drugset / Trial / NCT03766321
Fecal Microbiota Transplantation Effect on Amyotrophic Lateral Sclerosis Patients
Active not recruiting
42 enrolled
University Hospital of Modena
Azienda Ospedaliera di Perugia · collabAzienda Ospedaliero-Universitaria Careggi · collabCampus Bio-Medico University · collabCatholic University of the Sacred Heart · collabUniversity of Chieti · collabUniversity of Florence · collabUniversity of Modena and Reggio Emilia · collab
RandomizedParallel-groupQuadruple-blindTreatment
Summary
Given the role of adaptive immunity in ALS, the pathogenicity of some clostridial strains on motorneurons, the putative role of cyanobacteria in ALS development, and the increasing interest for microbiota in neurodegenerative disorders, the modification of intestinal microbiota might affect ALS at its core. This interventional study aims at evaluating the biological and disease-modifying effects of Fecal Microbiota Transplant (FMT) in patients affected by Amyotrophic Lateral Sclerosis. As a primary aim of the study, the investigators postulate ALS patients treated with FMT compared to the control arm will display increased Tregs number, which is a favourable biomarker of disease activity and progression. Clinical outcomes as disease progression measured by ALS Functional Rating Scale Revised (ALSFRS-R) score, survival, respiratory function and quality of life will be assessed during the whole treatment and follow-up period. Moreover, biological activity of FMT will be evaluated in different biomatrices, together with FMT safety and tolerability in a cohort of ALS patients.
Timeline
- Start
- 2020-07-01
- Primary completion
- 2024-10
- Completion
- 2025-02
Publications
- Results ALSUntangled Group. ALS Untangled No. 21: Fecal transplants. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Sep;14(5-6):482-5. doi: 10.3109/21678421.2013.814981. Epub 2013 Jul 22. No abstract available.
- Results Amedei A, Della Bella C, Niccolai E, Stanflin N, Benagiano M, Duranti R, Del Prete G, Murphy TF, D'Elios MM. Moraxella catarrhalis-specific Th1 cells in BAL fluids of chronic obstructive pulmonary disease patients. Int J Immunopathol Pharmacol. 2009 Oct-Dec;22(4):979-90. doi: 10.1177/039463200902200413.
- Results Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science. 2005 Mar 25;307(5717):1915-20. doi: 10.1126/science.1104816.
- Results Baxter M, Colville A. Adverse events in faecal microbiota transplant: a review of the literature. J Hosp Infect. 2016 Feb;92(2):117-27. doi: 10.1016/j.jhin.2015.10.024. Epub 2015 Dec 15.
- Results Beers DR, Henkel JS, Zhao W, Wang J, Huang A, Wen S, Liao B, Appel SH. Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain. 2011 May;134(Pt 5):1293-314. doi: 10.1093/brain/awr074.
- Results Bienenstock J, Kunze W, Forsythe P. Microbiota and the gut-brain axis. Nutr Rev. 2015 Aug;73 Suppl 1:28-31. doi: 10.1093/nutrit/nuv019.
- Results Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW. Onset and progression in inherited ALS determined by motor neurons and microglia. Science. 2006 Jun 2;312(5778):1389-92. doi: 10.1126/science.1123511.
- Results Borody TJ, Khoruts A. Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol. 2011 Dec 20;9(2):88-96. doi: 10.1038/nrgastro.2011.244.
- Results Bradley WG, Borenstein AR, Nelson LM, Codd GA, Rosen BH, Stommel EW, Cox PA. Is exposure to cyanobacteria an environmental risk factor for amyotrophic lateral sclerosis and other neurodegenerative diseases? Amyotroph Lateral Scler Frontotemporal Degener. 2013 Sep;14(5-6):325-33. doi: 10.3109/21678421.2012.750364. Epub 2013 Jan 4.
- Results Brandt LJ. Fecal Microbiota Transplant: Respice, Adspice, Prospice. J Clin Gastroenterol. 2015 Nov-Dec;49 Suppl 1:S65-8. doi: 10.1097/MCG.0000000000000346.
- Results Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. Diversity of the human intestinal microbial flora. Science. 2005 Jun 10;308(5728):1635-8. doi: 10.1126/science.1110591. Epub 2005 Apr 14.
- Results Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, Keren-Shaul H, Mahlakoiv T, Jakobshagen K, Buch T, Schwierzeck V, Utermohlen O, Chun E, Garrett WS, McCoy KD, Diefenbach A, Staeheli P, Stecher B, Amit I, Prinz M. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015 Jul;18(7):965-77. doi: 10.1038/nn.4030. Epub 2015 Jun 1.
- Results Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13780-5. doi: 10.1073/pnas.0706625104. Epub 2007 Aug 15.
- Results Hardiman O, van den Berg LH. Edaravone: a new treatment for ALS on the horizon? Lancet Neurol. 2017 Jul;16(7):490-491. doi: 10.1016/S1474-4422(17)30163-1. Epub 2017 May 15. No abstract available.
