Supplementary Material 2 for Gut The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines. Supplementary Material 2: Additional Appendices Appendix A. Scope 1. Guideline title The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines. 1.1. Short title The use of faecal microbiota transplant 2. The remit i. To review the evidence (include randomised trial evidence) for the efficacy of faecal microbiota transplant (FMT) in the treatment of adults (≥18 years), both in Clostridium difficile infection (CDI) and in other clinical conditions, and use this to make recommendations about optimal recipient selection and management, donor assessment, material preparation and administration, and other key elements of FMT delivery. ii. To provide specific guidance about best practice for an FMT service within the context of the regulatory framework for the intervention as it currently exists in the UK and beyond. Whilst this is not a guideline specifically addressing the management of Clostridium difficile infection (CDI), the working group will include consideration of where FMT should be considered within the conventional treatment algorithm of patients with CDI (specifically, in which patients it should be considered, and at which point in their care). The working group agreed that for the purposes of this guideline, faecal microbiota transplant would be defined as treatment that involves the administration of manipulated whole stool. 1 Supplementary Material 2 for Gut There is a growing literature of the use of ‘bacteriotherapy’ originally deriving from healthy donor stool as a potential alternative to FMT (including commensal bacteria, spores, bacteriophages and/ or bacterial proteins or metabolites). However, the working group considered this to still be at the research stage, and would not be considered further. 2.1. Population 2.1.1. Groups that will be covered Adults (≥18 years) in whom: i. FMT has been used as treatment for CDI. ii. FMT has been used as treatment for a non-CDI indication. Given the variability in the means used to diagnose CDI within different studies, the working group agreed to consider the suitability of the definition used on a study-by-study basis. 2.1.2. Groups that will not be covered Children and young people (<18 years). 2.2. Healthcare setting All settings in which National Health Service care is received, and/ or clinical trials are undertaken. 2.3. Clinical management 2.3.1. Key clinical issues that will be covered a) Appropriate selection of patients with CDI for FMT, and best practice in their management post- FMT. b) Optimal selection of donors of faecal material, and maintenance of a donor pool. c) Identification of the preferred means of preparation and administration of FMT to recipients. d) Evaluation of the safety and efficacy of FMT in treating non-CDI indications. e) Best practice in the development and delivery of an FMT service. 2.3.2. Clinical issues that will not be covered a) General management of CDI. 2 Supplementary Material 2 for Gut b) General management of non-CDI conditions in which FMT may have a role in therapy. 2.4. Main outcomes Recommendations for practice a) Patient/ recipient selection, and peri-FMT management b) Donor selection c) Preparation and administration of FMT d) Efficacy and safety of FMT for non-CDI indications e) Provision of an FMT service 2.5. Economic aspects Where FMT is being provided under a MHRA license according to Good Manufacturing Practice (GMP) standards, there are significant costs associated with initial setup and maintenance of the service. These include the cost of obtaining the relevant license, laboratory design and equipment to enable quality assurance, storage facilities for samples, etc. However, there is counterbalance to this, as the expectation of the working group is that the publication of this guideline may encourage provision of FMT as treatment for recurrent or refractory CDI. This has consistently been shown to be cost effective in comparison with anti-C. difficile antimicrobial therapy31–34, so overall costs associated with treating the condition may actually decrease. Furthermore, there may be changes to the practice of clinicians already offering the service. For example, encouraging the use of healthy unrelated donors (who can provide multiple stool donations after one screening) reduces the cost of screening when compared to the use of an FMT recipient’s relative as donor, who is likely to provide one donation only. 2.6. Status 2.6.1. Scope This is the final scope. 2.6.2. Timing The development of the guideline recommendation will begin in July 2017. 