Clinical trial NCT03766321: Fecal Microbiota Transplantation Effect on Amyotrophic Lateral Sclerosis Patients
Official title: Interplay Between Gut Microbiota and Adaptive Immunity in Amyotrophic Lateral Sclerosis: a Clinical Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Amyotrophic Lateral Sclerosis
Keywords: microbiota
fecal transplantation
adaptive immunity
T regulatory lymphocytes
Lead sponsor: Azienda Ospedaliero-Universitaria di Modena
Sponsor class: OTHER
Collaborators: name: University of Modena and Reggio Emilia
name: Catholic University of the Sacred Heart
name: Campus Bio-Medico University
name: Azienda Ospedaliero-Universitaria Careggi
name: Azienda Ospedaliera di Perugia
name: University of Chieti
name: University of Florence
First posted: 2018-12-06
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomized double blind multicentre study on FMT in ALS, with a randomization ratio 2:1 (FMT: placebo).
Primary purpose: TREATMENT

Brief 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.

Detailed 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) \</≥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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Tregs number
timeFrame: 6 months
Secondary outcomes:
measure: Change in T cell subsets frequency in blood and gut tissue samples
timeFrame: 12 months (at time points: baseline, month 3 - 6 (both arms)- 9 -12 (both arms))
measure: Change in heavy neurofilaments levels in CSF
timeFrame: 6 months (at baseline and at month 6)
measure: Changes in levels of pro-inflammatory cytokines and cytokines linked to T cell proliferation and differentiation
timeFrame: 6 months (at baseline and at month 6)
measure: Changes in microbiota profile
timeFrame: 12 months (at baseline and at month 6 and 12)
measure: Incidence of Adverse Events
timeFrame: 12 months ( at screening, baseline, month 1-3-6-7-9-12)
measure: Tracheostomy free survival
timeFrame: 12 months
measure: Forced vital capacity (FVC)
timeFrame: 12 months (at baseline and month 3, 6, 9, 12)
measure: disease progression
timeFrame: 12 months (at baseline and month 3, 6, 9, 12)
measure: quality of life: Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40)
timeFrame: 12 months (at baseline and month 6 and 12)
Other outcomes:
Locations:
city: Chieti
country: Italy
facility: Clinica Neurologica, Ospedale Clinicizzato "SS Annunziata"
city: Modena
country: Italy
facility: Azienda Ospedaliero Universitaria di Modena
city: Perugia
country: Italy
facility: UO Neurofisiopatologia, Azienda Ospedaliera dì Perugia
city: Roma
country: Italy
facility: Catholic University of Sacred Heart - Fondazione Policlinico "A. Gemelli"
city: Roma
country: Italy
facility: NEuroMuscular Omnicentre Centre (NeMO), Fondazione Serena Onlus-Fondazione Policlinico A. Gemelli
Study officials:
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