Clinical trial NCT03074227: The FAIS-Trial: Faecal Microbiota Transplantation (FMT) in Adolescents With Refractory Irritable Bowel Syndrome (IBS)
Official title: The FAIS-Trial: Faecal Transplantation in Adolescents With Refractory Irritable Bowel Syndrome
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Irritable Bowel Syndrome
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
First posted: 2017-03-08
Enrollment: 30
Sex: ALL
Minimum age (years): 16
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blind, randomised, placebo-controlled pilot study as well as a reversed translational part.
Primary purpose: TREATMENT

Brief summary: A Double-blind randomised placebo-controlled pilot study as well as a reversed translational part To investigate whether two faecal transplantations from either allogeneic (healthy) or autologous (own) donor, administered through a nasoduodenal tube, has beneficial effects on irritable bowel syndrome (IBS) symptoms such as abdominal pain frequency and severity. Secondary objective is to study microbiota changes in faeces samples.

Detailed description: Irritable bowel syndrome (IBS) is a chronic disorder characterized by abdominal pain or discomfort associated with a change in stool form or frequency, in the absence of a biochemical or structural explanation for these symptoms. The prevalence of IBS in the general adult population is 9.8-12.8%, which is in accordance to the prevalence of IBS in children and adolescents (6.2%-11.9%). Patients with IBS report a decreased quality of life, high work or school absence, and are more at risk than healthy controls of developing depressive and anxiety disorders. Consequently, the healthcare costs are substantial; annual costs of care for adults with IBS in the USA are estimated to be over $20 billion. Total annual costs per paediatric IBS patient in the Netherlands are estimated to be €2500. Although the pathophysiology of IBS has not been fully elucidated, pathophysiological abnormal gastrointestinal motility, visceral hypersensitivity, altered brain-gut function, low-grade inflammation, psychosocial disturbance and intestinal microbiota characteristics have been proposed to contribute to the pathophysiology. Current treatment focuses on abnormal gastrointestinal motility, altered brain-gut function and psychosocial disturbances. However, a significant amount of IBS patients has remaining symptoms, despite these treatment regimens. These patients are considered to be therapy-resistant, also called refractory. Treatment focusing on other components of the underlying pathophysiology, such as the intestinal microbiota, might therefore lead to new therapeutic successes in this group of patients. In this light, being able to modify the intestinal microbiota inrefractory IBS patients could have beneficial effects on symptoms. Faecal transplantation, a relatively new treatment regimen that enables the modification of the microbiome, has been shown to be highly effective in treating Clostridium difficile infections and also yielded promising results in patients with other diseases such as diabetes.

Objective: To investigate whether two faecal transplantations from either allogeneic (healthy) or autologous (own) donor, administered through a nasoduodenal tube, has beneficial effects on irritable bowel syndrome (IBS) symptoms such as abdominal pain frequency and severity. Secondary objective is to study microbiota changes in faeces samples.

Study design: Double-blind randomised placebo-controlled pilot study as well as a reversed translational part.

Study Population: Patients with refractory IBS, defined as a failure to improve after standard medical treatment, at least 6 sessions of a psychological therapy and absence of response to at least 1 pharmacological agent (aged 16-21 years, male/female, no concomitant medication, non-smoking), will be recruited by their (paediatric) gastroenterologist at the Academic Medical Centre (Amsterdam, the Netherlands) and patients from other hospitals will be enrolled. Donors: relatives or volunteers will serve as faeces donor, potential donors will be thoroughly screened.

Treatment: After bowel lavage with Klean-Prep, patients will be treated with faecal transplantation at t=0 and t=6 weeks, processed for duodenal tube infusion. Faeces will be collected from a healthy donor (allogeneic) as well as the patient him/herself (autologous), in which their own faeces will be used as a placebo.

Eligibility criteria: Inclusion Criteria:

Patients

* Age 16-21 years
* Non-smokers
* Ability to give informed consent
* Established irritable bowel syndrome diagnosis according to the Rome IV criteria for children or adults
* According to a recently published guideline by the Rome Foundation for the design of pharmacological clinical trials in adolescents, patients are required to have an average daily pain rate of at least 30mm on the pain component scale of the IBS-SSS
* Symptoms are present for ≥12 months
* The patient has received adequate explanation and reassurance for his/her symptoms
* Appropriate dietary interventions have occurred, including the normalisation of the insoluble fibre intake and a decrease in gas producing foods
* Absence of response to a minimum of six sessions of psychological treatment (i.e. cognitive behavioural therapy and/or hypnotherapy)
* Absence of response to an adequate dose of at least one IBS specific pharmacological agent tried for a minimum of 6 weeks (like Mebeverine or peppermint oil capsules)

Donors

* Age ≥18 years
* Non-smokers
* Ability to give informed consent
* BMI 18-25 kg/m2
* Regular stool pattern

Exclusion Criteria:

Patients

* Current treatment by another health care professional for abdominal symptoms
* Known concomitant organic gastrointestinal disease
* Known diagnosis of inflammatory bowel disease (i.e. Crohns disease or ulcerative colitis)
* Known diagnosis of an autoimmune disease (e.g. hypo- or hyperthyroidism, celiac disease, rheumatoid arthritis)
* Known diagnosis of cystic fibrosis
* Known diagnosis of porphyria
* Current use of drugs which influence gastrointestinal motility, such as erythromycin, azithromycin, butyl scopolamine, domperidone, peppermint oil capsules, and Iberogast
* Known pregnancy or current lactation
* Condition leading to profound immunosuppression (HIV, infectious diseases leading to immunosuppression, bone marrow malignancies/use of systematic chemotherapy)
* Life expectancy \< 12 months
* Use of concomitant medication, including proton pomp inhibitors (PPI), with the exception of pain medication (pain medication in the form of Paracetamol or NSAIDs is allowed)
* Use of systemic antibiotics in preceding 6 weeks
* Use of probiotic treatment in preceding 6 weeks
* Positive stool cultures for Clostridium difficile, Helicobacter pylori
* Positive Dual Faeces Test for Giardia lamblia, Dientamoeba fragilis, Entamoeba histolytica
* XTC, amphetamine or cocaine abuse
* History of surgery (hemicolectomy (defined as: surgery resulting in a resection of \> 0.5 of the colon), presence of a pouch due to surgery, presence of stoma)
* Known intra-abdominal fistula
* Vasopressive medication, ICU stay
* Signs of ileus, diminished passage
* Allergy to macrogol or substituents, e.g. peanuts, shellfish
* Insufficient knowledge of the Dutch language

