metformin hydrochloride for Myelodysplastic syndromes (MDS) - very low and low risk|Clonal cytopenia of undetermined significance (CCUS)

Inclusion criteria

• {"criterion_text":"- WP0: • Healthy individuals matched on age, sex, and BMI, if possible, to individual patient participants in WP1.\n- • Written informed consent prior to study procedures.\n- • Willingness to comply with mandatory aspects of the protocol.\n- WP1: • A diagnosis of: o MDS of very low- or low-risk according to the revised international prognostic scoring system (IPSS-R; IPSS-R score ≤3) in addition to a bone marrow blast percentage of <5% OR o CCUS defined as the presence of somatic mutation(s) or cytogenetic abnormality not diagnostic of MDS or any other malignancy in the context of persistent cytopenia (>6 months) with other common causes of cytopenia ruled out in the setting of bone marrow morphology that is not diagnostic of MDS or any other malignancy, and hemolytic conditions have been ruled out. Peripheral blood (PB) cytopenia is defined as hemoglobin (hgb) <11.3 g/dL (7 mmol/L) in women and hgb <12.9 g/dL (8 mmol/L) in men, thrombocytes <150 x 109/L, or neutrophilocytes <1.8 x 109/L.\n- • Menopause, if being a female, defined as females >45 years of age who have experienced amenorrhea for minimum 12 months, without any other obvious pathological or physiological cause.\n- • ≥18 years of age.\n- • Written informed consent prior to study procedures.\n- • Willingness to comply with mandatory aspects of the protocol.\n- • Ability to swallow pills."}

Exclusion criteria

• {"criterion_text":"- WP0: • Use of metformin within the past 3 years.\n- • A diagnosis of diabetes mellitus, rheumatological disorders, autoimmune diseases, or other inflammatory disorders, celiac disease, inflammatory bowel disease, or other gastrointestinal disorders or symptoms.\n- • Treatment with immunosuppressive drugs (with the exception of corticosteroids) or chemotherapy within the past year, or antibiotics within the past 6 months.\n- • Any contraindications to magnetic resonance scanning (MRS).\n- WP1: • Any prior treatment with metformin.\n- • A diagnosis of diabetes mellitus.\n- • Therapeutic radiation, immunosuppressive therapy (with the exception of corticosteroids), or chemotherapy within the past year.\n- • Treatment with G-CSF within the past 30 days.\n- • Prior therapy with hypomethylating agents (i.e., azacitidine, decitabine).\n- • eGFR <45 mL/min.\n- • Performance status according to the Eastern Cooperative Oncology Group >2.\n- • Other active malignancy within the past five years.\n- • Uncontrolled comorbidity including impaired hepatic function (total serum bilirubin >1.5 × upper limit of the normal range (ULN), serum alanine transaminase >3 × ULN), chronic hepatitis with decompensated cirrhosis, disabling psychiatric disease, severe neurologic disease, uncontrolled metabolic disease, or severe cardiac disease (NYHA class 3‐4)."}

Primary endpoints

• {"endpoint_text":"- WP0: To investigate: 1. The abundance and properties of bone marrow adipose tissue and bone marrow adipocytes, and 2. the gut microbiota and 3. the intestinal permeability of patients with CCUS or LR-MDS compared to age-, sex- and body mass index (BMI)-matched healthy controls.","definition_or_measurement_approach":"Compare abundance/properties of bone marrow adipose tissue and adipocytes, gut microbiota composition, and intestinal permeability between CCUS/LR-MDS patients and age-, sex-, BMI-matched healthy controls (visit-based comparisons)."}
• {"endpoint_text":"- WP1: Feasibility: 1. Recruitment and refusal rates and 12 months follow-up rates. 2. The number of participants who receive the intervention. 3. Protocol adherence. 4. Acceptability of interventions. Safety: 1. Numbers of adverse events and serious adverse events. 2. Numbers of suspected unexpected serious adverse reactions. 3. Drop-out rates. 4. Changes in individual medication doses including median maximum tolerated dose.","definition_or_measurement_approach":"Feasibility measured by recruitment/refusal rates, 12-month follow-up rates, counts of participants receiving intervention, adherence and acceptability metrics. Safety measured by counts of AEs, SAEs, SUSARs, drop-out rates, and changes in medication doses (including median maximum tolerated dose)."}

Secondary endpoints

• {"endpoint_text":"- WP0: To characterize: 1. DNA methylation and hydroxymethylation (5-mC and 5-hmC) patterns, and 2. hormone and cytokine levels in bone marrow plasma from healthy controls, and 3. compare these to the corresponding in patients from visit 1 in WP1.","definition_or_measurement_approach":"Characterisation of 5-mC and 5-hmC patterns and measurement of hormone/cytokine levels in bone marrow plasma; comparisons between healthy controls and patient samples at visit 1."}
• {"endpoint_text":"- WP1: Change in: 1. Variant allele frequency from visit 1 to 4. 2. Patient-reported outcome measures, based on the EORTC QLQ-C30, SF-36, and EQ-5D from visit 1 to 2, 3, and 4. 3. Bone marrow adipose tissue (BMAT) from visit 1 to 2 and 4. 4. Bone mineral density from visit 1 to 4. 5. Body composition from visit 1 to 4. 6. Fat distribution from visit 1 to 4. 7. Blast counts in bone marrow biopsies from visit 1 to 4. 8. Gut microbiota from visit 1 to 2 and 4.","definition_or_measurement_approach":"Measure changes across specified visits for variant allele frequency, PRO instruments (EORTC QLQ-C30, SF-36, EQ-5D), BMAT, bone mineral density, body composition, fat distribution, bone marrow blast counts, and gut microbiota composition."}
• {"endpoint_text":"- WP1 continued: Change in: 9. Small intestinal permeability from visit 1 to 2. 10. 5-mC and 5-hmC patterns, RNA expression, and protein profiles in hematopoietic cells, adipocytes, and MSCs from visit 1 to 2 and 4. 11. Disease status as according to the IWG response criteria from visit 1 to 4. 12. Inflammatory markers, hormones, and niche factors in blood and bone marrow plasma from visit 1 to 2 and 4. 13. Markers of organ function and serum biochemistry from visit 1 to 2, 3, and 4.","definition_or_measurement_approach":"Measure small intestinal permeability, epigenetic marks (5-mC/5-hmC), RNA/protein expression profiles, IWG disease status, inflammatory markers/hormones/niche factors, and organ function/biochemistry across specified visits."}

Denmark

Earliest CTIS Part Ii Submission Date

16-01-2025

Latest Decision Or Authorization Date

26-03-2025

Processing Time Days

69

Number Of Sites

1

Number Of Participants

70

Primary sponsor

Full Name

Rigshospitalet

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Denmark

Third parties

• {"country":"Denmark","full_name":"Frederiksberg Hospital","duties_or_roles":["1","12"],"organisation_type":"Hospital/Clinic/Other health care facility"}