3 Supplementary Material 2 for Gut 3. Related NICE guidance National Institute for Health and Care Excellence. Faecal microbiota transplant for recurrent Clostridium difficile infection. NICE Interventional Procedures Guidance IPG485. London: NICE; 2014. Available at: https://www.nice.org.uk/guidance/ipg485 [last accessed 19th December 2017]. 4. Further information Guideline development process Scottish Intercollegiate Guidelines Network. SIGN 50: a guideline developer's handbook. Revised edition. Edinburgh: Healthcare Improvement Scotland; 2014. Available at: http://www.sign.ac.uk [last accessed December 2017]. 4 Supplementary Material 2 for Gut Appendix B. Declarations of interest B.1. Introduction All members of the Working Group were required to make formal declarations of interest at the outset, and these were updated throughout the development process. No interests were declared that required any actions. B.2. Tariq Iqbal First meeting 19/07/17: no declarations of interest; second meeting 04/10/17: no change. Third meeting 19/10/17: consultant, advisor or speaker for: Pharmacosmos and Shield Therapeutics. B.3. Simon Goldenberg (co-chair) First meeting 19/07/17 Advisory board and/ or consultancy and/ or speaker fees: Astellas, MSD, Pfizer. Second meeting 04/10/17; third meeting 19/10/17: no change. No action required. B.4. Ailsa Hart First meeting 19/07/17 Advisory board and/ or consultancy and/ or speaker fees: AbbVie, Atlantic, Bristol-Myers Squibb, Celltrion, Falk, Ferring, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire and Takeda. Global steering committee for Genentech. Second meeting 04/10/17; third meeting 19/10/17: no change. No action required. No declared conflict of interests for the other participants. 5 Supplementary Material 2 for Gut Appendix C. Clinical evidence tables C.1. Reviewed case series of FMT for recurrent or refractory CDI 6 Supplementary Material 2 for Gut Study and patient Paper Donor characteristics FMT characteristics Outcomes Adverse events CRD characteristics Amount of stool per transplant / administered to patients: 30g stool in 50-70ml normal saline; only 25ml of Case series. total administered to patient. Number of patients: 18. Donors were 15 family Diluent used to prepare: Normal saline. members, and 3 clinical Female: male 13:5. volunteers. Diluent used to store if frozen: N/A – fresh. Age (mean): 73+/-9 Working in healthcare: Yes - for Selection/ eligibility (range 53-88) years. 3 donors. Preparation methods: Homogenised in Minor GI adverse reported: Yes. domestic blender, then coffee filter. events: Nil stated. Overall cure within Comorbidities: x1 Donor demographics: Not stated follow up Consecutively patient with Crohn's defined. Time from preparation to transplant Minor non-GI period: 83.3% recruited: Yes. colitis, x1 with (fresh): 6 hours. adverse events: Nil (n=15/18). leukaemia. Donor screening: Questionnaire stated. Aas et al, Clinical Prospectively not explicitly stated. Time period for storage (frozen): N/A. Infectious Cure with one recruited: No. CDI features: Recurrent Serious adverse Diseases, 2003 infusion alone: (at least 2 x laboratory- Travel and antibiotic exclusion Route administered: Upper GI: all events: Nil stated. 83.3% (n=15/18). Loss to follow up confirmed CDI after period: No antibiotics for 6 nasogatric (18); lower GI: nil; capsules: explained: Yes. initial antibiotic months prior; nil stated nil. Deaths: x2 - one Total follow-up treatment). regarding travel. related to ESRF, period: 90 days. At least 90% Number of infusions: Single infusion for one related to followed up: No - CDI diagnosis Screening blood tests: Hepatitis all patients. COPD. 89%. confirmation: Cytotoxin A, B and C, HIV-1/-2, syphilis. A and B positivity. Bowel purgative: Not described. Screening stool tests: C.difficile, Pre-FMT antibiotics: enteric pathogens, ova, cysts PPI: 20mg omeprazole on day prior to Metronidazole +/- and parasites. FMT and day of FMT. vancomycin (not defined). Antimotility: Not described. Prokinetics: Not described. 7 Supplementary Material 2 for Gut Time before CDI treatment was stopped before FMT: Continued until day of FMT. 8 Supplementary Material 2 for Gut Donors were identified by the Minor GI adverse Amount of stool per transplant / patient or - if not available - events: Nil stated. administered to patients: 60-100g of provided by the physician. fresh stool. Minor non-GI Working in healthcare: Not adverse events: Nil Diluent used to prepare: Normal saline, stated. stated. Case series. upper GI: 75-200ml; lower GI: 250- 400ml;