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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| VSL#3® | Active Comparator | VSL#3® 450 billion sachets, two sachets per day (900 billion of bacteria per day) for 28 days |
|
| Placebo | Placebo Comparator | Placebo sachets, two sachets per day for 28 days |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| VSL#3® | Dietary Supplement | VSL#3® 450 billions/sachets |
| |
| Placebo |
| 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 |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Flavio Caprioli, MD, PhD | Contact | +39 02 5503 2141 | flavio.caprioli@policlinico.mi.it | |
| Beatrice Marinoni, MD | Contact | +39 02 5503 2141 | beatrice.marinoni@unimi.it |
| Name | Affiliation | Role |
|---|---|---|
| Flavio Caprioli, MD, PhD | Fondazione IRCCS CÃ Granda, Ospedale Policlinico di Milano | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico | Recruiting | Milan | MI | 20122 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36969243 | Background | Ancona G, Alagna L, Alteri C, Palomba E, Tonizzo A, Pastena A, Muscatello A, Gori A, Bandera A. Gut and airway microbiota dysbiosis and their role in COVID-19 and long-COVID. Front Immunol. 2023 Mar 8;14:1080043. doi: 10.3389/fimmu.2023.1080043. eCollection 2023. | |
| 8463991 | Background | Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, Wright D, Wallace EP. Development of a fatigue scale. J Psychosom Res. 1993;37(2):147-53. doi: 10.1016/0022-3999(93)90081-p. |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 14, 2022 | May 21, 2023 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | May 15, 2022 | May 21, 2023 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D000094024 | Post-Acute COVID-19 Syndrome |
| D005221 | Fatigue |
| D064806 | Dysbiosis |
| D000086382 | COVID-19 |
| D018352 | Coronavirus Infections |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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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.
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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.
| Dietary Supplement |
Placebo sachets with maltose, cornstarch and dioxide |
|
|
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 |
| 34973396 | Background | Ceban F, Ling S, Lui LMW, Lee Y, Gill H, Teopiz KM, Rodrigues NB, Subramaniapillai M, Di Vincenzo JD, Cao B, Lin K, Mansur RB, Ho RC, Rosenblat JD, Miskowiak KW, Vinberg M, Maletic V, McIntyre RS. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis. Brain Behav Immun. 2022 Mar;101:93-135. doi: 10.1016/j.bbi.2021.12.020. Epub 2021 Dec 29. |
| 33833065 | Background | Chen Y, Gu S, Chen Y, Lu H, Shi D, Guo J, Wu WR, Yang Y, Li Y, Xu KJ, Ding C, Luo R, Huang C, Yu L, Xu M, Yi P, Liu J, Tao JJ, Zhang H, Lv L, Wang B, Sheng J, Li L. Six-month follow-up of gut microbiota richness in patients with COVID-19. Gut. 2022 Jan;71(1):222-225. doi: 10.1136/gutjnl-2021-324090. Epub 2021 Apr 8. No abstract available. |
| 35585196 | Background | Choutka J, Jansari V, Hornig M, Iwasaki A. Unexplained post-acute infection syndromes. Nat Med. 2022 May;28(5):911-923. doi: 10.1038/s41591-022-01810-6. Epub 2022 May 18. |
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| 36378309 | Background | Fernandez-de-Las-Penas C, Rodriguez-Jimenez J, Cancela-Cilleruelo I, Guerrero-Peral A, Martin-Guerrero JD, Garcia-Azorin D, Cornejo-Mazzuchelli A, Hernandez-Barrera V, Pellicer-Valero OJ. Post-COVID-19 Symptoms 2 Years After SARS-CoV-2 Infection Among Hospitalized vs Nonhospitalized Patients. JAMA Netw Open. 2022 Nov 1;5(11):e2242106. doi: 10.1001/jamanetworkopen.2022.42106. |
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| 36215063 | Background | 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. |
| 36758522 | Background | Guo C, Che X, Briese T, Ranjan A, Allicock O, Yates RA, Cheng A, March D, Hornig M, Komaroff AL, Levine S, Bateman L, Vernon SD, Klimas NG, Montoya JG, Peterson DL, Lipkin WI, Williams BL. Deficient butyrate-producing capacity in the gut microbiome is associated with bacterial network disturbances and fatigue symptoms in ME/CFS. Cell Host Microbe. 2023 Feb 8;31(2):288-304.e8. doi: 10.1016/j.chom.2023.01.004. |
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| 36155191 | Background | Nagata N, Takeuchi T, Masuoka H, Aoki R, Ishikane M, Iwamoto N, Sugiyama M, Suda W, Nakanishi Y, Terada-Hirashima J, Kimura M, Nishijima T, Inooka H, Miyoshi-Akiyama T, Kojima Y, Shimokawa C, Hisaeda H, Zhang F, Yeoh YK, Ng SC, Uemura N, Itoi T, Mizokami M, Kawai T, Sugiyama H, Ohmagari N, Ohno H. Human Gut Microbiota and Its Metabolites Impact Immune Responses in COVID-19 and Its Complications. Gastroenterology. 2023 Feb;164(2):272-288. doi: 10.1053/j.gastro.2022.09.024. Epub 2022 Sep 23. |
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| D014777 |
| Virus Diseases |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D000094025 | Post-Infectious Disorders |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012816 | Signs and Symptoms |