Assessing participants' experiences with the COVID-19 symptom diary in a clinical trial

Abstract

During a phase 2/3 study of twice-daily nirmatrelvir 300 mg coadministered with ritonavir 100 mg versus placebo for 5 days (NCT05011513), participants reported presence and severity of COVID-19 symptoms using a COVID-19 symptom diary in accordance with FDA guidance. Here, we aimed to evaluate the content validity of the COVID-19 symptom diary and global impression items through qualitative interviews as recommended by the FDA. Study participants kept a daily electronic diary to record the presence and severity of 14 COVID-19 symptoms (stuffy or runny nose, sore throat, shortness of breath, cough, low energy or tiredness, muscle or body aches, headache, chills/shivering, feeling hot or feverish, nausea, frequency of vomiting, frequency of diarrhea, sense of smell, and sense of taste). They also answered questions regarding 3 global impression items (return to health, return to usual activities, and overall symptom severity). A subset of clinical trial participants was interviewed at study completion to assess content validity of the diary. Overall, 25 participants were interviewed across 10 clinical sites. Each of the 14 symptoms included in the diary were reported by ≥ 1 participant, with low energy/tiredness being reported most frequently (88.0%). Twelve participants (48.0%) reported ≥ 1 symptom that was not captured by the diary, with dizziness being the most common (12.0%). Rates of these symptoms were lower (≤ 12.0%) than the 14 prespecified symptoms included in the diary (16.0-88.0%). Based on participant feedback, all 14 diary items were clear and generally easy to answer using the response scales, and all were interpreted as intended. The 3 global items received similar feedback, although a few participants noted that there were challenges in interpreting the items, describing questions as "vague" and "confusing", or that responses were too limited; one-third reported having difficulty calculating overall symptom experience for multiple symptoms. Participants reported that the electronic application for the diary and global items was easy to use and enabled the items to be easily completed. Exit interview results support the content validity of the COVID-19 symptom diary and global impression items, with the 14 symptoms included in the diary reflecting the most commonly experienced COVID-19 symptoms. NCT05011513; https://classic.clinicaltrials.gov/ct2/show/NCT05011513 .