Efficacy and Safety of Tianeptine Sodium in Treating Cognitive Dysfunction Post-COVID-19: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this randomized, double-blind, placebo-controlled trial is to compare the **efficacy** of tianeptine versus placebo in the treatment of **covid fog** symptoms in post-COVID-19 patients. This is clinically relevant as covid fog, characterized by slowed thinking, disorientation, difficulty remembering, and impaired attention and concentration, significantly impacts patients' quality of life and daily functioning. Understanding the efficacy of tianeptine could provide a therapeutic option for managing these symptoms.

Secondary objectives include:

• Comparing other parameters to assess the efficacy of tianeptine versus placebo in treating covid fog symptoms.
• Assessing the effect of treatment on the subjective severity of cognitive difficulties manifested in daily life.
• Evaluating the effect of treatment on subjective feelings of improved functioning and independence.
• Assessing the effect of treatment on depressive symptoms.
• Evaluating the effect of tianeptine treatment on quality of life.
• Assessing brain metabolic activity in the course of covid fog as evaluated by PET-CT.
• Comparing the safety profile of tianeptine treatment versus placebo.

The clinical trial focuses on evaluating the efficacy of tianeptine versus placebo in treating symptoms of **covid fog** in post-COVID-19 patients. The study population includes both male and female participants aged 18 years and older, with a history of COVID-19 infection confirmed by a positive SARS-CoV-2 test. Participants are required to have reported subjective cognitive decline following their COVID-19 infection and demonstrate cognitive dysfunction as defined by a Montreal Scale for the Assessment of Cognitive Function (MoCA) score of less than 26. The trial includes a vulnerable population, and women of childbearing potential must use effective contraception. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. Participants were selected based on their ability to provide written informed consent and meet the outlined inclusion criteria.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of **tianeptine sodium** in treating symptoms of **covid fog** in patients who have recovered from COVID-19. The trial will also explore the pathophysiology of covid fog using various diagnostic parameters, including positron emission tomography, biochemical, immunological, and electrophysiological assessments. The study is set to commence recruitment on February 17, 2023, and is expected to conclude by April 30, 2027. Participants will be involved in the trial for a maximum treatment period of 112 days, with the primary endpoint being an improvement in covid fog symptoms at week 16, as measured by a 2-point increase in the Montreal Scale for the Assessment of Cognitive Function (MoCA) score.

The trial will include several study visits, beginning with a screening visit to confirm eligibility based on criteria such as age (≥18 years), a history of COVID-19 infection, and cognitive dysfunction as indicated by a MoCA score of less than 26. Following randomization, participants will receive either tianeptine sodium or a placebo, administered orally in the form of film-coated tablets. The study will involve regular follow-up visits to monitor progress and assess secondary endpoints, including improvements in cognitive function, depressive and anxiety symptoms, and sleep difficulties. The end-of-study visit will evaluate the overall treatment efficacy and safety.

Participants are expected to adhere to the study protocol throughout the trial duration. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial is conducted under Phase 4, focusing on the safety and efficacy of the investigational therapy. The study aims to provide valuable insights into the treatment of covid fog and its underlying mechanisms, contributing to the broader understanding of post-COVID-19 cognitive impairments.

The clinical trial involves the administration of **Tianeptine Sodium**, marketed under the name Tianesal, in the form of **film-coated tablets**. Each tablet contains 12.5 mg of the active substance. The medication is administered **orally**. The maximum daily dose is 37.5 mg, with a total maximum dose of 4075 mg over the course of the study. The treatment period extends up to 112 days. Tianeptine Sodium is classified under the **ATC code N06AX14**, indicating its use as a psychoanaleptic. The pharmaceutical product is manufactured by ADAMED PHARMA S.A. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

The study also includes a **placebo** group to serve as a comparator. The placebo is designed to mimic the appearance of the active treatment but contains no active pharmaceutical ingredients. It is administered in the same **oral** form and frequency as the active treatment to maintain the double-blind nature of the trial. The use of a placebo allows for the assessment of the efficacy and safety of Tianeptine Sodium by providing a baseline for comparison. Participant compliance with the placebo regimen is similarly monitored to ensure the integrity of the trial results.

The efficacy of tianeptine in the treatment of **covid fog** symptoms in post-COVID-19 patients will be assessed through a randomized, double-blind, placebo-controlled trial. The primary endpoint for evaluating efficacy is the improvement in covid fog symptoms at week 16 after randomization, defined as a 2-point improvement in the Montreal Cognitive Assessment (MoCA) score. Secondary endpoints include the complete resolution of covid fog symptoms, indicated by a MoCA score normalization (26-30 points), and a 10% improvement in raw test scores across various cognitive domains, including the Color Trails Test (CTT), Controlled Oral Word Association Test (COWAT), Stroop Color and Word Test (SCWT), Repeating Digits from the Wechsler Adult Intelligence Scale-Revised (WAIS-R), and Digit Symbols from WAIS-R.

Additional secondary endpoints involve a 10% improvement in the Everyday Cognition (ECog-12) test raw scores, and improvements in subjectively assessed symptom severities, including depressive symptoms (Patient Health Questionnaire, PHQ score < 5), anxiety symptoms (Generalized Anxiety Disorder-7, GAD-7 score < 5), sleep difficulties (Athens Insomnia Scale, AIS score < 6), and loneliness (Social Loneliness Scale, SLS score < 5) at 16 weeks post-randomization. The reduction or resolution of depressive symptoms will also be assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS), with resolution defined as a MADRS score < 9 points. These efficacy parameters will be measured and collected at the specified timepoint of week 16 after randomization, utilizing validated scales and patient-reported outcomes to ensure accurate and reliable data collection and analysis.