Intestinal Microbiota Transplant Prior to Allogeneic Stem Cell Transplant (MAST) Trial

Обзор

The goal of this clinical trial is to test the ability to restore gut microbiota to healthier levels in patients with blood cancers scheduled to have stem cell transplant. The main questions it aims to answer are: * Tolerability and acceptability of intestinal microbiota transplantation (IMT) versus placebo (as assessed via patient perspective questionnaires * Changes in gut microbiome diversity across all timepoints * Markers of general health, infective/microbiological and haematological outcomes including, days of fever, admission to intensive care unit, survival, non-relapsed mortality, and incidence of graft-versus-host disease across all time points measured. Participants will be asked at their routine follow up visits to, * Provide stool, urine and blood samples at the scheduled study visits * Complete questionnaires at selected visits * Swallow either Placebo or IMT capsules once at the second study visit which will occur 2 weeks prior to the stem cell transplant (+/-3 days) Researchers will compare IMT capsules and Placebo to investigate the change in gut microbiota diversity.

Вмешательства

• Препарат EBX-102
  EBX-102 is a white size 0 gastro-resistant hydroxypropyl methylcellulose (HPMC) capsule containing communities of dried, intestinal microorganisms extracted from rigorously screened pooled human stool samples obtained from volunteer accredited donors.
• Препарат Placebo
  The capsules contain inactive ingredients microcrystalline cellulose and magnesium stearate.

Первичные конечные точки

• Change in gut microbiota diversity using Inverse Simpsons Index [Срок оценки: Screening - up to 42 before stem cell transplantation (HCT) and Assessment 5 - Day 28(+/-3) post stem cell transplantation (HCT)]

Вторичные конечные точки (12)

• Gut Microbiome Diversity - Alpha diversity [Срок оценки: All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14)]
• Alpha Diversity - Chao1 Index [Срок оценки: All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14)]
• Alpha Diversity - Shannon Index [Срок оценки: All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14)]
• Alpha Diversity - Faiths Phylogenetic Diversity (Faiths PD) [Срок оценки: All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14)]
• Beta Diversity - Aitchison Distance [Срок оценки: All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14)]
• Gut Microbiome Taxonomic Composition [Срок оценки: All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14)]
• Markers of general health - ITU Admission [Срок оценки: Days Post HCT: Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14)]
• Quality of life EQ-5D-5L [Срок оценки: Screening up to Day-42, Days Post HCT: Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14)]
• Quality of Life EORTC-QLQ-C30 [Срок оценки: Screening up to Day-42, Days Post HCT: Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14)]
• Infective Haematological Outcomes - Fever Occurrence [Срок оценки: All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14)]
• Infective Haematological Outcomes - Fever CTCAE Grade [Срок оценки: All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14)]
• Infective Haematological Outcomes - Infection [Срок оценки: All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14)]

Критерии участия

Критерии включения

• \- Patients aged 18 years and over with a morphological documented diagnosis of ALL, acute myeloid leukemia (AML), AL of ambiguous lineage, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and CML in blast phase (Appendix 2) who are deemed fit for allogenic HCT with one of the following disease characteristics: ALL, AML, AL of ambiguous lineage

• Patients in first complete remission (CR1) or second complete remission (CR2) including complete remission with incomplete blood count recovery with < 5% blasts (Appendix 2)
• Secondary leukaemia (defined as previous history of MDS, antecedent haematological disease or chemotherapy exposure) in CR1 or CR2 defined as < 5% blasts (Appendix 2) MDS and CMML
• Patients with advanced or high risk MDS with an International Prognostic Scoring System (IPSS-M) moderate high or higher including intermediate or high risk CMML who have < 5% blasts at the time of randomisation (Appendix 2) CML in blast phase
• Patients with Philadelphia or BCR:ABL1 positive chronic myeloid leukaemia (CML) in blast phase defined by the presence of ≥ 20% blasts in blood or bone marrow who have achieved second chronic phase with < 5% blasts (Appendix 2).
• Patients must have completed minimum of two cycles of intensive chemotherapy prior to trial enrolment (Appendix 1)
• Patients must have received broad-spectrum antibiotics within 3 months prior to trial enrolment
• Patients must be considered suitable/fit to undergo allogeneic hematopoietic cell transplantation (HCT) as clinically judged by the Local investigator
• Patients with an Karnofsky performance status score 60 or above (Appendix 3)
• Females of and male patients of reproductive potential (i.e., not post-menopausal or surgically sterilised) must use appropriate, highly effective, contraception from the point of commencing therapy until 6 months after treatment
• Patients have given written informed consent
• Patients willing and able to comply with scheduled study visits and laboratory tests

