STOP-Colitis Pilot Trial 

STOP-Colitis logo

A prospective, open-label, randomised pilot study to assess two possible routes of Faecal Microbiota Transplant (FMT) delivery in patients with ulcerative colitis.

 

Rationale and background

Ulcerative Colitis (UC) is a chronic debilitating disease with an increased risk of bowel cancer. Management relies on life-long anti-inflammatory/immunosuppressive agents and, in some cases, patients need colectomy. There is a pressing need for better and more effective medical treatments to reduce the need for surgery and reduce the long-term cancer risk.

Recently we have begun to understand the relationship between ourselves and the many bacteria which share our gastrointestinal tract. What is becoming clearer is the vital role these bacteria play in maintaining health and the damage that can result when the delicate partnership between us and our gut bacteria is disrupted. We now know that there is a difference in the proportion of various colonic bacteria between people with and without UC. It is believed that this difference is related to the colonic inflammation seen in people with UC and that changing the balance of bacteria may have a beneficial effect in reducing the inflammation.

There have been numerous small studies concerning the effects of replacing the bacteria in the gut of patients with UC using probiotics which have been disappointing because the products lack bacterial diversity and concentration. In contrast, Faecal Microbial Transplant (FMT), which is a technique of attempting to alter the gut bacteria makeup of a patient with UC, with bacteria derived from a healthy person, involves the transfer of potentially an entire dense colonic microbial community. In this regard, FMT represents a very low-cost, potentially paradigm-changing, treatment for UC. In theory this treatment would, for the first time, address the cause of the disease rather that reactively treating the resulting inflammation.

FMT has been administered by both the colonic route and via a nasogastric tube (NGT). This latter method has been particularly successful in treating colitis caused by clostridium difficile infection (C Diff). In general, the results of FMT in UC have been encouraging and the treatments have been administered without causing harm. However, these studies in most part have been ‘uncontrolled’ with no comparison between the FMT treatment and an alternative therapy to accurately gauge the effect of FMT in UC. In addition the variability in design and processes used makes the results of these studies difficult to compare. To date, there have been few fully published randomised controlled trials in this field.

The STOP-Colitis trial is a planned 2-stage investigation. The first stage is a pilot trial to determine the optimum route of FMT delivery for the treatment of UC, and secondly, the efficacy of such treatment in patients with active UC which is refractory to standard treatment. At the end of the pilot an independent oversight committee will decide (1) which (if any) of the two routes of FMT delivery to take forward to the main trial; and (2) whether a full randomised control trial (RCT) is feasible (based on a review of the pilot data in terms of assessing treatment efficacy, tolerability, patient adherence to allocated treatment and qualitative perspectives on FMT and trial experience). We propose to proceed forward to the main RCT taking the preferred method into a randomised double-blind, placebo-controlled trial with an efficacy outcome measure of clinical remission.

Further details of the RCT will follow when available.

Trial Design

Pilot stage

Design: Prospective, open-label, multi-centre, randomised pilot feasibility study.

Participants: Men and women aged between 16 and 70 with active (mild to moderate) ulcerative colitis (Mayo score between 4 and 8).

Intervention: Patients will be randomised to receive FMT by either the Naso-gastric (NG) or COLONIC route. All patients will receive 8 FMT treatments. NG patients will receive a total 240g FMT and Colonic patients will receive a total 360g FMT.

Sample size: A total sample size of 30 patients, to be randomised from 3 UK participating hospitals over a recruitment period of 3 months.

Trial Scheme for pilot stage:

 Trial Schema

RCT

Design: Prospective, double blinded, multi-centre, randomised, placebo controlled study.

Participants: Men and women aged between 16 and 70 in addition to young people (from age 12) with active (mild to moderate) ulcerative colitis (Mayo score between 4 and 8)

Interventions:  Patients will be randomised to receive FMT or placebo by the chosen route taken forward from the pilot study, i.e. NG or COLONIC route.

Sample size: A total sample size of 230 patients, to be randomised from UK participating hospitals over a recruitment period of 2 years.

Trial Scheme for RCT is currently under development.

Objectives

Pilot stage

Primary objectives
  • To determine which FMT administration route (NG or COLONIC) should be taken forward to a double-blinded placebo-controlled RCT to investigate the efficacy of FMT in achieving and maintaining remission in patients with ulcerative colitis.
  • To determine whether a full double-blinded placebo RCT is feasible.
Secondary Objectives

Clinical Objectives

  • Whether FMT by the NG route induces clinical response in patients with active UC
  • Whether FMT by the colonic route induces clinical response in patients with active UC
  • Tolerability and safety
  • Which route of FMT delivery (if any) is suitable to investigate in the RCT

Qualitative Objectives

  • Patient acceptability of FMT (NG)
  • Patient acceptability of FMT (COLON)

Mechanistic Objectives

  • Whether FMT by either route is associated with a change in faecal calprotectin as a surrogate marker of colonic inflammation
  • Changes in the colonic microbiome and metabolome (short chain fatty acids (SCFA)) induced by FMT via each route
  • Reduction in C-reactive protein (CRP)
  • Engraftment of donor microbiota in recipients by culturing donor stool to strain level

Other Objectives

  • Effect of diet (donors)
  • Time from stool donation to treatment

RCT

Primary objective

To determine whether there is a significant difference between intervention vs. placebo in clinical remission in patients with active UC where clinical remission is defined as a Mayo score of ≤2 and no individual subscore >1 at 8 weeks.

Outcome Measures

Pilot stage

The primary outcome from the pilot trial will be a recommendation about a route of FMT administration to take forward to the main RCT. This decision will be based on comparing the two methods NG and COLONIC using a composite assessment of both quantitative and qualitative data. This will include assessment of efficacy (using clinical response), acceptability and safety.

Clinical Outcome Measures

  • Clinical response (primary measure of efficacy) defined as ≥3 point reduction in the full Mayo score from randomisation to week 8, and 30% reduction from randomisation and at least 1 point reduction of rectal bleeding subscore or an absolute rectal bleeding subscore of 0 or 1
  • Time to clinical response (where clinical response is defined as ≥2 point reduction in partial Mayo)
  • Clinical remission at week 8 (full Mayo score of ≤2, with no subscore >1)
  • Participant’s weight at week 8 and week 12
  • Quality of Life (QoL) using generic Short-Form 36 (SF-36) and the disease specific Inflammatory Bowel Disease Questionnaire (IBDQ) at week 8 and week 12

Mechanistic Outcome Measures

  • Faecal calprotectin
  • Measures of microbiome (faecal and mucosal)
  • Mucosal healing
  • Urinary metabolome (SCFA)
  • CRP

Other Outcome Measures

  • Association between the donor’s dietary profile and microbiome
  • Time from stool donation to treatment

RCT

Clinical outcome measures

  • Clinical response (reduction in Mayo score of ≥3 points)
  • Endoscopic response
  • Time to relapse
  • Relapse needing steroids
  • Colectomy rates
  • Remission rates
  • Sustained clinical remission
  • Reduction in CRP
  • Reduction in faecal calprotectin
  • Change in faecal microbiome, metabolomics and mucosa-associated microbiome (increase in diversity)
  • Safety of FMT
  • QoL
  • Patient and clinician acceptability
  • Feasibility of FMT in an NHS setting

Mechanistic outcome measures

  • Characteristics of donor stool and relation of donor to recipient microbiome post FMT
  • “Dysbiosis” of recipients
  • Relationship between faecal and mucosal microbiome
  • Reduction in CRP
  • Reduction in faecal calprotectin
  • Change in faecal microbiome
  • Change in mucosa-associated microbiome (change in diversity)
  • Change in urinary and faecal metabolome
  • Changes in major faecal bacterial metabolites previously implicated in IBD (e.g. SCFA (C2-C8 plus branched chained fatty acids), sulphide, ammonia, lactate, phenols and cresols.
  • Relationship between microbiome diversity (16S) with genetic functional capacity (WGS) and faecal and urinary metabolites
  • Time from stool donation to treatment
  • Effect of diet

Eligibility Criteria

Pilot stage

Inclusion Criteria

  1. Clinically confirmed UC for at least 12 weeks prior to the screening visit
  2. Aged 16-70 years
  3. Partial Mayo score of ≥4 and ≤8 despite stable 5ASA+/- thiopurine, methotrexate or no treatment
  4. Rectal bleeding subscore of ≥1 on the partial Mayo
  5. Written, signed informed consent to the study

Exclusion Criteria

  1. Stool positive for Clostridium difficile or infection by either PCR or ELISA
  2. Positive for Hepatitis A/B/C, and/or Human Immunodeficiency Virus (HIV) infection
  3. Antibiotics in the preceding 12  weeks prior to date of the screening visit
  4. Systemic/topical steroids in the preceding 2 weeks prior to the date of the screening visit
  5. Biologics in the preceding 12 weeks prior to the date of screening visit
  6. Commercial probiotics and prebiotics in the preceding 12 weeks prior to the date of the screening visit
  7. On oral nutritional supplements or enteral/parenteral nutrition in the preceding 4 weeks prior to the date of the screening visit
  8. Pregnant or lactating. Note: Spot urine will be performed at screening and randomisation to rule out pregnancy in females
  9. Not willing to take appropriate contraceptive measures to prevent pregnancy during trial participation:
  • Female participants of child bearing potential, unless willing to use two forms of contraception, one of which must be a barrier contraception (e.g. female condom or occlusive cap (diaphragm or cervical vault/caps) with spermicide) during the study and for 30 days from the date of last FMT dose (however a male condom should not be used in conjunction with the female condom);
  • Male participants whose partner is of child bearing potential, unless willing to use an appropriate barrier method of contraception (condom and spermicide) in addition to having their female partner use another form of barrier contraception (e.g. occlusive cap (diaphragm or cervical vault/caps) with spermicide) during the study and for 30 days from date of last FMT dose (however a male condom should not be used in conjunction with a female condom).

 

RCT

The inclusion and exclusion criteria for the RCT will be similar to the pilot study, with the addition of children aged 12 years and over. However, as the protocol is under development and is yet to be submitted for regulatory approval the eligibility criteria has not been listed here.