<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03766321</url>
  </required_header>
  <id_info>
    <org_study_id>FeTr-ALS</org_study_id>
    <nct_id>NCT03766321</nct_id>
  </id_info>
  <brief_title>Fecal Microbiota Transplantation Effect on Amyotrophic Lateral Sclerosis Patients</brief_title>
  <acronym>FETR-ALS</acronym>
  <official_title>Interplay Between Gut Microbiota and Adaptive Immunity in Amyotrophic Lateral Sclerosis: a Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Azienda Ospedaliero-Universitaria di Modena</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Modena and Reggio Emilia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Catholic University of the Sacred Heart</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Campus Bio-Medico University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Azienda Ospedaliero-Universitaria Careggi</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Azienda Ospedaliera di Perugia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Chieti</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Florence</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Azienda Ospedaliero-Universitaria di Modena</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Given the role of adaptive immunity in ALS, the pathogenicity of some clostridial strains on&#xD;
      motorneurons, the putative role of cyanobacteria in ALS development, and the increasing&#xD;
      interest for microbiota in neurodegenerative disorders, the modification of intestinal&#xD;
      microbiota might affect ALS at its core.&#xD;
&#xD;
      This interventional study aims at evaluating the biological and disease-modifying effects of&#xD;
      Fecal Microbiota Transplant (FMT) in patients affected by Amyotrophic Lateral Sclerosis. As a&#xD;
      primary aim of the study, the investigators postulate ALS patients treated with FMT compared&#xD;
      to the control arm will display increased Tregs number, which is a favourable biomarker of&#xD;
      disease activity and progression. Clinical outcomes as disease progression measured by ALS&#xD;
      Functional Rating Scale Revised (ALSFRS-R) score, survival, respiratory function and quality&#xD;
      of life will be assessed during the whole treatment and follow-up period.&#xD;
&#xD;
      Moreover, biological activity of FMT will be evaluated in different biomatrices, together&#xD;
      with FMT safety and tolerability in a cohort of ALS patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study will include 42 ALS patients with 2:1 allocation in 2 groups of subjects (28 FMT vs&#xD;
      14 placebo); computerized randomization will be stratified by progression rate (ΔFS) &lt;/≥0.7.&#xD;
      Randomization time will last 18 months. Treatment will be double blinded to patients and&#xD;
      physicians, and will be done at baseline and at month 6. FMT is regarded as the active&#xD;
      treatment. Post-treatment follow up will be 6 months.&#xD;
&#xD;
      ALS patients will undergo upper GI endoscopy with small-intestine biopsies (n° 4 biopsies of&#xD;
      small intestine, performed with a standard biopsy forces) at baseline and after 6 months. At&#xD;
      baseline patients will be randomized (2:1) to either an allogenic (from donors) infusion of&#xD;
      collected feces (fecal microbiota transplantation, FMT) (or no procedure in case of&#xD;
      allocation to placebo) in the duodenum-jejunum. The infusion will be performed through a&#xD;
      standard nasojejunal tube, that will be placed during endoscopy. Infusion of feces will be&#xD;
      performed at time 0 and repeated at month 6. The patients allocated to placebo arm will not&#xD;
      receive treatment, but will undergo intestinal biopsy.&#xD;
&#xD;
      Upper GI endoscopy 12 months after FMT will be performed only to identify specific microbioma&#xD;
      and mucosal immunological evaluation. Fecal samples and small intestine biopsy samples (at&#xD;
      baseline, before treatment, and at month 6 and 12) will be obtained from patients to perform&#xD;
      the gut microbiota typing.&#xD;
&#xD;
      Every endoscopic procedure will be performed with sedation of the patient. Feces for FMT will&#xD;
      be obtained by healthy donors for C. difficile infection. Procedures that are usually&#xD;
      performed for the selection of donors for transplantation of feces are as follows. Potential&#xD;
      donors stool will be chosen in healthy volunteers that will have given a questionnaire with&#xD;
      questions about lifestyle, health status, current therapy, etc., significant clinical&#xD;
      symptoms of gastrointestinal disease, etc.. Based on this questionnaire, the potential donor&#xD;
      will be considered eligible if excluded: I) Habits of life and risk behaviors, II)&#xD;
      Concomitant significant known disorders, III) chronic or recent use of concomitant&#xD;
      medications that may interfere with the state of the intestinal microflora (eg, antibiotics),&#xD;
      IV) Clinical symptoms indicative of gastrointestinal disease or other diseases of importance,&#xD;
      V) Personal or family medical history known of neurodegenerative diseases or other autoimmune&#xD;