Критерии исключения

• Patients with contraindications to receiving allogeneic HCT.
• Female patients who are pregnant or breastfeeding. All women of childbearing potential must have a negative pregnancy test before commencing treatment.
• Adults of reproductive potential not willing to use appropriate, highly effective, contraception during the specified period.
• Patients with renal or hepatic impairment as clinically judged by the Local Investigator.
• Patients with active infection, HIV-positive or chronic active hepatitis B virus (HBV) or hepatitis C virus (HCV).
• Patients with a concurrent active malignancy or a prior malignancy, except lobular breast carcinoma in situ, fully resected basal cell or squamous cell carcinoma of skin or treated cervical carcinoma in situ, incidental histologic finding of prostate cancer (T1a or T1b using the tumour, node, metastasis (TNM) clinical staging system), previous MDS, CMML, Myeloproliferative neoplasms (MPN) resulting in secondary AML. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent < 5 years previously will not be allowed.
• Swallowing difficulties that may preclude safe use of IMT capsules.
• Administration of IMT within 3 months prior to enrolment (probiotic administration prior to enrolment is allowed but should be recorded at screening).
• Patients taking probiotics after enrolment to the trial.
• Gastrointestinal disorders and diseases, including delayed gastric emptying, coeliac disease, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, chronic diarrhoea, and colonic perforation or fistula.
• Any autoimmune disease requiring, or that may require, systemic treatment with steroids and/or other immunosuppressants/immunomodulators.
• Significant bleeding disorder (ALL, AML, AL of ambiguous lineage, MDS, CMML, and CML satisfying inclusion criteria are not excluded).
• Anaphylactic food allergy.
• Requirement for vasopressors.
• Valvular heart disease or known structural defects of the heart.
• Known severe allergy to capsule components.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Профилактика

Центры проведения

Великобритания · 8 центров

• University Hospitals Birmingham NHS Foundation Trust — Birmingham
• Leeds Teaching Hospital NHS Trust — Leeds
• University College London Hospitals NHS Trust — London
• Kings College NHS Foundation Trust — London
• Imperial College Healthcare NHS Trust — London
• Royal Mardsen Hostpital — London
• Manchester University NHS Foundation Trust — Manchester
• Manchester University NHS Trust — Manchester

Публикации

• Sargent DJ, Taylor JM. Current issues in oncology drug development, with a focus on Phase II trials. J Biopharm Stat. 2009;19(3):556-62. doi: 10.1080/10543400902802474. PMID 19384696
• Rubinstein LV, Korn EL, Freidlin B, Hunsberger S, Ivy SP, Smith MA. Design issues of randomized phase II trials and a proposal for phase II screening trials. J Clin Oncol. 2005 Oct 1;23(28):7199-206. doi: 10.1200/JCO.2005.01.149. PMID 16192604
• van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013 Jan 31;368(5):407-15. doi: 10.1056/NEJMoa1205037. Epub 2013 Jan 16. PMID 23323867
• Malard F, Vekhoff A, Lapusan S, Isnard F, D'incan-Corda E, Rey J, Saillard C, Thomas X, Ducastelle-Lepretre S, Paubelle E, Larcher MV, Rocher C, Recher C, Tavitian S, Bertoli S, Michallet AS, Gilis L, Peterlin P, Chevallier P, Nguyen S, Plantamura E, Boucinha L, Gasc C, Michallet M, Dore J, Legrand O, Mohty M. Gut microbiota diversity after autologous fecal microbiota transfer in acute myeloid leu PMID 34035290
• Taur Y, Coyte K, Schluter J, Robilotti E, Figueroa C, Gjonbalaj M, Littmann ER, Ling L, Miller L, Gyaltshen Y, Fontana E, Morjaria S, Gyurkocza B, Perales MA, Castro-Malaspina H, Tamari R, Ponce D, Koehne G, Barker J, Jakubowski A, Papadopoulos E, Dahi P, Sauter C, Shaffer B, Young JW, Peled J, Meagher RC, Jenq RR, van den Brink MRM, Giralt SA, Pamer EG, Xavier JB. Reconstitution of the gut microb PMID 30257956
• Peled JU, Gomes ALC, Devlin SM, Littmann ER, Taur Y, Sung AD, Weber D, Hashimoto D, Slingerland AE, Slingerland JB, Maloy M, Clurman AG, Stein-Thoeringer CK, Markey KA, Docampo MD, Burgos da Silva M, Khan N, Gessner A, Messina JA, Romero K, Lew MV, Bush A, Bohannon L, Brereton DG, Fontana E, Amoretti LA, Wright RJ, Armijo GK, Shono Y, Sanchez-Escamilla M, Castillo Flores N, Alarcon Tomas A, Lin RJ PMID 32101664
• van Lier YF, Davids M, Haverkate NJE, de Groot PF, Donker ML, Meijer E, Heubel-Moenen FCJI, Nur E, Zeerleder SS, Nieuwdorp M, Blom B, Hazenberg MD. Donor fecal microbiota transplantation ameliorates intestinal graft-versus-host disease in allogeneic hematopoietic cell transplant recipients. Sci Transl Med. 2020 Aug 12;12(556):eaaz8926. doi: 10.1126/scitranslmed.aaz8926. PMID 32801142
• Shouval R, Geva M, Nagler A, Youngster I. Fecal Microbiota Transplantation for Treatment of Acute Graft-versus-Host Disease. Clin Hematol Int. 2019 Apr 18;1(1):28-35. doi: 10.2991/chi.d.190316.002. eCollection 2019 Mar. PMID 34595408

Идентификаторы

NCT: NCT06355583 · C/42/2022 · 2022-003617-10

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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