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The FIGHT-RP1 Study (FIGHT-RP1)

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ClinicalTrials.gov Identifier: NCT03063021
Recruitment Status : Active, not recruiting
First Posted : February 24, 2017
Last Update Posted : June 19, 2018
Sponsor:
Information provided by (Responsible Party):
Johns Hopkins University

Brief Summary:

Retinitis Pigmentosa (RP) is a devastating eye disease and at present there are no known treatment options that can alter the rate of vision loss. In a series of studies in animal models, the effects of exposing cones in the periphery of the retina to a large excess of oxygen results in progressive oxidative damage to cone photoreceptors and cone cell death. Compared to control patients, those with RP showed significant reduction in the reduced to oxidized glutathione ratio (GSH/GSSG) in aqueous humor and a significant increase in protein carbonyl content. This demonstration of oxidative stress and oxidative damage in the eyes of patients with RP, suggests that oxidative damage-induced cone cell death in animal models of RP may translate to humans with RP and support the hypotheses that (1) potent antioxidants will promote cone survival and function in patients with RP and (2) aqueous GSH/GSSG ratio and carbonyl content on proteins provide useful biomarkers of disease activity in this patient population. Orally administered N-Acetylcysteine (NAC) has been found to be a particularly effective antioxidant that promotes prolonged cone survival and maintenance of cone function in a mouse model of RP. There is good rationale to test the effect of NAC in patients with RP. The first step is to do test different dosing regimens to identify the lowest dose that is able restore aqueous GSH/GSSG ratio and reduce carbonyl adducts on aqueous proteins.

In patients with Idiopathic Pulmonary Fibrosis, polymorphisms within the TOLLIP gene were found to influence outcomes of NAC-treated patients. The product of the TOLLIP gene, toll-interacting protein, is an inhibitory adaptor protein downstream of toll-like receptors, mediators of innate and adaptive immunity. The identification of the influence of TOLLIP polymorphisms on the effect of NAC in Idiopathic Pulmonary Fibrosis provides rationale for collecting DNA and genotyping the same single nucleotide polymorphisms (SNPs) in the current trial. In addition to this candidate gene genetic analysis, patient RNA will be collected and banked for future transcriptome analysis. The rationale for this is to identify gene expression changes that modify disease progression in RP. There is substantial variability in rate of progression among patients with RP. A patient who loses all vision early in life can have a sibling with the same mutation who maintains vision into advanced age. This suggests that modifier genes can have a major impact on cone survival. This study will test the hypothesis that the level of expression of gene products that contribute to the antioxidant defense system may influence cone cell death and hence the rate of loss of visual field. It is also possible that gene expression differences may contribute to differences in response to NAC. For these reasons collecting RNA samples from patients will allow next generation sequencing in the future to understand the transcriptome background on which the study intervention has been performed.


Condition or disease Intervention/treatment Phase
Retinitis Pigmentosa Drug: N-Acetyl Cysteine (NAC) Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Open Label Dose Ranging Study to Assess the Safety and Tolerability of N-Acetylcysteine (NAC) in Patients With Retinitis Pigmentosa (FIGHT-RP1 Study)
Actual Study Start Date : February 15, 2017
Estimated Primary Completion Date : February 2019
Estimated Study Completion Date : February 2020


Arm Intervention/treatment
Experimental: Experimental Arm (carbonyl content >0.6, GSH/GSSG <3)
Subjects with RP will be enrolled in the experimental arm if they have a high carbonyl content (>0.6) and a reduced GSH/GSSG ratio (<3.0) in the aqueous.
Drug: N-Acetyl Cysteine (NAC)
Oral tablets of N-acetyl-cysteine

Experimental: Exploratory Arm (carbonyl content <0.6, GSH/GSSG >3)
Subjects with RP who don't have a high carbonyl content (>0.6) and a reduced GSH/GSSG ratio (<3.0) but otherwise are good candidates for the study will be enrolled in the exploratory arm.
Drug: N-Acetyl Cysteine (NAC)
Oral tablets of N-acetyl-cysteine




Primary Outcome Measures :
  1. Assessment of safety and tolerability of N-Acetylcysteine including incidence and severity of systemic and ocular adverse events (AEs) and changes from baseline vital signs and physical examination. [ Time Frame: Up to 10 months ]
    Assessment of safety and tolerability of N-Acetylcysteine including incidence and severity of systemic and ocular adverse events (AEs) and changes from baseline vital signs and physical examination.


