Prospective Interventional Study Exploring the Microbiota Recolonization in SR-GvHD Patients Receiving MaaT013

Study Overview
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Brief Summary
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The objective of the ORION study is to explore the changes of gut microbiota composition following MaaT013 administration and its impact on the immune system in GVHD patients.

Detailed Description
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The french regulatory authority ANSM approved in July 2019 the use of MaaT013, a pooled microbiome-based enema formulation, under a formalized named-patient use program in France called Autorisation Temporaire d'Utilisation - ATU nominative protocolisée - ATUn or Early Access. The ATUn is indicated to provide a benefit in the treatment of patients with grade III-IV aGVHD: In case of initial resistance to CS alone or in association or in case of failure to other treaments In first-line therapy in association with CS in case of steroid-dependance (inability to taper CS dose <0.5 mg/kg/d) In case of digestive aGvHD with overlap syndrome The objective of the ORION study is to explore the changes of gut microbiota composition following MaaT013 administration and its impact on the immune system in GVHD patients. Blood and stool samples will be collected at each visit which explained why the study is thus categorized as research involving the human person with low risks and constraints clinical trial (RIPH2).

Official Title
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PrOspective inteRventional Study Exploring the mIcrobiota recolONization in Steroid-Refractory Graft-versus-Host Disease Patients Receiving MaaT013

Conditions
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Intestinal GVHD, Steroid Refractory GVHD

Intervention / Treatment
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* Procedure: Blood and stool sample collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient ≥18 years old with Grade III-IV aGVHD with gut involvement undergoing treatment with MaaT013 through named-patient use program ATUn / Early Access Signature of informed and written consent by the subject or by the subject's legally acceptable representative for patients under guardianship or trusteeship. Affiliated or recipient from a social security scheme Exclusion Criteria: Pregnancy and breastfeeding Vulnerable patients such as: minors, persons deprived of liberty, persons in Intensive Care Unit unable to provide informed consent prior to the intervention.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective interventional with low risks and constraints study (RIPH2)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Patient population<br>The population of the study will be adult patients with GI-aGVHD grade III to IV undergoing MaaT013 treatment through named-patient use program ATUn (Early Access Program). Blood and stool samples will be collected at each visit to analyse the gut microbiota and the immune cells. | Procedure: Blood and stool sample collection<br>* Collection of blood samples (55 mL) Collection of fecal samples (10g)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of gut microbiota diversity | Diversity of gut microbiota will be evaluated using alpha-diversity metric (Simpson or Shannon or Richness indice) throughout the study | inclusion (day 0) to month 6 | 
| Change of gut microbiota composition | Sample comparisons will be performed using similarity metric such as Bray-Curtis, Jaccard distances, Sorensen, Pearson or Spearman indice. | inclusion (day 0) to month 6 | 
| Change of gut microbiota composition (phylogenetic profiles) | Gut microbiota composition will be evaluated with phylogenetic profiling. Relative abundance of bacterial taxa will be described at each visit throughout the study. | inclusion (day 0) to month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation between gut microbiota and immune parameters | Multiparameter analyses will be performed to identify correlations between changes in gut microbiota composition and immune parameters (Citrulline, Zonulin, ST2, 3 indoxyl sulfate, Reg3a, Total antioxidant status, TGFb1.2.3., IL-1b, IL-2, sIL-2ra, IL-6, IL-8, IL10, IL17-A, IL-18, IFNg, TNFa, sCD14, MCP1, CCL25, CCL28, sCD30, CXCL10) | inclusion (day 0) to month 6 | 
| Gut microbiota baseline characterization based on clinical response | Stratification of patients will be based on response to MaaT013 treatment at day 28. Then gut microbiota composition will be described in responder versus non responder patients. | day 0 | 
| Change in immune parameters following MaaT013 administration | Cytokines and immune parameters of interest (Citrulline, Zonulin, ST2, 3 indoxyl sulfate, Reg3a, Total antioxidant status,TGFb1.2.3., IL-1b, IL-2, sIL-2ra, IL-6, IL-8, IL10, IL17-A, IL-18, IFNg, TNFa, sCD14, MCP1, CCL25, CCL28, sCD30, CXCL10) will be measured in plasma/serum by Luminex and ELISA at each visit and compared to baseline. Results will be expressed as ratios on D0 value and heatmap. Peripheral blood mononuclear cells will be purified then analyzed by flow cytometry using specific antibodies (CD4, CD8α, CD8β,TCRαβ, CD49a, CCR6, CXCR6, CD25, CD127, CCR7, CD69, CD45RA, CD27, CD57, GITR, CD39, C. Transcriptomic analysis by single cell CITE-seq will be performed on some lymphocytes subgroups. | inclusion (day 0) to month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gut microbiota, fecal microbiotherapy, intestinal GvHD