Evaluation of Metformin and Colchicine for Post-Acute Sequelae of SARS-CoV-2 Infection: A Randomized Controlled Trial

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 of each IP versus control on patient-reported specific PASC symptoms, including 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 outcomes 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 participants experiencing **post-acute sequelae of SARS-CoV-2 infection (PASC)**, with the primary objective of assessing the impact of investigational products on patient-reported physical health-related quality of life. The study population includes adults aged 18 years or older, encompassing both male and female subjects. Participants are required to have persistent PASC signs and symptoms, such as fatigue and/or post-exertional malaise, for at least 12 weeks following a confirmed SARS-CoV-2 infection. The trial includes individuals who are willing to provide informed consent and participate in trial procedures. The sponsor has not provided information regarding the total number of participants. The trial population selection considers individuals residing in the study area for the trial's duration, and it involves a vulnerable population. Participants' general health status is characterized by the presence of PASC symptoms, which were not present prior to the infection but may have partially subsided and resurged. The trial does not specify particular lifestyle considerations such as diet or physical activity.

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 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 in September 2024 and conclude by October 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 include an initial screening visit to confirm eligibility based on criteria such as age, residence, and persistent PASC symptoms. Participants must have a self-reported confirmation of a prior SARS-CoV-2 infection. Following the screening, participants will be randomized to receive either the active treatment or a placebo. The trial includes regular follow-up visits to monitor adherence, safety, and efficacy, with assessments conducted at 12 weeks to evaluate primary and secondary endpoints, including the PROMIS-29 physical and mental health summary scores, and other relevant health measures.

The end-of-study visit will occur at 24 weeks, 12 weeks after the cessation of IP use, to assess the long-term maintenance of HRQoL improvements. 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 is not categorized as low intervention and is considered a phase III trial with off-label use of marketed investigational medicinal products. The trial's design ensures rigorous evaluation of the therapeutic potential of the study drugs in improving the quality of life for individuals affected by PASC.

The clinical trial involves the administration of **Metformin**, a chemical compound classified as a biguanide, which is utilized in the study to evaluate its effects on post-acute sequelae of SARS-CoV-2 infection (PASC). Metformin is provided in the form of a **tablet** and is administered **orally**. The maximum daily dose of Metformin is 1500 mg, with a total maximum dose of 3000 mg over the course of the treatment period. The treatment duration is set for a maximum of 12 months. Compliance with the dosing schedule is monitored to ensure adherence to the prescribed regimen.

Additionally, the trial includes the administration of **Colchicine**, an anti-inflammatory agent, also in **tablet** form. Colchicine is administered **orally**, with a maximum daily dose of 1 mg and a total maximum dose of 2 mg. Similar to Metformin, the treatment period for Colchicine is capped at 12 months. Participant compliance is closely monitored to maintain the integrity of the dosing schedule and ensure accurate assessment of the treatment's impact on patient-reported physical health-related quality of life (HRQoL).

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 patient-reported outcomes and clinical measures. 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 involve the Checklist Individual Strength (CIS-20R), DePaul Symptom Questionnaire (DSQ-2) for post-exertional malaise (PEM) questions, PROMIS cognitive function 8a, and DSQ-2 for postural orthostatic tachycardia syndrome (POTS) questions. The frequency and severity of related and unrelated serious adverse events (SAEs) in each investigational product (IP) arm compared to its control arm will also be assessed at 12 weeks. Adherence levels to each IP versus the matching placebo control, if available, and the percentage of participants with adequate adherence will be evaluated.

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 assessed. Exploratory analyses will stratify these outcomes by phenotype and pre-enrollment PASC symptom duration. These assessments will provide comprehensive data on the efficacy of the treatments under investigation for PASC.