Abstract: We reviewed 394 titles and abstracts and nine ClinicalTrials.gov records and included three RCTs that met our eligibility criteria. The three trials included a total of 866 participants aged four to 55 years with RP of all forms of genetic predisposition. One trial evaluated the effect of vitamin A alone, one trial evaluated DHA alone, and a third trial evaluated DHA and vitamin A versus vitamin A alone. None of the RCTs had protocols available, so selective reporting bias was unclear for all. In addition, one trial did not specify the method for random sequence generation, so there was an unclear risk of bias. All three trials were graded as low risk of bias for all other domains. We did not perform meta-analysis due to clinical heterogeneity of participants and interventions across the included trials. The primary outcome, mean change of visual field from baseline at one year, was not reported in any of the studies. No toxicity or adverse events were reported in these three trials. No trial reported a statistically significant benefit of vitamin supplementation on the progression of visual field loss or visual acuity loss. Two of the three trials reported statistically significant differences in ERG amplitudes among some subgroups of participants, but these results have not been replicated or substantiated by findings in any of the other trials. Based on the results of three RCTs, there is no clear evidence for benefit of treatment with vitamin A and/or DHA for people with RP, in terms of the mean change in visual field and ERG amplitudes at one year and the mean change in visual acuity at five years follow-up. In future RCTs, since some of the studies in this review included unplanned subgroup analysis that suggested differential effects based on previous vitamin A exposure, investigators should consider examining this issue. Future trials should take into account the changes observed in ERG amplitudes and other outcome measures from trials included in this review, in addition to previous cohort studies, when calculating sample sizes to assure adequate power to detect clinically and statistically meaningful difference between treatment arms.

Plain-language summary: We identified three clinical studies conducted in the USA and Canada. These studies included 866 participants with RP aged between four and 55 years, who were followed for an average of four years after administration of treatment. One study compared a fish oil extract (docosahexaenoic acid (DHA, 400 mg per day)), to placebo (pretend medicine); the second study compared vitamin A (15000 IU per day) to vitamin E (400 IU per day) and to very low levels of vitamins (vitamin A trace + vitamin E trace); and the third study compared DHA (1200 mg per day) + vitamin A (15000 IU per day) to vitamin A alone (15000 IU per day). The evidence is current to August 2013. All these studies measured the following outcomes: worsening in visual field, worsening in visual acuity (sharpness), and worsening in electroretinography results. Generally, comparison of participants who received vitamin A with or without fish oils (DHA) with participants who received placebo, did not show any difference for these outcomes, which means that the use of high-dose vitamin A or fish oils does not significantly slow progressive visual loss in people with RP. None of the studies reported any systemic adverse events from vitamin A or fish oil. However, the long-term adverse effects of high-dose vitamin A and fish oil are not known. The trials appear to have been well designed and well conducted, so we determined the quality was good for all included studies.