Clinical trial NCT05697640: Study to Investigate Improvement in Physical Function in SF-36 With Vericiguat Compared With Placebo in Participants With Post-COVID-19 Syndrome
Official title: A Parallel-group Treatment, Phase 2a, Double-blind, Placebo-controlled 2-arm Study to Show Improvement of Physical Function in SF-36 (SF-36-PF) in Participants Treated With Vericiguat Compared to Placebo Tablets in Male and Female Participants Aged 18-50 Years With Post-COVID-19 Syndrome Without (PCS) or With (PCS/CFS) Fulfillment of ME/CFS Criteria (VERI-LONG).
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Post-COVID ME/CFS
Keywords: Post-COVID Syndrome
Long COVID
Chronic Fatigue Syndrome
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2023-01-26
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two-arm parallel-group, randomized, placebo-controlled, double-blind, single-centre clinical trial in participants with post-COVID syndrome with and without ME/CFS.
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to evaluate the therapeutic value of an approved drug (Vericiguat) in patients with post-COVID-19 syndrome, who suffer from profound tiredness or fatigue, regardless of bed rest.The main questions it aims to answer are: • Does Vericiguat relieve fatigue and/or other symptoms associated with post-COVID-19 syndrome? • What are the side effects of Vericiguat in this patient population; and how common are they?

Participants will be asked to participate for approx. 18 weeks. After screening, participants will receive assigned intervention of either 10 weeks of treatment with Vericiguat or matching placebo tablet, followed by 30 day follow-up period. Every participant will undergo trial, cardiovascular safety, and monitoring assessments.

The results of this study will provide information on whether Vericiguat can alleviate PCS-related symptoms as well as insights into the pathophysiological processes of PCS, which in turn can help to develop therapies.

Detailed description: Although of high socioeconomic relevance, the pathomechanisms of post-COVID-19 syndrome (PCS) are not well understood and there is no established therapy. Preliminary evidence suggests that systemic tissue and organ hypoperfusion, resulting from impaired microvascular blood flow secondary to chronic endothelial dysfunction (ED), plays a key role in many symptoms.

The objective is to demonstrate improvement in physical function measured using the short form-36 health questionnaire (SF-36) in patients with post-COVID-19 syndrome with or without fulfillment of ME/CFS criteria treated with Vericiguat compared with placebo. Vericiguat is a drug that bridges endothelial dysfunction to improve microvascular perfusion and tissue and organ blood flow.

This is a two-arm parallel-group, randomized, placebo-controlled, double-blind, single-centre clinical trial in participants with PCS and PCS/CFS. Patients participate for approx. 18 weeks. Participants will be stratified according to diagnosis (with vs. without ME/CFS) and sex, and randomly assigned 1:1 after a screening phase of up to 28 days to receive assigned intervention of either 10 weeks of treatment with Vericiguat (including titration phase) or placebo, followed by 30 days follow-up period. One group receives a tablet of Vericiguat once daily for 10 weeks with a dosage titration to tolerated dose of 2.5 mg for 2 weeks, 5 mg for 2 weeks, 10 mg for 6 weeks. The other group receives a matching placebo tablet once daily for 10 weeks with the same titration regimen to ensure blinding. The starting dose is 2.5 mg Vericiguat or matching placebo, once daily, and a controlled and blood pressure-tolerated titration regimen will be used to achieve the anticipated target dose of 10 mg Vericiguat or matching placebo. Every participant will undergo trial, cardiovascular safety, and monitoring assessments. During the screening visit, the study team i) records the patient's medical history, ii) checks the in- and exclusion criteria, iii) performs a medical check-up, iv) performs an echocardiogram, and v) measures the patient's vital parameters. In female participants, a pregnancy test is carried out 5 times during the study.

The results of this study will provide information on whether Vericiguat can alleviate PCS-related symptoms such as fatigue, cognitive impairment, and impaired physical function (e.g., walking, stair climbing) and/or modulate paraclinical markers such as parameters of endothelial function. Moreover, the clinical trial will provide insights into the pathophysiological processes of PCS, which in turn can help to elucidate the disease etiology and to develop effective therapies.

Eligibility criteria: Inclusion Criteria:

* Male or female adult who is 18-50 years old
* Confirmed (PCR or serology), non-hospitalized, mild to moderate acute COVID-19 cases according to WHO criteria with proven chronic ED and either: ME/CFS Canadian Consensus Criteria (CCC) with post exertional malaise (PEM) 2 - 14 hours = PCS or ME/CFS CCC criteria with PEM \> 14 hours = PCS/CFS
* Ongoing symptoms of PCS or PCS/CFS for ≥ 6 months
* Bell Score: 30-60
* Evidence for endothelial dysfunction (ED) \[as indicated by reactive hyperemia index (RHI) \< 1.8 and/or ET-1 level \> 90 percentile of healthy age- and gender matched controls or muscle fatigue (below cut-off values of area under the curve reference values for age-matched healthy controls and/or pathological optical coherence tomography angiography (OCTA))\]
* For female subjects: Confirmed post-menopausal state (defined as amenorrhea for at least 12 months) or for women of childbearing potential: Negative highly sensitive urine or serum pregnancy test before inclusion/randomisation and practicing a highly effective birth control method (failure rate of less than 1 %):

  * combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral/intravaginal/transdermal), or
  * progestogen-only hormonal contraception associated with inhibition of ovulation (oral/injectable/implantable), or
  * intrauterine device, or
  * intrauterine hormone-releasing system, or
  * bilateral tubal occlusion, or
  * vasectomised partner, or
  * heterosexual abstinence.

Exclusion Criteria:

* COVID-19 vaccination within the last 4 weeks before inclusion
* Pre-COVID history of chronic fatigue syndrome or other fatigue syndromes that are due to associated diseases (e.g., cancer, autoimmune diseases \[patients with a preexisting Hashimoto thyroiditis and/or fibromyalgia without fatigue syndromes can be included\])
* Concomitant use of Vericiguat due to other diseases
* Contraindications against IMP
* Concurrent or anticipated concomitant use of PDE-5 inhibitors such as vardenafil, tadalafil, and sildenafil, nitrates, or sGC-stimulators
* Use of other sGC stimulators, e.g., riociguat
* Hypersensitivity to the active substance or any of the other ingredients
* Systolic blood pressure: \< 100 mmHg at screening
* Known SARS-CoV-2 infection-related organ damage/comorbidity
* Severe renal or hepatic insufficiency
* Pregnancy or breastfeeding

Primary outcomes:
measure: Improvement in Physical Function (PF) as measured by the Short Form 36 Health Survey Questionnaire (SF-36)
timeFrame: 10 weeks after first IMP intake
Secondary outcomes:
measure: Difference in responder rate in Physical Function (PF) as measured by the Short Form 36 Health Survey Questionnaire (SF-36) comparing Vericiguat with placebo
timeFrame: 10 weeks after first IMP intake
measure: Improvement in other sub-domains of the Short Form 36 Health Survey Questionnaire (SF-36) comparing Vericiguat with placebo
timeFrame: 10 weeks after first IMP intake
measure: Improvement in fatigue as measured by the Fatigue Severity Score (FSS)
timeFrame: 10 weeks after first IMP intake
measure: Improvement in severity of muscle pain and headache as measured by the Canadian Consensus Criteria (CCC) symptom score
timeFrame: 10 weeks after first IMP intake
measure: Improvement in symptoms of myalgic encephalomyelitis (ME)/ chronic fatigue syndrome (CFS) as measured by Canadian Consensus Criteria (CCC) Symptom Score
timeFrame: 10 weeks after first IMP intake
measure: Improvement in functional disability as measured by the Bell disability scale
timeFrame: 10 weeks after first IMP intake
measure: Improvement in symptoms of autonomic dysfunction as measured by the Composite Autonomic Symptom Score (COMPASS-31)
timeFrame: 10 weeks after first IMP intake
measure: Improvement in disease severity based on self- reported symptoms as measured by the Munich Berlin Symptom Questionnaire (MBSQ)
timeFrame: 10 weeks after first IMP intake
measure: Improvement in disease severity based on self- reported symptoms as measured by the Munich Long Covid Symptom Questionnaire (MLCSQ)
timeFrame: 10 weeks after first IMP intake
measure: Improvement in post exertional malaise (PEM) frequency, strength and severity as measured by the PEM questionnaire
timeFrame: 10 weeks after first IMP intake
measure: Improvement in muscle fatigue measured by the repetitive hand grip strength test (HGS)
timeFrame: 10 weeks after first IMP intake
measure: Improvement in orthostatic intolerance measured by the passive standing test
timeFrame: 10 weeks after first IMP intake
measure: Improvement of endothelial cell function as assessed using EndoPAT
timeFrame: 10 weeks after first IMP intake
measure: Improvement in cognitive function measured by the Symbol Digit Modalities Test (SDMT)
timeFrame: 10 weeks after first IMP intake
measure: Improvement in ET-1 serum levels
timeFrame: 10 weeks after first IMP intake
measure: Difference of occurring AE and SAE comparing Vericiguat with placebo (IMP safety).
timeFrame: 10 weeks after first IMP intake
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
Study officials:
affiliation: Charite University, Berlin, Germany
name: Judith Bellmann-Strobl, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, Hernandez AF, Butler J, Lam CSP, Ponikowski P, Voors AA, Jia G, McNulty SE, Patel MJ, Roessig L, Koglin J, O'Connor CM; VICTORIA Study Group. Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2020 May 14;382(20):1883-1893. doi: 10.1056/NEJMoa1915928. Epub 2020 Mar 28.