Intestinal GVHD, Steroid Refractory GVHD
Conditions
Keywords
gut microbiota, fecal microbiotherapy, intestinal GvHD
Brief summary
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
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).
Interventions
PROCEDUREBlood and stool sample collection
Collection of blood samples (55 mL) Collection of fecal samples (10g)
Sponsors
MaaT Pharma
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention model description
Prospective interventional with low risks and constraints study (RIPH2)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of gut microbiota diversity | inclusion (day 0) to month 6 | Diversity of gut microbiota will be evaluated using alpha-diversity metric (Simpson or Shannon or Richness indice) throughout the study |
| Change of gut microbiota composition | inclusion (day 0) to month 6 | Sample comparisons will be performed using similarity metric such as Bray-Curtis, Jaccard distances, Sorensen, Pearson or Spearman indice. |
| Change of gut microbiota composition (phylogenetic profiles) | inclusion (day 0) to month 6 | Gut microbiota composition will be evaluated with phylogenetic profiling. Relative abundance of bacterial taxa will be described at each visit throughout the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Correlation between gut microbiota and immune parameters | inclusion (day 0) to month 6 | 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) |
| Gut microbiota baseline characterization based on clinical response | day 0 | 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. |
| Change in immune parameters following MaaT013 administration | inclusion (day 0) to month 6 | 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. |
Countries
France
Contacts
Primary ContactJuliette JOUVE
Outcome results
None listed