Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa

Effects of Oral N- Acetylcysteine on Macular Function in Retinitis Pigmentosa; a Phase 2 Randomized Controlled Trial

Retinitis pigmentosa (RP) is an inherited retinal disease with great heterogeneity. RP comprises a large group of genetic disorders causing progressive loss of vision. Despite many suggested treatments, there is actually no effective therapy for most types of RP at present. Mutations that cause RP initially lead to rod cell death. After rod photoreceptors' death, cone photoreceptors also gradually die. There are several hypotheses as to why mutation-induced rod photoreceptor cell death invariably leads to gradual dysfunction and death of cone photoreceptors resulting in severe visual acuity loss and blindness. Rods constitute 95 percent of cells in the outer retina. As they degenerate, oxygen consumption is reduced and the level of tissue oxygen markedly increases. After rods degeneration, several markers of oxidative damage appear in cones. This oxidative stress over time may lead to cone dysfunction and death. Antioxidants reduce markers of oxidative damage and promote cone function and survival. In RP, cone death occurs as a result of the death of rods, rather than as the result of the pathogenic mutations and therefore treatment with antioxidants may have the potential to be applied to all patients with RP irrespective of the disease-causing mutation.

N-acetylcysteine is a derivative of L cysteine that plays a role in the biosynthesis of glutathione and neutralizes reactive oxygen species. It also has a direct antioxidant activity via its reactive sulfhydryl agent. Its systemic use shows an acceptable safety profile. It has been shown that the use of systemic N-acetylcysteine provides significant intraocular concentration and antioxidant activity that may lead to the promotion of cone function and survival.

In a recent phase 1 randomized clinical trial (RCT), it was revealed that oral N-acetylcysteine (NAC) was safe and well-tolerated in patients with moderately advanced RP and might improve sub-optimally functioning macular cones. The authors concluded that a randomized, placebo-controlled trial is needed to determine if oral NAC can provide long-term stabilization and/or improvement in visual function in patients with RP. In this phase 2 RCT, eligible patients with the diagnosis of moderately advanced RP are randomly divided into two groups; treatment group (N-acetylcysteine tablets) and controls (placebo). Each group will be treated for 6 months. In this study, we will investigate if the use of oral N- acetylcysteine as a potent antioxidant agent can slow down or reverse the disease process in RP patients with prior moderate loss of vision. It may potentially demonstrate a treatment modality regardless of the genetic type of RP. The primary outcome measure will be the stability or improvement of the best-corrected visual acuity (BCVA). The secondary outcome measures will be changes in color vision, electroretinogram, visual field, structural OCT indices after 6 months. The same parameters will be re-evaluated 3 months after discontinuation of treatment at month 9.

Study Overview

• Status: Active, not recruiting
• Conditions: Retinitis Pigmentosa
• Intervention / Treatment: Drug: Prescribe N-acetylcysteine tablets; Drug: Prescribe placebo tablets

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Iran, Islamic Republic of
  • Tehran, Iran, Islamic Republic of
    • Ophthalmic Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• RP patients with the best-corrected visual acuity (BCVA) between 20/30 and 20/120.

Exclusion Criteria:

• Patients with other types of retinal dystrophy
• Systemic or syndromic RP
• RP patients with cystoid macular edema (CME) and the presence of cystoid changes in the foveal area
• RP patients with other concomitant ocular diseases
• RP patients with a history of any ocular surgery or intravitreal injection within 6 months before the study enrollment
• RP patients who have received any supplemental drugs during the past three months before the study enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Prescribe N-acetylcysteine tablets	Drug: Prescribe N-acetylcysteine tablets; N-acetylcysteine tablets ,1200 mg two times daily
PLACEBO_COMPARATOR: Prescribe placebo tablets	Drug: Prescribe placebo tablets; manufactured by Daroo Salamat Pharmed, two times daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of the best corrected visual acuity (BCVA) from baseline to month 6	ETDRS chart	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of the ellipsoid zone (EZ) width from baseline to month 6	spectral domain optical coherence tomography (SD-OCT)	6 months
Changes of the wave amplitude of the flicker response from baseline to month 6	Full field electroretinograph (ffERG) testing	6 months
Change of the foveal and macular sensitivity from baseline to month 6	visual field testing	6 months
Change of the color discrimination parameters from baseline to month 6	D15 Fransworth 100 Hue Test	6 months

Collaborators and Investigators

• Sponsor: Shahid Beheshti University of Medical Sciences

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 17, 2021
• Primary Completion (ANTICIPATED): March 1, 2022
• Study Completion (ANTICIPATED): December 20, 2022

Study Registration Dates

• First Submitted: April 21, 2021
• First Submitted That Met QC Criteria: April 27, 2021
• First Posted (ACTUAL): April 29, 2021

Study Record Updates

• Last Update Posted (ACTUAL): April 29, 2021
• Last Update Submitted That Met QC Criteria: April 27, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Genetic Diseases, Inborn; Eye Diseases, Hereditary; Retinal Dystrophies; Retinitis; Retinitis Pigmentosa; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: 1400

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No