Secondary Outcome Measures :
  1. Change from baseline aqueous and serum carbonyl content and GSH/GSSG ratio at 1 month after initiation of N-Acetylcysteine . [ Time Frame: 1 month after initiation of N-Acetylcysteine ]
  2. Change from baseline aqueous and serum carbonyl content and GSH/GSSG ratio at 2 months after initiation of N-Acetylcysteine . [ Time Frame: 2 months after initiation of N-Acetylcysteine ]
  3. Change from baseline aqueous and serum carbonyl content and GSH/GSSG ratio at 3 months after initiation of N-Acetylcysteine . [ Time Frame: 3 months after initiation of N-Acetylcysteine ]
  4. Change from baseline aqueous and serum carbonyl content and GSH/GSSG ratio at 4 months after initiation of N-Acetylcysteine . [ Time Frame: 4 months after initiation of N-Acetylcysteine ]
  5. Change from baseline aqueous and serum carbonyl content and GSH/GSSG ratio at 5 months after initiation of N-Acetylcysteine . [ Time Frame: 5 months after initiation of N-Acetylcysteine ]
  6. Change from baseline aqueous and serum carbonyl content and GSH/GSSG ratio at 6 months after initiation of N-Acetylcysteine . [ Time Frame: 6 months after initiation of N-Acetylcysteine ]
  7. Change from baseline aqueous and serum carbonyl content and GSH/GSSG ratio at 7 months after initiation of N-Acetylcysteine . [ Time Frame: 7 months after initiation of N-Acetylcysteine ]
  8. Change from baseline aqueous and serum carbonyl content and GSH/GSSG ratio at 8 months after initiation of N-Acetylcysteine . [ Time Frame: 8 months after initiation of N-Acetylcysteine ]
  9. Change from baseline aqueous and serum carbonyl content and GSH/GSSG ratio at 9 months after initiation of N-Acetylcysteine . [ Time Frame: 9 months after initiation of N-Acetylcysteine ]
  10. Change from baseline best corrected visual acuity (BCVA) 6 months after initiation of N-Acetylcysteine [ Time Frame: 6 months after initiation of N-Acetylcysteine ]
  11. Change from baseline central retinal sensitivity by microperimetry 3 months after initiation of N-Acetylcysteine [ Time Frame: 3 months after initiation of N-Acetylcysteine ]
  12. Change from baseline central retinal sensitivity by microperimetry 6 months after initiation of N-Acetylcysteine [ Time Frame: 6 months after initiation of N-Acetylcysteine ]
  13. Change from baseline central retinal sensitivity by microperimetry 9 months after initiation of N-Acetylcysteine [ Time Frame: 9 months after initiation of N-Acetylcysteine ]
  14. Change from baseline ellipsoid zone (EZ) width by spectral domain optical coherence tomography (SD-OCT) 6 months after initiation of N-Acetylcysteine [ Time Frame: 6 months after initiation of N-Acetylcysteine ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

All subjects must meet the following criteria to be eligible for study entry:

  • Signed informed consent and authorization of use and disclosure of protected health information
  • Age >18 years
  • Patients diagnosed with RP by the investigators, based on clinical phenotype and diagnostic tests

Exclusion Criteria:

Subjects who meet any of the following criteria will be ineligible for study entry:

  • Patients with concurrent retinal pathologies that result in vision loss, including but not limited to retinal vein occlusion, diabetic retinopathy and neovascular age-related macular degeneration. If one eye does not have any retinal pathology other than RP, it may be enrolled in the study.
  • Patients with uncontrolled arterial hypertension defined as diastolic blood pressure > 95 mm Hg or systolic blood pressure > 160 mm Hg despite medical therapy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03063021


Locations
United States, Maryland
Wilmer Eye Institute, Johns Hopkins
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
Johns Hopkins University

Responsible Party: Johns Hopkins University
ClinicalTrials.gov Identifier: NCT03063021     History of Changes
Other Study ID Numbers: IRB00103296
First Posted: February 24, 2017    Key Record Dates
Last Update Posted: June 19, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Retinitis
Retinitis Pigmentosa
Cone-Rod Dystrophies
Retinal Diseases
Eye Diseases
Eye Diseases, Hereditary
Retinal Dystrophies
Retinal Degeneration
Genetic Diseases, Inborn
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes