Fecal Microbiota Transplantation Effect on Amyotrophic Lateral Sclerosis Patients

Amyotrophic Lateral Sclerosis Clinical Trial

— FETR-ALS  

Official title:

Interplay Between Gut Microbiota and Adaptive Immunity in Amyotrophic Lateral Sclerosis: a Clinical Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03766321
• Other study ID #: FeTr-ALS
• Status: Active, not recruiting
• Phase: N/A
• Start date: July 1, 2020
• Est. completion date: February 2025

Study information

• Verified date: February 2024
• Source: Azienda Ospedaliero-Universitaria di Modena
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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)

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 42
• Est. completion date: February 2025
• Est. primary completion date: April 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Patients diagnosed with a laboratory supported, clinically "probable" or "definite" amyotrophic lateral sclerosis according to the Revised El Escorial criteria (Brooks, 2000)

• Sporadic or familial ALS

• Female or male patients aged between 18 and 70 years old

• Disease duration from symptoms onset no longer than 18 months at the screening visit

• Patients treated with a stable dose of Riluzole (100 mg/day) for at least 30 days prior to screening

• Patients with a weight > 50 kg and a BMI =18

• Patients with a FVC (Forced Vital Capacity) equal or more than 70% predicted normal value for gender, height, and age at the screening visit

• Patients able and willing to comply with study procedures as per protocol

• Patients able to understand, and capable of providing informed consent at screening visit prior to any protocol-specific procedures

• Use of effective contraception both for males and females

Exclusion Criteria:

• Known organic gastrointestinal disease

• History of gastrointestinal malignancy; ongoing malignancies

• Use of immunosuppressive or chemotherapy within the past 2 years

• Celiac disease and/or food (e.g.lactose) intolerance

• Previous gastrointestinal surgery

• Any condition that would make endoscopic procedures contraindicated

• Acute infections requiring antibiotics

• Antimicrobial treatment or probiotics 4 weeks prior to screening

• Severe comorbidities (heart, renal, liver failure); severe renal (eGFR< 30ml/min/1.73m2), or liver failure or liver aminotransferase (ALT/AST > 2x Upper limit of normal),

• Autoimmune diseases, inflammatory disorders (SLE, Rheumatoid arthritis, connective tissue disorder) or chronic infections (HIV, hepatitis B or C infection)

• Abuse of alcohol or drugs

• HIV, tuberculosis, hepatitis

• Participation in clinical trials <30 days before screening

• Existing blood dyscrasia (e.g., myelodysplasia)

• White blood cells<4,000/mm³, platelets count<100,000/mm³, hematocrit<30%

• Patients who underwent non-invasive ventilation, tracheotomy and /or gastrostomy

• Women who are pregnant or breastfeeding

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease
• Sclerosis

Intervention

Biological:
• Fecal microbiota transplantation
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.
• Placebo
patients will undergo endoscopic procedure with biopsy during sedation but without any kind of intervention

Locations

Country	Name	City	State
Italy	Clinica Neurologica, Ospedale Clinicizzato "SS Annunziata"	Chieti
Italy	Azienda Ospedaliero Universitaria di Modena	Modena
Italy	UO Neurofisiopatologia, Azienda Ospedaliera dì Perugia	Perugia
Italy	Catholic University of Sacred Heart - Fondazione Policlinico "A. Gemelli"	Roma
Italy	NEuroMuscular Omnicentre Centre (NeMO), Fondazione Serena Onlus-Fondazione Policlinico A. Gemelli	Roma

Sponsors (8)

Lead Sponsor	Collaborator
Azienda Ospedaliero-Universitaria di Modena	Azienda Ospedaliera di Perugia, Azienda Ospedaliero-Universitaria Careggi, Campus Bio-Medico University, Catholic University of the Sacred Heart, University of Chieti, University of Florence, University of Modena and Reggio Emilia

Country where clinical trial is conducted

Italy, 

References & Publications (32)

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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. Ep — View Citation

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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 Defi — View Citation

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* Note: There are 32 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Tregs number	to assess whether FMT increases Tregs' number in ALS patients treated with FMT compared to the control arm	6 months
Secondary	Change in T cell subsets frequency in blood and gut tissue samples	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.	12 months (at time points: baseline, month 3 - 6 (both arms)- 9 -12 (both arms))
Secondary	Change in heavy neurofilaments levels in CSF	assessment of ongoing disease activity by measuring neurofilaments in CSF only after a proper given consent (lumbar puncture will not be mandatory)	6 months (at baseline and at month 6)
Secondary	Changes in levels of pro-inflammatory cytokines and cytokines linked to T cell proliferation and differentiation	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-1ß, IL-2, IL-4, IL-5, IP-10, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IFN?, GM-CSF, TNFa, IFNa, MCP-1, IL-9, P-selectin, IL-1a, 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).	6 months (at baseline and at month 6)
Secondary	Changes in microbiota profile	analysis of fecal, gut and saliva samples to assess whether FMT consistently modifies microbiota in treated patients versus placebo arm	12 months (at baseline and at month 6 and 12)
Secondary	Incidence of Adverse Events	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.	12 months ( at screening, baseline, month 1-3-6-7-9-12)
Secondary	Tracheostomy free survival	Overall survival from randomization to date of documented death or tracheostomy	12 months
Secondary	Forced vital capacity (FVC)	respiratory function	12 months (at baseline and month 3, 6, 9, 12)
Secondary	disease progression	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)	12 months (at baseline and month 3, 6, 9, 12)
Secondary	quality of life: Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40)	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).	12 months (at baseline and month 6 and 12)