      diseases.&#xD;
&#xD;
      Moreover, each suitable potential donor will be subjected to the following screening tests:&#xD;
      I) Examination of stool for Clostridium difficile bacterial pathogens and protozoa and&#xD;
      helminths of the small intestine and colon, Vancomycin-resistant Enterococci (VRE ),&#xD;
      Methicillin-resistant Staphylococcus aureus (MRSA), Gram-negative Multidrug-Resistant&#xD;
      Organisms (MDR), II) Serological screening for hepatitis virus A,B and C, HIV 1-2, Treponema&#xD;
      pallidum, H. pylori, blood count with differential, dose transaminasemia, creatinine and&#xD;
      C-reactive protein.&#xD;
&#xD;
      Potential donors negative for this screening will be considered definitively suitable and&#xD;
      will be invited to give a stool sample to prepare than for the fecal transplant. The donation&#xD;
      will be made in the appropriate circles in the Department of Internal Medicine and&#xD;
      Gastroenterology, and the preparation of faeces (manual homogenization in 500 mL of saline&#xD;
      solution) for infusion will be performed at the Unit of Analysis 2 ° (Virology and&#xD;
      Microbiology).&#xD;
&#xD;
      Analysis of T cell sub-populations will be performed both in peripheral blood and gut mucosa:&#xD;
      especially the ratio T Regulatory cells (Tregs)/Th17 cells A Contract Research Organization&#xD;
      (CRO) will be in charge for study monitoring.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 1, 2020</start_date>
  <completion_date type="Anticipated">August 2024</completion_date>
  <primary_completion_date type="Anticipated">August 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>randomized double blind multicentre study on FMT in ALS, with a randomization ratio 2:1 (FMT: placebo).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>placebo will be unrecognizable from active treatment because the patients will undergo endoscopic procedure with sedation</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Tregs number</measure>
    <time_frame>6 months</time_frame>
    <description>to assess whether FMT increases Tregs' number in ALS patients treated with FMT compared to the control arm</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in T cell subsets frequency in blood and gut tissue samples</measure>
    <time_frame>12 months (at time points: baseline, month 3 - 6 (both arms)- 9 -12 (both arms))</time_frame>
    <description>Change from baseline to each time point (month 3, 6, 9, 12) of the T cell distribution especially the ratio Tregs/Th1 or Tregs/Th17comparing FMT arm and placebo arm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in heavy neurofilaments levels in CSF</measure>
    <time_frame>6 months (at baseline and at month 6)</time_frame>
    <description>assessment of ongoing disease activity by measuring neurofilaments in CSF only after a proper given consent (lumbar puncture will not be mandatory)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in levels of pro-inflammatory cytokines and cytokines linked to T cell proliferation and differentiation</measure>
    <time_frame>6 months (at baseline and at month 6)</time_frame>
    <description>Changes from baseline to each time point (month 3, 6, 9, 12) in inflammatory status (cytokines profile in CSF) comparing FMT and placebo arm, only after a proper given consent (lumbar puncture will not be mandatory). We will measure: MIP1a, IL-27, IL-1β, IL-2, IL-4, IL-5, IP-10, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IFNγ, GM-CSF, TNFα, IFNα, MCP-1, IL-9, P-selectin, IL-1α, IL-23, IL-18, IL-21, sICAM-1, IL-22, E-selectin content using specifically assembled kits (Custom Mix&amp;Match panel Human Panel- 27 Plex) for Luminex Screening Assays (Affymetrix, eBioscience).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in microbiota profile</measure>
    <time_frame>12 months (at baseline and at month 6 and 12)</time_frame>
    <description>analysis of fecal, gut and saliva samples to assess whether FMT consistently modifies microbiota in treated patients versus placebo arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Adverse Events</measure>
    <time_frame>12 months ( at screening, baseline, month 1-3-6-7-9-12)</time_frame>
    <description>Patients will be monitored with particular attention to possible side effects, including but not limited to increased risk of infections, constipation, diarrhea, pain, nausea, headache, fever. Routine blood samples will be performed at each neurological examination including blood cell count, serum cholesterol and triglycerides, liver and renal function, urine examination, fecal calprotectin.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tracheostomy free survival</measure>
    <time_frame>12 months</time_frame>
    <description>Overall survival from randomization to date of documented death or tracheostomy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forced vital capacity (FVC)</measure>
    <time_frame>12 months (at baseline and month 3, 6, 9, 12)</time_frame>
    <description>respiratory function</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>disease progression</measure>