- Results Henkel JS, Beers DR, Wen S, Rivera AL, Toennis KM, Appel JE, Zhao W, Moore DH, Powell SZ, Appel SH. Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol Med. 2013 Jan;5(1):64-79. doi: 10.1002/emmm.201201544. Epub 2012 Nov 9.
- Results Kelly CR, Ihunnah C, Fischer M, Khoruts A, Surawicz C, Afzali A, Aroniadis O, Barto A, Borody T, Giovanelli A, Gordon S, Gluck M, Hohmann EL, Kao D, Kao JY, McQuillen DP, Mellow M, Rank KM, Rao K, Ray A, Schwartz MA, Singh N, Stollman N, Suskind DL, Vindigni SM, Youngster I, Brandt L. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014 Jul;109(7):1065-71. doi: 10.1038/ajg.2014.133. Epub 2014 Jun 3.
- Results Khanna S. Microbiota Replacement Therapies: Innovation in Gastrointestinal Care. Clin Pharmacol Ther. 2018 Jan;103(1):102-111. doi: 10.1002/cpt.923. Epub 2017 Nov 14.
- Results Kimura F, Fujimura C, Ishida S, Nakajima H, Furutama D, Uehara H, Shinoda K, Sugino M, Hanafusa T. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology. 2006 Jan 24;66(2):265-7. doi: 10.1212/01.wnl.0000194316.91908.8a.
- Results Kadowaki A, Miyake S, Saga R, Chiba A, Mochizuki H, Yamamura T. Gut environment-induced intraepithelial autoreactive CD4(+) T cells suppress central nervous system autoimmunity via LAG-3. Nat Commun. 2016 May 20;7:11639. doi: 10.1038/ncomms11639.
- Results Lee YK, Menezes JS, Umesaki Y, Mazmanian SK. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1(Suppl 1):4615-22. doi: 10.1073/pnas.1000082107. Epub 2010 Jul 26.
- Results Longstreth WT Jr, Meschke JS, Davidson SK, Smoot LM, Smoot JC, Koepsell TD. Hypothesis: a motor neuron toxin produced by a clostridial species residing in gut causes ALS. Med Hypotheses. 2005;64(6):1153-6. doi: 10.1016/j.mehy.2004.07.041.
- Results Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. J Clin Invest. 2015 Mar 2;125(3):926-38. doi: 10.1172/JCI76304. Epub 2015 Feb 17.
- Results Moreno-Igoa M, Calvo AC, Penas C, Manzano R, Olivan S, Munoz MJ, Mancuso R, Zaragoza P, Aguilera J, Navarro X, Osta Pinzolas R. Fragment C of tetanus toxin, more than a carrier. Novel perspectives in non-viral ALS gene therapy. J Mol Med (Berl). 2010 Mar;88(3):297-308. doi: 10.1007/s00109-009-0556-y.
- Results Piccione EA, Sletten DM, Staff NP, Low PA. Autonomic system and amyotrophic lateral sclerosis. Muscle Nerve. 2015 May;51(5):676-9. doi: 10.1002/mus.24457. Epub 2015 Mar 31.
- Results Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12204-9. doi: 10.1073/pnas.0909122107. Epub 2010 Jun 21.
- Results Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell. 2016 Dec 1;167(6):1469-1480.e12. doi: 10.1016/j.cell.2016.11.018.
- Results Tremlett H, Bauer KC, Appel-Cresswell S, Finlay BB, Waubant E. The gut microbiome in human neurological disease: A review. Ann Neurol. 2017 Mar;81(3):369-382. doi: 10.1002/ana.24901. Epub 2017 Mar 20.
- Results van Es MA, Hardiman O, Chio A, Al-Chalabi A, Pasterkamp RJ, Veldink JH, van den Berg LH. Amyotrophic lateral sclerosis. Lancet. 2017 Nov 4;390(10107):2084-2098. doi: 10.1016/S0140-6736(17)31287-4. Epub 2017 May 25.
- Results van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013 Jan 31;368(5):407-15. doi: 10.1056/NEJMoa1205037. Epub 2013 Jan 16.
- Results Wang S, Xu M, Wang W, Cao X, Piao M, Khan S, Yan F, Cao H, Wang B. Systematic Review: Adverse Events of Fecal Microbiota Transplantation. PLoS One. 2016 Aug 16;11(8):e0161174. doi: 10.1371/journal.pone.0161174. eCollection 2016.
- Results Wu S, Yi J, Zhang YG, Zhou J, Sun J. Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model. Physiol Rep. 2015 Apr;3(4):e12356. doi: 10.14814/phy2.12356.
- Results Zhao W, Xie W, Xiao Q, Beers DR, Appel SH. Protective effects of an anti-inflammatory cytokine, interleukin-4, on motoneuron toxicity induced by activated microglia. J Neurochem. 2006 Nov;99(4):1176-87. doi: 10.1111/j.1471-4159.2006.04172.x. Epub 2006 Oct 2.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Comparator | Ornidazole | Other / unclassified | — | Other |