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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05874089
Recruitment Status : Recruiting
First Posted : May 24, 2023
Last Update Posted : May 24, 2023
Sponsor:
Information provided by (Responsible Party):
Flavio Caprioli, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

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

Condition or disease Intervention/treatment Phase
Long COVID Dietary Supplement: VSL#3® Dietary Supplement: Placebo Not Applicable

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 96 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Investigator)
Masking Description: Double blinding is achieved by packaging probiotics and placebo in the same sealed and consecutively numbered containers with sachets similar in packaging, smell, and taste. All study participants and on-site study personnel will remain masked for the treatment allocation (randomized controlled trial phase) until database lock and signature of the statistical analysis plan.
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : November 3, 2022
Estimated Primary Completion Date : September 3, 2023
Estimated Study Completion Date : November 3, 2023


Arm Intervention/treatment
Active Comparator: VSL#3®
VSL#3® 450 billion sachets, two sachets per day (900 billion of bacteria per day) for 28 days
Dietary Supplement: VSL#3®
VSL#3® 450 billions/sachets

Placebo Comparator: Placebo
Placebo sachets, two sachets per day for 28 days
Dietary Supplement: Placebo
Placebo sachets with maltose, cornstarch and dioxide
Other Name: Placebo (for VSL#3®)




Primary Outcome Measures :
  1. Assessment of Fatigue variation after 4 weeks of treatment (t4) [ Time Frame: 4 weeks ]
    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)


Secondary Outcome Measures :
  1. Assessment of Fatigue variation after 4 weeks of follow-up (t8) [ Time Frame: 8 weeks ]
    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

  2. Evaluation of Anxiety and Depression variation after 4 weeks of treatment (t4) [ Time Frame: 4 weeks ]
    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

  3. Evaluation of Anxiety and Depression variation after 4 weeks of follow-up (t8) [ Time Frame: 8 weeks ]
    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

  4. Measurement of Quality of Life variation after 4 weeks of treatment (t4) [ Time Frame: 4 weeks ]
    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

  5. Measurement of Quality of Life variation after 4 weeks of follow-up (t8) [ Time Frame: 8 weeks ]
    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

  6. Assessment of Gastrointestinal Symptoms variation after 4 weeks of treatment (t4) [ Time Frame: 4 weeks ]
    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

  7. Assessment of Gastrointestinal Symptoms variation after4 weeks of follow-up (t8) [ Time Frame: 8 weeks ]
    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. Analysis of Somatization variation after 4 weeks of treatment (t4) [ Time Frame: 4 weeks ]
    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

  9. Analysis of Somatization variation after 4 weeks of treatment (t4) [ Time Frame: 8 weeks ]
    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

  10. Evaluation of Functional Status variation after 4 weeks of treatment (t4) [ Time Frame: 4 weeks ]
    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

  11. Evaluation of Functional Status variation after 4 weeks of follow-up (t8) [ Time Frame: 8 weeks ]
    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

  12. Physician's Assessment of General Health variation after 4 weeks of treatment (t4) [ Time Frame: 4 weeks ]
    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

  13. Physician's Assessment of General Health variation after 4 weeks of follow-up (t8) [ Time Frame: 8 weeks ]
    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

  14. Analysis of PBMC and Serum Expression of inflammatory mediators at baseline (t0) and after 4 weeks of treatment (t4) [ Time Frame: 4 weeks ]
    Evaluation of multiple cytokines and chemokines in plasma samples and of immune cell phenotypes in peripheral blood mononuclear cells (PBMCs)

  15. Investigation of Faecal Microbiota Variation after 4 weeks of treatment (t4) [ Time Frame: 4 weeks ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05874089


Contacts
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Contact: Flavio Caprioli, MD, PhD +39 02 5503 2141 flavio.caprioli@policlinico.mi.it
Contact: Beatrice Marinoni, MD +39 02 5503 2141 beatrice.marinoni@unimi.it

Locations
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Italy
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Recruiting
Milan, MI, Italy, 20122
Contact: Beatrice Marinoni, MD    +39 02 5503 2141    beatrice.marinoni@unimi.it   
Sponsors and Collaborators
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Investigators
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Study Director: Flavio Caprioli, MD, PhD Fondazione IRCCS Cà Granda, Ospedale Policlinico di Milano
  Study Documents (Full-Text)

Documents provided by Flavio Caprioli, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico:
Informed Consent Form  [PDF] May 15, 2022