    <time_frame>12 months (at baseline and month 3, 6, 9, 12)</time_frame>
    <description>Amyotrophic lateral sclerosis functional rating scale-revised score, a scale which measures individual functioning through questions regarding communication, eating, motricity and respiration (values: maximum 48 corresponding to no disability; minimum 0 corresponding to extreme disability; higher values represent a good outcome)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>quality of life: Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40)</measure>
    <time_frame>12 months (at baseline and month 6 and 12)</time_frame>
    <description>measurement of quality of life by changes in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) a scale used to measure the subjective well-being of patients with amyotrophic lateral sclerosis; it includes 40 items / questions. Dimension scores are coded on a scale of 0 (perfect health as assessed by the measure) to 100 (worst health as assessed by the measure).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">42</enrollment>
  <condition>Amyotrophic Lateral Sclerosis</condition>
  <arm_group>
    <arm_group_label>Fecal microbiota transplantation (FMT)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Fecal microbiota transplantation will be performed during two endoscopic procedures (at baseline and at 6 months) by allogenic infusion of collected feces in the duodenum-jejunum. Fecal microbiota will be diluted in saline solution 200 ml and infused at 30 ml/minute speed. Every endoscopic procedure will be performed with sedation of the patient.&#xD;
Feces for FMT will be obtained by known healthy donors for C. difficile infection according to standard selection procedures.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>ALS patients will undergo upper GI endoscopy with small-intestine biopsies at baseline and after 6 months. Patients in the placebo arm will not receive any treatment during these procedures, but will undergo intestinal biopsy.&#xD;
Every endoscopic procedure will be performed with sedation of the patient.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Fecal microbiota transplantation</intervention_name>
    <description>Fecal microbiota transplantation will be performed during two endoscopic procedures (baseline and at 6 months) by allogenic infusion of collected feces in the duodenum-jejunum.</description>
    <arm_group_label>Fecal microbiota transplantation (FMT)</arm_group_label>
    <other_name>FMT</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>patients will undergo endoscopic procedure with biopsy during sedation but without any kind of intervention</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients diagnosed with a laboratory supported, clinically &quot;probable&quot; or &quot;definite&quot;&#xD;
             amyotrophic lateral sclerosis according to the Revised El Escorial criteria (Brooks,&#xD;
             2000)&#xD;
&#xD;
          -  Sporadic or familial ALS&#xD;
&#xD;
          -  Female or male patients aged between 18 and 70 years old&#xD;
&#xD;
          -  Disease duration from symptoms onset no longer than 18 months at the screening visit&#xD;
&#xD;
          -  Patients treated with a stable dose of Riluzole (100 mg/day) for at least 30 days&#xD;
             prior to screening&#xD;
&#xD;
          -  Patients with a weight &gt; 50 kg and a BMI ≥18&#xD;
&#xD;
          -  Patients with a FVC (Forced Vital Capacity) equal or more than 70% predicted normal&#xD;
             value for gender, height, and age at the screening visit&#xD;
&#xD;
          -  Patients able and willing to comply with study procedures as per protocol&#xD;
&#xD;
          -  Patients able to understand, and capable of providing informed consent at screening&#xD;
             visit prior to any protocol-specific procedures&#xD;
&#xD;
          -  Use of effective contraception both for males and females&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known organic gastrointestinal disease&#xD;
&#xD;
          -  History of gastrointestinal malignancy; ongoing malignancies&#xD;
&#xD;
          -  Use of immunosuppressive or chemotherapy within the past 2 years&#xD;
&#xD;
          -  Celiac disease and/or food (e.g.lactose) intolerance&#xD;
&#xD;
          -  Previous gastrointestinal surgery&#xD;
&#xD;
          -  Any condition that would make endoscopic procedures contraindicated&#xD;
&#xD;
          -  Acute infections requiring antibiotics&#xD;
&#xD;
          -  Antimicrobial treatment or probiotics 4 weeks prior to screening&#xD;
&#xD;
          -  Severe comorbidities (heart, renal, liver failure); severe renal (eGFR&lt;&#xD;
             30ml/min/1.73m2), or liver failure or liver aminotransferase (ALT/AST &gt; 2x Upper limit&#xD;
             of normal),&#xD;
&#xD;
          -  Autoimmune diseases, inflammatory disorders (SLE, Rheumatoid arthritis, connective&#xD;
             tissue disorder) or chronic infections (HIV, hepatitis B or C infection)&#xD;
&#xD;
          -  Abuse of alcohol or drugs&#xD;
&#xD;
          -  HIV, tuberculosis, hepatitis&#xD;
&#xD;
          -  Participation in clinical trials &lt;30 days before screening&#xD;
