Adaptive Platform Trial Assessing Minocycline, Colchicine, and Metformin on Physical Health‑Related Quality of Life in Post‑Acute Sequelae of SARS‑CoV‑2 Infection (PASC)

The primary objective of the study is to determine the impact of each investigational product (**IP**) versus control on patient-reported physical health-related quality of life (**HRQoL**) in individuals with post-acute sequelae of SARS-CoV-2 infection (**PASC**). This is clinically relevant as it aims to assess the effectiveness of treatments in improving the physical well-being of patients suffering from long-term effects of COVID-19.

Secondary objectives include:

• Determining the impact of each IP versus control on patient-reported mental HRQoL and on the seven PROMIS-29 domains individually.
• Assessing the impact on specific PASC symptoms such as fatigue, post-exertional malaise (**PEM**), cognitive functioning, and autonomic dysfunction.
• Evaluating the safety and tolerability of each IP in PASC patients.
• Assessing the durability of IP treatment responses.
• Exploratory objectives include exploring the above by PASC disease phenotype and pre-enrolment PASC symptom duration, investigating PASC pathophysiology and mechanisms of action of potential treatments, and identifying biomarkers for PASC symptom clusters and treatment-associated recovery.

The clinical trial focuses on individuals experiencing **post-acute sequelae of SARS-CoV-2 infection (PASC)**, with a primary objective to assess the impact of investigational products versus control on patient-reported physical health-related quality of life. The study population includes adults aged 18 years or older, encompassing both male and female participants. Participants are required to have persistent PASC signs and symptoms, such as fatigue and/or post-exertional malaise, for at least 12 weeks following the onset of a SARS-CoV-2 infection. These symptoms must not have been present prior to the infection but may have partially subsided and resurged post-infection. The trial includes a vulnerable population, and participants must reside in the study area for the duration of the trial. The sponsor has not provided information regarding the total number of participants. Participants' lifestyle considerations, such as diet and physical activity, are not specified. Key inclusion criteria involve self-reported confirmation of a SARS-CoV-2 infection through various diagnostic methods and the ability to provide informed consent and perform trial procedures. The exchange of relevant medical information between the participant's general practitioner or pharmacy and the trial team is also a requirement for participation.

The clinical trial is designed to evaluate the efficacy of **metformin** and **colchicine** in treating post-acute sequelae of SARS-CoV-2 infection (PASC). This study is a randomized, double-blind, controlled trial with a primary objective to assess the impact of each investigational product (IP) versus control on patient-reported physical health-related quality of life (HRQoL). The trial is expected to commence recruitment on February 10, 2025, and conclude by October 1, 2026. Participants will be involved for a maximum treatment period of 12 weeks, with an additional follow-up period extending to 24 weeks post-treatment cessation.

Study visits are structured to ensure comprehensive data collection and participant safety. The inclusion visit, or screening, will confirm eligibility based on criteria such as age (18 years or older), residence in the study area, and persistent PASC symptoms for at least 12 weeks post-SARS-CoV-2 infection. Participants must provide informed consent and agree to trial procedures. Follow-up visits will occur at regular intervals to monitor adherence, collect patient-reported outcomes, and assess any adverse events. The end-of-study visit will evaluate the primary endpoint using the Patient-Reported Outcomes Measurement Information System Profile29 (PROMIS-29) physical health summary score at 12 weeks.

Participants may be withdrawn from the study if they experience severe adverse events, fail to adhere to the study protocol, or withdraw consent. The trial will also assess secondary endpoints, including mental health summary scores and domain-specific scores, at 12 weeks. Exploratory analyses will stratify results by phenotype and symptom duration. The trial's design ensures rigorous evaluation of the investigational products' impact on PASC, contributing valuable insights into potential therapeutic options for this condition.

The clinical trial involves the administration of **METFORMIN**, a chemical compound classified as a biguanide. The pharmaceutical form of METFORMIN is a tablet, intended for **oral** administration. The maximum daily dose is 1500 mg, with a total maximum dose of 3000 mg over the course of the treatment. The treatment period is set for a maximum of 12 months. METFORMIN is not a pediatric formulation and is not classified as an orphan drug. Participant compliance with the dosing schedule will be monitored throughout the trial.

Another experimental medication used in the trial is **COLCHICINE**, which is categorized as an anti-inflammatory agent. Similar to METFORMIN, COLCHICINE is provided in tablet form for **oral use**. The maximum daily dose for COLCHICINE is 1 mg, with a total maximum dose of 2 mg. The treatment duration is also capped at 12 months. Like METFORMIN, COLCHICINE is not formulated for pediatric use and is not designated as an orphan drug. Compliance with the administration schedule will be closely monitored to ensure adherence to the protocol.

Both medications are being evaluated for their impact on patient-reported physical health-related quality of life in individuals experiencing post-acute sequelae of SARS-CoV-2 infection (PASC). The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The study is designed to assess the efficacy of these medications in improving health outcomes in the specified patient population.

Efficacy in the clinical trial titled "RECLAIM: an Adaptive Platform Trial for the Evaluation of Treatments for Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)" will be assessed using a variety of endpoints. The primary endpoint is the Patient-Reported Outcomes Measurement Information System Profile29 (PROMIS-29) physical health summary score, which will be evaluated at 12 weeks, marking the end of the trial product use period. Secondary endpoints include the PROMIS-29 mental health summary score and domain scores such as physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance, all assessed at 12 weeks. Additional secondary endpoints include the Checklist Individual Strength (CIS-8), DePaul Symptom Questionnaire (DSQ-2) post-exertional malaise (PEM) questions, PROMIS cognitive function 8a, and DSQ-2 postural orthostatic tachycardia syndrome (POTS) questions, also assessed at 12 weeks.

The trial will further evaluate the frequency of related and unrelated serious adverse events (SAEs) in each investigational product (IP) arm compared to its control arm, including their severity and outcome, at 12 weeks. Adherence levels to each IP versus the matching placebo control, if available, and the percentage of participants with adequate adherence for the specific IP will also be assessed at 12 weeks. At 24 weeks, which is 12 weeks after the cessation of IP use, the proportion of participants maintaining health-related quality of life (HRQoL) treatment success will be evaluated. Exploratory analyses will stratify these assessments by phenotype and pre-enrolment PASC symptom duration, as described in relevant trial-specific appendices (TSAs).