Investigation of pregabalin therapy and complex rehabilitation in treating chronic fatigue associated with post-COVID syndrome

The primary objective is to assess the efficacy of pregabalin and complex rehabilitation in treating chronic fatigue syndrome associated with post-COVID syndrome. This evaluation is clinically relevant as chronic fatigue syndrome represents a significant sequela of COVID-19 infection, with limited established therapeutic interventions. Determining the effectiveness of pharmacological treatment with pregabalin, an anticonvulsant and analgesic agent, compared to rehabilitation approaches may provide evidence-based management strategies for this debilitating condition.

The secondary objective is to assess the influence of pregabalin on selected cytokine levels in patients with chronic fatigue syndrome associated with post-COVID syndrome. This objective addresses potential immunomodulatory mechanisms underlying the therapeutic effects and may elucidate the pathophysiological role of inflammatory mediators in post-COVID chronic fatigue syndrome.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consists of both **male and female** adults aged **18 to 65 years** at the time of informed consent. Participants are individuals diagnosed with **chronic fatigue syndrome** associated with **post-COVID syndrome**, with a minimum of 6 months having elapsed since documented **SARS-CoV-2 infection**. The diagnosis of chronic fatigue syndrome follows the criteria established by the National Academy of Medicine (2015). Female participants of childbearing potential are required to use highly effective contraception methods throughout the trial and for 7 days following the last administration of the investigational medicinal product. All participants must provide written informed consent and demonstrate the ability to understand study information prior to enrollment. The trial includes a vulnerable population.

This is a **phase IV**, **randomized**, **controlled** clinical trial evaluating the efficacy of **pregabalin** therapy and complex **rehabilitation** in the treatment of **chronic fatigue syndrome** associated with **post-COVID syndrome**. The study employs a **placebo-controlled** design, with participants receiving either pregabalin tablets (75 mg) administered via **oral use** or a matching placebo. The active substance in the investigational medicinal product is pregabalin, a chemical compound, with a maximum daily dose of 300 mg and a maximum total dose of 150 mg per administration. The maximum treatment period extends to 201 days. The trial is designed to assess the efficacy of pharmacological intervention with pregabalin compared to complex rehabilitation approaches in alleviating chronic fatigue symptoms in patients who have experienced **SARS-CoV-2 infection**.

The overall trial duration spans from the estimated recruitment start date in March 2023 to the estimated end date in March 2028. Participant involvement is expected to last approximately six months from enrollment. The study includes a structured sequence of visits beginning with a **screening visit** to assess eligibility. During screening, participants must meet specific inclusion criteria, including documented SARS-CoV-2 infection at least six months prior, fulfillment of diagnostic criteria for chronic fatigue syndrome according to the National Academy of Medicine (2015), age between 18 and 65 years, and provision of written **informed consent**. Women of childbearing potential must demonstrate a negative **pregnancy test** and commit to using highly effective **contraception** throughout the treatment period and for seven days following the last dose of the investigational medicinal product. Participants must also agree to complete all study activities and demonstrate the capacity to understand the study information.

Following enrollment, participants attend scheduled **follow-up visits** at three months and six months after baseline. These visits are designed to assess changes in primary and secondary outcome measures. The **primary endpoints** include the change in fatigue intensity measured by the **Multidimensional Fatigue Inventory-20 (MFI-20)** score and the walking distance assessed through the **6 Minute Walking Test** at both three and six months compared to baseline values. Secondary endpoints encompass a comprehensive evaluation of psychological and cognitive functioning, including assessments using the **Life Satisfaction Scale**, **Beck Depression Inventory (BDI-II)**, **State and Trait Anxiety Inventory (STAI)**, **Illness Acceptance Scale**, and various neuropsychological tests such as the **Wisconsin Card Sorting Test (WCST)**, **Stroop interference test**, and **d2-R test**. Additional measures include gait quality assessment, walking speed, reaction time via the **Peg Insertion Test**, sleep quality using the **Athens Insomnia Scale**, and coping strategies assessed by the **Mini-Cope** inventory. An exploratory endpoint examines changes in inflammatory **cytokine** profiles at six months compared to baseline.

Safety-related endpoints are monitored throughout the study and include the number and percentage of participants experiencing **adverse events**, treatment-related adverse events, **serious adverse events**, and treatment-related serious adverse events. The study also tracks the number and percentage of participants who discontinue due to adverse events, along with changes in laboratory parameters and vital signs. Conditions that may lead to **early termination** from the study include the occurrence of serious adverse events, participant withdrawal of consent, protocol violations, or the investigator's determination that continued participation is not in the participant's best interest. The **end-of-study visit** occurs at six months or at the time of early discontinuation, during which final assessments are completed and participant safety is evaluated.

The experimental medication utilized in this clinical trial is Preato, containing the active substance pregabalin. The product is manufactured by Neuraxpharm Arzneimittel GmbH and is available in a tablet formulation with a strength of 75 mg. The medication is administered via the oral route. The maximum daily dose is 300 mg, with a maximum total dose of 150 mg per administration. The treatment period extends up to 201 days. The active substance pregabalin is of chemical origin and is classified under ATC code N02BF02. The marketing authorization number for this product is 25295.

A placebo comparator, designated as Preato-Placebo, is employed in this trial to provide a control arm for comparison with the active treatment. The placebo serves as a non-experimental comparator to assess the efficacy of pregabalin therapy in the treatment of chronic fatigue syndrome associated with post-COVID syndrome. Specific details regarding the pharmaceutical formulation, route of administration, and dosing schedule of the placebo are not provided in the available documentation.

Efficacy will be assessed through primary and secondary endpoints measured at baseline, 3 months, and 6 months. The primary efficacy parameters include the change in **fatigue** intensity measured by the Multidimensional Fatigue Inventory-20 (MFI-20) score and the change in walking distance assessed using the 6 Minute Walking Test, both evaluated at 3 and 6 months relative to baseline values.

Secondary efficacy endpoints encompass multiple domains including psychological well-being, cognitive function, physical performance, and sleep quality. Life satisfaction will be evaluated using the Life Satisfaction Scale, while depressive symptoms will be assessed with the Beck Depression Inventory (BDIII). Anxiety levels will be measured through the State and Trait Anxiety Inventory (STAI), and disease acceptance will be evaluated using the Illness Acceptance Scale. Cognitive function assessment will include the CTT-1 and CTT-2 tests, Wisconsin Card Sorting Test (WCST), RFFT test, WAIS-R Digit Repetition subtest, Stroop interference test for reaction time, and the d2-R test. Physical performance parameters will include gait quality assessment, walking speed, and reaction time measured by the Peg Insertion Test. Sleep disturbances will be evaluated using the Athens Insomnia Scale, and coping strategies will be assessed with the Mini-Cope instrument. All secondary endpoints will be measured at 3 and 6 months compared to baseline. An exploratory endpoint involves the evaluation of changes in inflammatory cytokine profiles at 6 months compared to baseline values.