&#xD;
          -  Existing blood dyscrasia (e.g., myelodysplasia)&#xD;
&#xD;
          -  White blood cells&lt;4,000/mm³, platelets count&lt;100,000/mm³, hematocrit&lt;30%&#xD;
&#xD;
          -  Patients who underwent non-invasive ventilation, tracheotomy and /or gastrostomy&#xD;
&#xD;
          -  Women who are pregnant or breastfeeding&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Clinica Neurologica, Ospedale Clinicizzato &quot;SS Annunziata&quot;</name>
      <address>
        <city>Chieti</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliero Universitaria di Modena</name>
      <address>
        <city>Modena</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UO Neurofisiopatologia, Azienda Ospedaliera dì Perugia</name>
      <address>
        <city>Perugia</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Catholic University of Sacred Heart - Fondazione Policlinico &quot;A. Gemelli&quot;</name>
      <address>
        <city>Roma</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NEuroMuscular Omnicentre Centre (NeMO), Fondazione Serena Onlus-Fondazione Policlinico A. Gemelli</name>
      <address>
        <city>Roma</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
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  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>20660719</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>15823706</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>25689247</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>19921501</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>25211238</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>20566854</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>27912057</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>28220542</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>28552366</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>23323867</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>27529553</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>25847918</PMID>
  </results_reference>
  <results_reference>
    <citation>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.</citation>
    <PMID>17018025</PMID>
  </results_reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>November 30, 2018</study_first_submitted>
  <study_first_submitted_qc>December 4, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 6, 2018</study_first_posted>
  <last_update_submitted>February 28, 2023</last_update_submitted>
  <last_update_submitted_qc>February 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Azienda Ospedaliero-Universitaria di Modena</investigator_affiliation>
    <investigator_full_name>JESSICA MANDRIOLI</investigator_full_name>
    <investigator_title>sponsor-investigator</investigator_title>
  </responsible_party>
  <keyword>microbiota</keyword>
  <keyword>fecal transplantation</keyword>
  <keyword>adaptive immunity</keyword>
  <keyword>T regulatory lymphocytes</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Motor Neuron Disease</mesh_term>
    <mesh_term>Amyotrophic Lateral Sclerosis</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>de-identified individual participant data will be made available after study completion upon specific request</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>The data will become available at study completion (after final data analysis)</ipd_time_frame>
    <ipd_access_criteria>specific personal request by the subject</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03766321
org study id: FeTr-ALS
nct id: NCT03766321
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
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.
The study will include 42 ALS patients with 2:1 allocation in 2 groups of subjects (28 FMT vs
      14 placebo); computerized randomization will be stratified by progression rate (ΔFS) </≥0.7.
      Randomization time will last 18 months. Treatment will be double blinded to patients and
      physicians, and will be done at baseline and at month 6. FMT is regarded as the active
      treatment. Post-treatment follow up will be 6 months.

      ALS patients will undergo upper GI endoscopy with small-intestine biopsies (n° 4 biopsies of
      small intestine, performed with a standard biopsy forces) at baseline and after 6 months. At
      baseline patients will be randomized (2:1) to either an allogenic (from donors) infusion of
      collected feces (fecal microbiota transplantation, FMT) (or no procedure in case of
      allocation to placebo) in the duodenum-jejunum. The infusion will be performed through a
      standard nasojejunal tube, that will be placed during endoscopy. Infusion of feces will be
      performed at time 0 and repeated at month 6. The patients allocated to placebo arm will not
      receive treatment, but will undergo intestinal biopsy.

      Upper GI endoscopy 12 months after FMT will be performed only to identify specific microbioma
      and mucosal immunological evaluation. Fecal samples and small intestine biopsy samples (at
      baseline, before treatment, and at month 6 and 12) will be obtained from patients to perform
      the gut microbiota typing.

