VSL#3® vs Placebo in the Treatment of Fatigue and Other Symptoms in Long Covid (DELong#3)

Study Overview
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Brief Summary
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This study aims to evaluate the effectiveness of VSL#3® in reducing Fatigue and other symptoms in Long Covid Syndrome compared to placebo.

Detailed Description
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Long Covid syndrome is a chronic condition characterized by persistent symptoms experienced by individuals who have recovered from acute coronavirus disease (COVID-19). Among the various symptoms reported, fatigue stands out as a particularly burdensome and pervasive issue, significantly impacting the quality of life and daily functioning of Long Covid patients. Recent studies report that gut microbiota is altered during acute illness and not restored even after several months from recovery. Based on this evidence, modulation of intestinal microbiota can be considered as a possible therapeutic approach for Long Covid Syndrome. On this basis, the aim of this study is to evaluate efficacy of VSL#3® compared to placebo in reducing Fatigue in Long Covid Symptoms.

Official Title
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The Role of VSL#3® in the Treatment of Fatigue and Other Symptoms in Long Covid-19 Syndrome: a Randomized, Double-blind, Placebo-controlled Study (DELong#3)

Conditions
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Long COVID

Intervention / Treatment
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* Dietary Supplement: VSL#3®
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18; <65 yo Previous diagnosis of SARS-CoV-2 infection, documented by nasopharyngeal or antigenic molecular swab; Not currently be in quarantine or isolation; No antibiotics treatment in the 30 days prior to the trial; Chalder Fatigue Scale (in dichotomous form)>=4 possibly associated with signs and symptoms of Long COVID-19 syndrome: signs and symptoms that develop during or after SARS-CoV-2 infection, which persist for more than 4 weeks and are not reasonably explained otherwise; signs and symptoms include: fatigue, sleep disturbances, cognitive deficits (i.e. brain fogging, loss of concentration and memory, anxiety, depression), strength deficits, arthralgias and myalgias, gastroenterological alterations (reduced appetite, nausea, changes in bowel habits, abdominal pain Exclusion Criteria: Cardiovascular and pulmonary disease with moderately severe organ dysfunction (NYHA>2, Borg scale>=2); Decompensated endocrine and metabolic diseases (child cirrhosis >= B, decompensated hypo/hyperthyroidism, decompensated hypoadrenalism) Diagnosis of FM, CFS/ME, and/or IBS prior to SARS-CoV-2 infection; Confirmed diagnoses of neurological pathologies, psychiatric diseases and cognitive disorders prior to SARS-CoV-2 infection; Previous confirmed diagnosis of chronic musculoskeletal pathologies prior to prior to SARS-CoV-2 infection; Refusal to participate in the study / refusal to process personal data; Pregnancy or breastfeeding; Addiction to alcohol or drugs in previous years; Use of other probiotics during the trial; Use of antibiotics during the trial and in the previous 30 days; Substantial change of diet during the trial; Participation in another clinical study in the previous 30 days or previous participation in this same trial; Known intolerance/hypersensitivity to the investigational drug or to the excipients of the placebo formulation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a single-center randomized, double-blind, placebo-controlled trial. Patients will be recruited from Long Covid out-patient Clinics at Policlinico di Milano Hospital (Milan, Italy) and randomly assigned (1:1) to receive VSL#3® or placebo at the dosage of 2 sachets/die for 28 days. Fasting blood samples and feces will be collected before (t0) and after treatment (t4). Primary and secondary outcome will be assessed at baseline (t0), end of treatment (t4) and end of follow-up (t8) using validated questionnaires (i.e. CFS- Chalder Fatigue Scale; HAD- Hospital Anxiety and Depression Scale, SF36 - Short Form Health Survey, Structured Assessment of Gastrointestinal Symptoms Scale - SAGIS; Symptoms Check List 12 - SCL-12; Karnofsky Performance Status - KPS; Visual Analogue Scale- VAS). Subject participation in this study will be approximately 10 weeks, which include 2-weeks screening/run in period, 4-weeks treatment period and 4-weeks follow-up period.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: VSL#3®<br>VSL#3® 450 billion sachets, two sachets per day (900 billion of bacteria per day) for 28 days | Dietary Supplement: VSL#3®<br>* VSL#3® 450 billions/sachets<br>|