Publications:
Global Burden of Disease Long COVID Collaborators; Wulf Hanson S, Abbafati C, Aerts JG, Al-Aly Z, Ashbaugh C, Ballouz T, Blyuss O, Bobkova P, Bonsel G, Borzakova S, Buonsenso D, Butnaru D, Carter A, Chu H, De Rose C, Diab MM, Ekbom E, El Tantawi M, Fomin V, Frithiof R, Gamirova A, Glybochko PV, Haagsma JA, Haghjooy Javanmard S, Hamilton EB, Harris G, Heijenbrok-Kal MH, Helbok R, Hellemons ME, Hillus D, Huijts SM, Hultstrom M, Jassat W, Kurth F, Larsson IM, Lipcsey M, Liu C, Loflin CD, Malinovschi A, Mao W, Mazankova L, McCulloch D, Menges D, Mohammadifard N, Munblit D, Nekliudov NA, Ogbuoji O, Osmanov IM, Penalvo JL, Petersen MS, Puhan MA, Rahman M, Rass V, Reinig N, Ribbers GM, Ricchiuto A, Rubertsson S, Samitova E, Sarrafzadegan N, Shikhaleva A, Simpson KE, Sinatti D, Soriano JB, Spiridonova E, Steinbeis F, Svistunov AA, Valentini P, van de Water BJ, van den Berg-Emons R, Wallin E, Witzenrath M, Wu Y, Xu H, Zoller T, Adolph C, Albright J, Amlag JO, Aravkin AY, Bang-Jensen BL, Bisignano C, Castellano R, Castro E, Chakrabarti S, Collins JK, Dai X, Daoud F, Dapper C, Deen A, Duncan BB, Erickson M, Ewald SB, Ferrari AJ, Flaxman AD, Fullman N, Gamkrelidze A, Giles JR, Guo G, Hay SI, He J, Helak M, Hulland EN, Kereselidze M, Krohn KJ, Lazzar-Atwood A, Lindstrom A, Lozano R, Malta DC, Mansson J, Mantilla Herrera AM, Mokdad AH, Monasta L, Nomura S, Pasovic M, Pigott DM, Reiner RC Jr, Reinke G, Ribeiro ALP, Santomauro DF, Sholokhov A, Spurlock EE, Walcott R, Walker A, Wiysonge CS, Zheng P, Bettger JP, Murray CJL, Vos T. Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021. JAMA. 2022 Oct 25;328(16):1604-1615. doi: 10.1001/jama.2022.18931.
Marasco G, Cremon C, Barbaro MR, Cacciari G, Falangone F, Kagramanova A, Bordin D, Drug V, Miftode E, Fusaroli P, Mohamed SY, Ricci C, Bellini M, Rahman MM, Melcarne L, Santos J, Lobo B, Bor S, Yapali S, Akyol D, Sapmaz FP, Urun YY, Eskazan T, Celebi A, Kacmaz H, Ebik B, Binicier HC, Bugdayci MS, Yagci MB, Pullukcu H, Kaya BY, Tureyen A, Hatemi I, Koc ES, Sirin G, Caliskan AR, Bengi G, Alis EE, Lukic S, Trajkovska M, Hod K, Dumitrascu D, Pietrangelo A, Corradini E, Simren M, Sjolund J, Tornkvist N, Ghoshal UC, Kolokolnikova O, Colecchia A, Serra J, Maconi G, De Giorgio R, Danese S, Portincasa P, Di Sabatino A, Maggio M, Philippou E, Lee YY, Salvi D, Venturi A, Borghi C, Zoli M, Gionchetti P, Viale P, Stanghellini V, Barbara G; GI-COVID19 study group. Post COVID-19 irritable bowel syndrome. Gut. 2022 Dec 9:gutjnl-2022-328483. doi: 10.1136/gutjnl-2022-328483. Online ahead of print.

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Responsible Party: Flavio Caprioli, Associate Professor of Gastroenterology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
ClinicalTrials.gov Identifier: NCT05874089    
Other Study ID Numbers: DELong#3
First Posted: May 24, 2023    Key Record Dates
Last Update Posted: May 24, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Flavio Caprioli, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico:
Long Covid
Fatigue
Gut Microbioma
Dysbiosis
COVID-19
Coronavirus Infections
Additional relevant MeSH terms:
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Post-Acute COVID-19 Syndrome
COVID-19
Fatigue
Pneumonia, Viral
Pneumonia
Respiratory Tract Infections
Infections
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Post-Infectious Disorders
Chronic Disease
Disease Attributes
Pathologic Processes