      Every endoscopic procedure will be performed with sedation of the patient. Feces for FMT will
      be obtained by healthy donors for C. difficile infection. Procedures that are usually
      performed for the selection of donors for transplantation of feces are as follows. Potential
      donors stool will be chosen in healthy volunteers that will have given a questionnaire with
      questions about lifestyle, health status, current therapy, etc., significant clinical
      symptoms of gastrointestinal disease, etc.. Based on this questionnaire, the potential donor
      will be considered eligible if excluded: I) Habits of life and risk behaviors, II)
      Concomitant significant known disorders, III) chronic or recent use of concomitant
      medications that may interfere with the state of the intestinal microflora (eg, antibiotics),
      IV) Clinical symptoms indicative of gastrointestinal disease or other diseases of importance,
      V) Personal or family medical history known of neurodegenerative diseases or other autoimmune
      diseases.

      Moreover, each suitable potential donor will be subjected to the following screening tests:
      I) Examination of stool for Clostridium difficile bacterial pathogens and protozoa and
      helminths of the small intestine and colon, Vancomycin-resistant Enterococci (VRE ),
      Methicillin-resistant Staphylococcus aureus (MRSA), Gram-negative Multidrug-Resistant
      Organisms (MDR), II) Serological screening for hepatitis virus A,B and C, HIV 1-2, Treponema
      pallidum, H. pylori, blood count with differential, dose transaminasemia, creatinine and
      C-reactive protein.

      Potential donors negative for this screening will be considered definitively suitable and
      will be invited to give a stool sample to prepare than for the fecal transplant. The donation
      will be made in the appropriate circles in the Department of Internal Medicine and
      Gastroenterology, and the preparation of faeces (manual homogenization in 500 mL of saline
      solution) for infusion will be performed at the Unit of Analysis 2 ° (Virology and
      Microbiology).

      Analysis of T cell sub-populations will be performed both in peripheral blood and gut mucosa:
      especially the ratio T Regulatory cells (Tregs)/Th17 cells A Contract Research Organization
      (CRO) will be in charge for study monitoring.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: randomized double blind multicentre study on FMT in ALS, with a randomization ratio 2:1 (FMT: placebo).
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: placebo will be unrecognizable from active treatment because the patients will undergo endoscopic procedure with sedation
measure: Change in Tregs number
time frame: 6 months
description: to assess whether FMT increases Tregs' number in ALS patients treated with FMT compared to the control arm
measure: Change in T cell subsets frequency in blood and gut tissue samples
time frame: 12 months (at time points: baseline, month 3 - 6 (both arms)- 9 -12 (both arms))
description: Change from baseline to each time point (month 3, 6, 9, 12) of the T cell distribution especially the ratio Tregs/Th1 or Tregs/Th17comparing FMT arm and placebo arm.
measure: Change in heavy neurofilaments levels in CSF
time frame: 6 months (at baseline and at month 6)
description: assessment of ongoing disease activity by measuring neurofilaments in CSF only after a proper given consent (lumbar puncture will not be mandatory)
measure: Changes in levels of pro-inflammatory cytokines and cytokines linked to T cell proliferation and differentiation
time frame: 6 months (at baseline and at month 6)
description: Changes from baseline to each time point (month 3, 6, 9, 12) in inflammatory status (cytokines profile in CSF) comparing FMT and placebo arm, only after a proper given consent (lumbar puncture will not be mandatory). We will measure: MIP1a, IL-27, IL-1β, IL-2, IL-4, IL-5, IP-10, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IFNγ, GM-CSF, TNFα, IFNα, MCP-1, IL-9, P-selectin, IL-1α, IL-23, IL-18, IL-21, sICAM-1, IL-22, E-selectin content using specifically assembled kits (Custom Mix&Match panel Human Panel- 27 Plex) for Luminex Screening Assays (Affymetrix, eBioscience).
measure: Changes in microbiota profile
time frame: 12 months (at baseline and at month 6 and 12)
description: analysis of fecal, gut and saliva samples to assess whether FMT consistently modifies microbiota in treated patients versus placebo arm
measure: Incidence of Adverse Events
time frame: 12 months ( at screening, baseline, month 1-3-6-7-9-12)
description: Patients will be monitored with particular attention to possible side effects, including but not limited to increased risk of infections, constipation, diarrhea, pain, nausea, headache, fever. Routine blood samples will be performed at each neurological examination including blood cell count, serum cholesterol and triglycerides, liver and renal function, urine examination, fecal calprotectin.
