How do patients rate their subjective symptoms after CNGA3 gene therapy: First application of the instrument A3-PRO

Purpose: There are limitations of wide-spread standard measures for vision-oriented quality of life like the VFQ25. Specific symptoms in low vision caused by hereditary disorders and their short-term variations during an interventional trial may not be sufficiently reflected. This is especially true for Achromatopsia, a hereditary retinal degeneration with severe visual impairment in daily life, its leading symptom being glare in normal daylight conditions. Our aim was to develop a patient reported outcome (PRO) measure as a complement to the VFQ25 in the first gene therapy trial in CNGA3-linked Achromatopsia. Methods: A3-PRO is a short questionnaire to measure the patients' subjective visual performance and its development during therapy in a clinical trial, using five criteria - each represented by a single item. In order to also consider the possibility of sporadic deteriorations we provided a symmetric response scale, although distinctive declines were not expected. The patients rate the development of all aspects on a scale ranging from “almost always worse” (-4) to “almost always better” (+4) in nine indicated steps, including “unchanged” (0) as middle category. The questions are read by an interviewer, so the questionnaire contains a brief instruction and supplementary explanations to each item. The inventory is completed by a simple five-level scale of the patient's overall satisfaction with the therapy. The questions were deduced from the key symptoms identified in an observational trial in the target cohort. Results: A3-PRO was easy to assess for both patient and interviewer. The time need was appr. five minutes per test. Interim results of the ongoing trial (n=9; 1 f, 8 m; age range: 24 to 59 y) are reported (NCT02610582). The questionnaire was able to reflect intra- and interindividual changes of subjective symptoms over the time of the study in all three dosage groups. Our preliminary findings need to be confirmed in the final analysis. Conclusions: A3-PRO is an easy applicable tool for the investigation of Achromatopsia. It provides valuable quantitative data on patient perception of symptom development after treatment and is superior to open, non-standardized questions in the clinical trial setting.