Donors

* Abnormal bowel motions, abdominal complaints or symptoms indicative of irritable bowel syndrome
* An extensive travel behaviour
* Unsafe sex practice (questionnaire)
* Use of any medication including PPI
* Antibiotic treatment in the past 12 weeks
* A positive history/clinical evidence for inflammatory bowel disease (Crohns disease or ulcerative colitis) or other gastrointestinal diseases, including chronic diarrhoea or chronic constipation
* A positive history/clinical evidence for autoimmune disease (type 1 diabetes, Hashimoto hypothyroidism, Graves hyperthyroidism, rheumatoid arthritis, celiac disease) and/or patients receiving immunosuppressive medications
* History of or present known malignant disease and/or patients who are receiving systemic anti-neoplastic agents
* Known psychiatric disease (depression, schizophrenia, autism, Asperger's syndrome)
* Known chronic neurological/neurodegenerative disease (e.g. Parkinson's disease, multiple sclerosis)
* Predisposing factors for potential transmittable diseases (e.g. regular sexual contact with prostitutes/promiscuity)
* Positive blood tests for the presence of: HIV, HTLV, lues, Strongyloides, amoebiasis
* Active hepatitis A, B-, C- or E-virus infection or known exposure within recent 12 months, acute infection with cytomegalovirus (CMV) or Epstein-Barr virus (EBV)
* Positive faecal tests for the presence of:

  * Bacteria (Clostridium difficile, Helicobacter pylori, Salmonella spp., Shigella spp., pathogenic Campylobacter spp., Yersinia enterocolitica, Aeromonas spp., Plesiomonas shigelloides, Antibiotic resistant bacteria: Extended spectrum beta-lactamase (ESBL)-producing Enterobactereacceae, VRE (vancomycin resistant enterococ)
  * Viruses (faecal PCR-test: Norovirus Type I and II, Astrovirus, Sapovirus, Adenovirus type 40/41, Rotavirus, Enterovirus, Adenovirus non-41/41)
  * Parasites (Giardia lamblia, Cryptosporidium spp., Entamoeba histolytica, Dientamoeba fragilis, Microsporidium spp., Blastocystis hominis, Isospora spp. Or more than 1 of the following non-pathogenic parasites: Entamoeba gingivalis, Entamoeba hartmanni, Entamoeba coli, Entamoeba polecki, Endolimax nana, Iodamoeba bütschlii, Entamoeba dispar, Entamoeba moshkovskii
* If a donor turns out positive for only 1 of the above mentioned non-pathogenic parasites, inclusion is acceptable

  o Parasitic worm eggs, larvae, protozoan cysts and oocysts
* Chronic pain syndromes (e.g. fibromyalgia)
* Major relevant allergies (e.g. food allergy, multiple allergies)
* Recent (gastrointestinal) infection (within last 6 months)
* Tattoo or body piercing placement within last 6 months
* Known risk of Creutzfeldt Jacobs disease
* History of current use of IV drugs
* History of treatment with growth factors
* Untreated infection with: Treponematoses, TBC, Herpes virus

Primary outcomes:
measure: The proportion of patients with > 50% reduction of their abdominal pain intensity and pain frequency at t=12 weeks after the first faecal transplantation
timeFrame: T=12 weeks
Secondary outcomes:
measure: Intra-individual changes in faecal gut microbiota composition
timeFrame: At baseline, 6 weeks, 12 weeks, 6 months and 12 months after faecal transplantation
measure: Adverse events
timeFrame: At t=3, t=6, t=12 and t=16 weeks, and t=6 and 12 months
measure: The proportion of patients with > 50% reduction of their abdominal pain intensity and pain frequency
timeFrame: At t=6 and t=12 months
measure: Total IBS-SSS score
timeFrame: At baseline, t=3, t=6, t=12 and t=16 weeks, and t=6 and 12 months
measure: Health related quality of life
timeFrame: baseline, t=6 and t=12 weeks, and t=6 and 12 months
measure: Depression and anxiety
timeFrame: baseline, t=6 and t=12 weeks, and t=6 and 12 months.
measure: Absence of school or work, health care resources and costs
timeFrame: baseline, t=6 and t=12 weeks, and t=6 and 12 months.
measure: Adequate relief
timeFrame: t=6 and t=12 weeks, and t=6 and 12 months
measure: Number of participants with treatment-related adverse events as assessed by CRP, liver profile and renal profile
timeFrame: t=0, t=6 and t=12 weeks
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: AMC
state: Noord Holland
Study officials:
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Marc Benninga, Prof.dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zeevenhooven J, de Bruijn CMA, Vlieger A, Nieuwdorp M, Benninga MA. Protocol for a pilot randomised, double-blind, placebo-controlled trial for assessing the feasibility and efficacy of faecal microbiota transplantation in adolescents with refractory irritable bowel syndrome: FAIS Trial. BMJ Paediatr Open. 2020 Aug 20;4(1):e000689. doi: 10.1136/bmjpo-2020-000689. eCollection 2020.