measure: Tracheostomy free survival
time frame: 12 months
description: Overall survival from randomization to date of documented death or tracheostomy
measure: Forced vital capacity (FVC)
time frame: 12 months (at baseline and month 3, 6, 9, 12)
description: respiratory function
measure: disease progression
time frame: 12 months (at baseline and month 3, 6, 9, 12)
description: Amyotrophic lateral sclerosis functional rating scale-revised score, a scale which measures individual functioning through questions regarding communication, eating, motricity and respiration (values: maximum 48 corresponding to no disability; minimum 0 corresponding to extreme disability; higher values represent a good outcome)
measure: quality of life: Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40)
time frame: 12 months (at baseline and month 6 and 12)
description: measurement of quality of life by changes in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) a scale used to measure the subjective well-being of patients with amyotrophic lateral sclerosis; it includes 40 items / questions. Dimension scores are coded on a scale of 0 (perfect health as assessed by the measure) to 100 (worst health as assessed by the measure).
arm group label: Fecal microbiota transplantation (FMT)
arm group type: Active Comparator
description: Fecal microbiota transplantation will be performed during two endoscopic procedures (at baseline and at 6 months) by allogenic infusion of collected feces in the duodenum-jejunum. Fecal microbiota will be diluted in saline solution 200 ml and infused at 30 ml/minute speed. Every endoscopic procedure will be performed with sedation of the patient.
Feces for FMT will be obtained by known healthy donors for C. difficile infection according to standard selection procedures.
arm group label: Placebo
arm group type: Placebo Comparator
description: ALS patients will undergo upper GI endoscopy with small-intestine biopsies at baseline and after 6 months. Patients in the placebo arm will not receive any treatment during these procedures, but will undergo intestinal biopsy.
Every endoscopic procedure will be performed with sedation of the patient.
intervention type: Biological
intervention name: Fecal microbiota transplantation
description: Fecal microbiota transplantation will be performed during two endoscopic procedures (baseline and at 6 months) by allogenic infusion of collected feces in the duodenum-jejunum.
arm group label: Fecal microbiota transplantation (FMT)
other name: FMT
intervention type: Biological
intervention name: Placebo
description: patients will undergo endoscopic procedure with biopsy during sedation but without any kind of intervention
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
country: Italy
citation: 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.
PMID: 23870000
citation: 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.
PMID: 20074461
citation: 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.
PMID: 15790844
citation: 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.
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citation: 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.
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citation: 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.
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citation: 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.
PMID: 16741123
citation: 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.
PMID: 22183182
citation: 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.
PMID: 23286757
citation: Brandt LJ. Fecal Microbiota Transplant: Respice, Adspice, Prospice. J Clin Gastroenterol. 2015 Nov-Dec;49 Suppl 1:S65-8. doi: 10.1097/MCG.0000000000000346.
PMID: 26447968
citation: 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.
PMID: 15831718
citation: 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.
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PMID: 17699621
citation: 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.
PMID: 28522180
citation: 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. Erratum In: EMBO Mol Med. 2013 Feb;5(2):326.
PMID: 23143995
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PMID: 24890442
citation: 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.
PMID: 29071710
citation: 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.
PMID: 16434671
citation: 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.
PMID: 27198196
citation: 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.
PMID: 20660719
citation: 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.
PMID: 15823706
citation: 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.
PMID: 25689247
citation: 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.
PMID: 19921501
citation: 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.
PMID: 25211238
citation: 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.
PMID: 20566854
citation: 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.
PMID: 27912057
citation: 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.
PMID: 28220542
citation: 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.
PMID: 28552366
citation: 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.
PMID: 23323867
citation: 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.
PMID: 27529553
citation: 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.
PMID: 25847918
citation: 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.
PMID: 17018025
responsible party type: Principal Investigator
investigator affiliation: Azienda Ospedaliero-Universitaria di Modena
investigator full name: JESSICA MANDRIOLI
investigator title: sponsor-investigator
mesh term: Motor Neuron Disease
mesh term: Amyotrophic Lateral Sclerosis
mesh term: Sclerosis
sharing ipd: Yes
ipd description: de-identified individual participant data will be made available after study completion upon specific request
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: The data will become available at study completion (after final data analysis)
ipd access criteria: specific personal request by the subject