| Placebo Comparator: Placebo<br>Placebo sachets, two sachets per day for 28 days | Dietary Supplement: Placebo<br>* Placebo sachets with maltose, cornstarch and dioxide<br>* Other names: Placebo (for VSL#3®);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Fatigue variation after 4 weeks of treatment (t4) | To determine if there is a statistically significant variation in the scores on the Chalder Fatigue Scale between the treated group and the placebo group after 4 weeks of treatment (t4) | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Fatigue variation after 4 weeks of follow-up (t8) | To determine if there is a statistically significant difference in the scores on the Chalder Fatigue Scale between the treated group and the placebo group after 4 weeks of follow-up | 8 weeks | 
| Evaluation of Anxiety and Depression variation after 4 weeks of treatment (t4) | To determine if there is a statistically significant difference in the scores on the Hospital Anxiety and Depression Scale (HAD) between the treated group and to the placebo group after 4 weeks of treatment | 4 weeks | 
| Evaluation of Anxiety and Depression variation after 4 weeks of follow-up (t8) | To determine if there is a statistically significant difference in the scores on the Hospital Anxiety and Depression Scale (HAD) between the treated group and to the placebo group after 4 weeks of follow-up | 8 weeks | 
| Measurement of Quality of Life variation after 4 weeks of treatment (t4) | To determine if there is a statistically significant difference in the scores on the Short Form Health Survey (SF)-36 between the treated group and placebo group after 4 weeks of treatment | 4 weeks | 
| Measurement of Quality of Life variation after 4 weeks of follow-up (t8) | To determine if there is a statistically significant difference in the scores on the Short Form Health Survey (SF)-36 between the treated group and the placebo group after 4 weeks of follow-up | 8 weeks | 
| Assessment of Gastrointestinal Symptoms variation after 4 weeks of treatment (t4) | To determine if there is a statistically significant difference in the scores on the Structured Assessment of Gastrointestinal Symptoms Scale (SAGIS) between the placebo group and the treated group after 4 weeks of treatment | 4 weeks | 
| Assessment of Gastrointestinal Symptoms variation after4 weeks of follow-up (t8) | To determine if there is a statistically significant difference in the scores on the Structured Assessment of Gastrointestinal Symptoms Scale (SAGIS) between the placebo group and the treated group after 4 weeks of follow-up | 8 weeks | 
| Analysis of Somatization variation after 4 weeks of treatment (t4) | To identify the level of somatization of symptoms by comparing the scores on the SCL-12 for the somatization of Symptom Checklist-90 (SCL-90) between the treated group and the placebo group after 4 weeks of treatment | 4 weeks | 
| Analysis of Somatization variation after 4 weeks of treatment (t4) | To identify the level of somatization of symptoms by comparing the scores on the SCL-12 for the somatization of Symptom Checklist-90 (SCL-90) between the treated groups and the placebo group after 4 weeks of follow-up | 8 weeks | 
| Evaluation of Functional Status variation after 4 weeks of treatment (t4) | To assess the general functional status of the patients by comparing the scores on the Karnofsky Performance Status (KPS) Scale between the treated group and the placebo group after 4 weeks of treatment | 4 weeks | 
| Evaluation of Functional Status variation after 4 weeks of follow-up (t8) | To assess the general functional status of the patients by comparing the scores on the Karnofsky Performance Status (KPS) Scale between the treated group and the placebo group after 4 weeks of follow-up | 8 weeks | 
| Physician's Assessment of General Health variation after 4 weeks of treatment (t4) | To determine the physician's evaluation of the patient's general state of health using a visual-analogue scale (VAS) and comparing it between the treated group and the placebo group after 4 weeks of treatment | 4 weeks | 
| Physician's Assessment of General Health variation after 4 weeks of follow-up (t8) | To determine the physician's evaluation of the patient's general state of health using a visual-analogue scale (VAS) and comparing it between the treated group and the placebo group after 4 weeks of follow-up | 8 weeks | 
| Analysis of PBMC and Serum Expression of inflammatory mediators at baseline (t0) and after 4 weeks of treatment (t4) | Evaluation of multiple cytokines and chemokines in plasma samples and of immune cell phenotypes in peripheral blood mononuclear cells (PBMCs) | 4 weeks | 
| Investigation of Faecal Microbiota Variation after 4 weeks of treatment (t4) | To analyze the variation of the bacterial component of the faecal microbiota in terms of alpha and beta diversity and explore its correlation with clinical response on fatigue in both the placebo group and the treated group by using. Shotgun metagenomics and 16S sequencing of faecal samples at baseline and after 4 weeks of treatment (t4) generate serial gut microbial taxonomic and bacterial functional profiles. | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Long Covid, Fatigue, Gut Microbioma, Dysbiosis, COVID-19, Coronavirus Infections