Randomized Adaptive Trial of Bupropion Hydrochloride for Fatigue in Post‑COVID‑19 Syndrome (RAPID‑ELAPSE)

The primary objective of the RAPID‑ELAPSE trial is to determine whether bupropion improves fatigue in individuals with Post Covid Syndrome by assessing the intra‑patient change from baseline in the total score of the Fatigue Severity Scale; a statistically significant reduction would indicate therapeutic efficacy. Contingent upon achieving significance for this endpoint, the secondary primary objective evaluates the effect on overall physical function using the change in the Short Form‑36 Physical Function score, reflecting clinically relevant improvements in daily activity capacity.

The trial enrolled adult men and women who met the criteria for Post Covid Syndrome, defined by documented SARS‑CoV‑2 infection at least three months prior and persistent fatigue with a Fatigue Severity Scale score of 45 or higher. Eligible participants were required to be 18 years of age or older, to exhibit moderate to severe overall disability (Bell Scale 20–60), and to present at least one additional post‑COVID symptom such as dyspnea, reduced exercise capacity, cognitive impairment, or post‑exertional malaise. All subjects had to demonstrate stable health without an alternative diagnosis that could explain the symptoms and possess the capacity to understand and comply with trial procedures. Contraceptive use according to stringent guidelines was mandatory for persons of childbearing potential and for male participants with fertile partners. Participants were asked to maintain consistent medication regimens and to avoid alterations in type, dosage, or frequency of concomitant drugs through Day 84. The sponsor did not provide information on the total number of participants enrolled.

The RAPID‑ELAPSE trial is a randomized, double‑blind, placebo‑controlled, adaptive Phase II/IV study evaluating the efficacy of oral bupropion (300 mg/day) versus matching placebo for the treatment of fatigue in adults with Post Covid Syndrome. Participants meeting defined inclusion criteria undergo a screening visit, followed by a baseline assessment on Day 1 (V2) when study medication is initiated. Subsequent visits occur at Day 28 (mid‑treatment assessment, V4‑MOT), Day 56 (end of treatment, V5‑EOT), and Day 84 (end‑of‑study, V6‑EOS) to collect efficacy endpoints, safety data, and biosamples. The primary endpoints are the intra‑patient change in Fatigue Severity Scale total score and the change in Short Form‑36 Physical Function score from baseline to Day 56. Secondary assessments include fatigue, physical function, mood, dyspnea, exercise capacity, and cognitive function measured at specified intervals. Study involvement for each participant spans approximately 12 weeks, with continuous monitoring for adverse events, pregnancy, non‑adherence to study medication, or emergence of alternative diagnoses, any of which may lead to early discontinuation. Recruitment is planned to commence in April 2026 with an anticipated study completion by December 2028.

The investigational product is bupropion-ratiopharm 150 mg tablets with modified release, containing bupropion hydrochloride as the active substance. Each tablet is administered orally, and two tablets are given per dose to achieve a total of 300 mg per administration. The dosing schedule follows a once‑daily regimen throughout the treatment period.

The comparator is a matching placebo consisting of an HPMC capsule, size 000, filled with mannitol. The placebo contains no active pharmaceutical ingredient and is administered orally using the same schedule as the active product.

Drug administration is performed under blinded conditions. Compliance is assessed by pill count at each study visit, review of patient‑maintained dosing diaries, and verification of capsule integrity. Any missed doses are recorded, and participants receive reminders to adhere to the prescribed regimen.

The primary efficacy assessment will evaluate the intra‑patient change in fatigue severity from baseline to Day 56 using the total score of the Fatigue Severity Scale (FSS). If this endpoint reaches statistical significance, a second hierarchical primary endpoint will be examined: the intra‑patient change in overall physical function from baseline to Day 56 as measured by the Short Form‑36 Physical Function (SF‑36‑PF) score. Both instruments are validated patient‑reported outcome measures and will be administered at the defined visits.

Secondary efficacy evaluations include:

• Change in SF‑36‑PF from baseline to Day 28 (mid‑treatment) and Day 84 (28 days post‑treatment).
• Change in FSS from screening to Day 28 and Day 84.
• Change in depressive symptoms measured by the PHQ‑9 from baseline (Day 1) to Days 28, 56 and 84.
• Change in generalized anxiety measured by the GAD‑7 at the same time points.
• Change in somatic symptom severity measured by the PHQ‑15 and psychosocial strain measured by the PHQ‑stress from baseline to Days 28, 56 and 84.
• Change in dyspnea severity using the mMRC scale from screening to Days 28, 56 and 84.
• Change in physical exercise capacity assessed by the 1‑Minute Sit‑to‑Stand Test (1MSTS) from screening to Days 28 and 56.
• Change in cognitive function evaluated with the Symbol Digit Modalities Test (SDMT) from screening to Days 28 and 56.
• Exploratory biosample collection (serum, EDTA‑plasma, PBMCs, cytometry/CyTOF) at baseline, Day 1 and Day 56 for future stratification analyses.