linear mixed model
Time frame: baseline to week 52
Population: The analysis followed the intent-to-treat principle in that all randomized participants were included and analyzed according to their treatment assignment regardless of amount or type of treatment received. Only observed data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo--Right Eye | Mean Change in Visual Field Area From Baseline to 52 Weeks--I4e Isopter | 80.9 Visual field area (degrees squared) | Standard Deviation 406.2 |
| Placebo--Left Eye | Mean Change in Visual Field Area From Baseline to 52 Weeks--I4e Isopter | 115.7 Visual field area (degrees squared) | Standard Deviation 696.89 |
| Valproic Acid--Right Eye | Mean Change in Visual Field Area From Baseline to 52 Weeks--I4e Isopter | 5.3 Visual field area (degrees squared) | Standard Deviation 759.46 |
| Valproic Acid--Left Eye | Mean Change in Visual Field Area From Baseline to 52 Weeks--I4e Isopter | 19.5 Visual field area (degrees squared) | Standard Deviation 703.83 |
p-value: 0.581Mixed Models Analysis
Secondary
Static Perimetry by Treatment Arm--Full Field Hill of Vision
Mean change from baseline at week 52 for Full field Hill of Vision (Static perimetry)
Time frame: baseline to week 52
Population: The analysis followed the intent-to-treat principle in that all randomized participants were included and analyzed according to their treatment assignment regardless of amount or type of treatment received. Only observed data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo--Right Eye | Static Perimetry by Treatment Arm--Full Field Hill of Vision | -0.3 db-steridians | Standard Deviation 2.55 |
| Placebo--Left Eye | Static Perimetry by Treatment Arm--Full Field Hill of Vision | -1.4 db-steridians | Standard Deviation 3.27 |
| Valproic Acid--Right Eye | Static Perimetry by Treatment Arm--Full Field Hill of Vision | -0.2 db-steridians | Standard Deviation 5.11 |
| Valproic Acid--Left Eye | Static Perimetry by Treatment Arm--Full Field Hill of Vision | -0.6 db-steridians | Standard Deviation 4.68 |
p-value: 0.409Wilcoxon (Mann-Whitney)
Secondary
Static Perimetry Volume--30 Degree Hill of Vision
Mean Change from baseline to week 52 for Static Perimetry Volume --30 Degree Hill of Vision. Full field static perimetry protocol was followed using the Octopus 900 (Haag-Streit) for a single session for each eye.
Time frame: baseline to week 52
Population: The analysis followed the intent-to-treat principle in that all randomized participants were included and analyzed according to their treatment assignment regardless of amount or type of treatment received. Only observed data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo--Right Eye | Static Perimetry Volume--30 Degree Hill of Vision | -0.3 db-steridans | Standard Deviation 0.61 |
| Placebo--Left Eye | Static Perimetry Volume--30 Degree Hill of Vision | -0.3 db-steridans | Standard Deviation 0.73 |
| Valproic Acid--Right Eye | Static Perimetry Volume--30 Degree Hill of Vision | -0.2 db-steridans | Standard Deviation 1.07 |
| Valproic Acid--Left Eye | Static Perimetry Volume--30 Degree Hill of Vision | -0.2 db-steridans | Standard Deviation 0.96 |
p-value: 0.229Wilcoxon (Mann-Whitney)