Clonal cytopenia of undetermined significance (CCUS) and lower-risk myelodysplastic syndrome (LR-MDS). MedDRA version: 21.1 Level: PT Classification code 10028533 Term: Myelodysplastic syndrome System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Metformin "Medical Valley"
Pharmaceutical Form: Tablet
Sponsors
Kirsten Grønbæk
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion criteria, WP1: Patients are eligible to be included in the pilot study (WP1) if they meet all of the following criteria: • A diagnosis of: o LR-MDS according to the revised international prognostic scoring system (IPSS-R), i.e., very low to intermediate risk (IPSS-R score =3) in addition to a bone marrow blast percentage 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 hematolytic conditions have been ruled out. Peripheral blood (PB) cytopenia is defined as hemoglobin (hgb) 45 years of age who have experienced amenorrhea for minimum 12 months, without any other obvious pathological or physiological cause. • =18 years of age. • Written informed consent prior to study procedures. • Willingness to comply with mandatory aspects of the protocol. • Ability to swallow pills. Inclusion criteria, WP0: • Healthy individuals matched on age, sex and BMI, if possible, to individual patient participants in WP1. • Written informed consent prior to study procedures. • Willingness to comply with mandatory aspects of the protocol. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 15 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 45
Exclusion criteria
Exclusion criteria: Exclusion criteria, WP1: • Any prior treatment with metformin. • A diagnosis of diabetes mellitus • Therapeutic radiation, immunosuppressive therapy (with the exception of corticosteroids) or chemotherapy within the past year. • Treatment with G-CSF within the past 30 days. • Prior therapy with hypomethylating agents (i.e., azacitidine, decitabine). • eGFR 2. • Other active malignancy within the past five years. • 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). An eGFR calculation performed up to one month prior to inclusion may be used to assess renal function. If such an assessment is not available, it is performed at baseline. If the patient is not willing or capable of donating feces, or have a MRS, DEXA scan or functional test of intestinal permeability (by urine collection) performed, the patient may still be enrolled. Exclusion criteria, WP0: • Use of metformin within the past 3 years. • A diagnosis of diabetes mellitus, rheumatological disorders, autoimmune diseases or other inflammatory disorders, celiac disease, inflammatory bowel disease or other gastrointestinal disorders or symptoms. • Treatment with immunosuppressive drugs (with the exception of corticosteroids) or chemotherapy within the past year, or antibiotics within the past 6 months. • Any contraindications to MRS. Due to the large magnetic field, MRS is contraindicated and may not be performed on individuals with implanted medical pumps and nerve stimulators, or magnetic metallic foreign bodies in sensitive areas, e.g., the eye. In addition, pacemakers and protheses might be a contraindication to MRS and will be evaluated individually. The ability of the healthy controls to have a MRS is evaluated using a control scheme (appendix 1).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The main objective of this pilot study is to investigate safety of metformin and feasibility of the study protocol in patients with clonal cytopenia of undetermined significance (CCUS) and lower-risk myelodysplastic syndromes (LR-MDS) and examine potential mechanisms of action of metformin in controlling disease progression in order to inform the design of a future phase 3 randomized controlled trial (RCT) of the efficacy of metformin in CCUS and LR-MDS patients.;Secondary Objective: Secondary objectives are to characterize: - the abundance and properties of bone marrow adipose tissue (BMAT) and bone marrow (BM) adipocytes, - the gut microbiota and intestinal permeability, - DNA methylation and hydroxymethylation (5-mC and 5-hmC) patterns, and - hormone and cytokine levels in BM plasma of patients with CCUS or LR-MDS compared to age-, sex- and body mass index (BMI)-matched healthy controls. Secondary objectives also include comparison of safety and preliminary efficacy of metformin in patients with CCUS or LR-MDS to a cohort of patients with CCUS or LR-MDS receiving placebo in context of our EVI-2 randomized controlled trial (NCT03999723). ;Primary end point(s): The primary endpoints of WP1 are: Feasibility A quantitative and qualitative feasibility assessment will be undertaken to inform the decision to proceed with a RCT to assess the effect of this intervention. 1.To estimate recruitment and refusal rates and 12 months follow-up rates. 2.To determine how many participants receive the intervention. 3.To estimate protocol adherence. 4.To explore, qualitatively, the acceptability of interventions and assessments with patients. Safety 1.To describe the type, grade and number of adverse events and serious adverse events in the patients. 2.To assess any suspected unexpected serious adverse reactions. 3.To estimate drop-out rates. 4.To describe any changes in individual medication doses including median maximum tolerated dose.;Timepoint(s) of evalu | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary endpoints of WP1 are: Interim efficacy 1. The change in variant allele frequency (?VAF) from visit 1 to visit 4. 2. The change in patient-reported outcome measures (PROM), based on the validated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), Short Form 36 Health Survey Questionnaire (SF-36), and European Quality of Life Five Dimension questionnaire (EQ-5D) from visit 1 to visit 2, 3, and 4/EOT, respectively. 3. The change in bone marrow adipose tissue (BMAT) content in BM from visit 1 to visit 2 and 4, respectively. 4. The change in bone mineral density (BMD) from visit 1 to visit 4. 5. The change in body composition from visit 1 to 4. 6. The change in fat distribution from visit 1 to 4. 7. The change in blast counts in BM biopsies from visit 1 to visit 4. 8. The change in gut microbiota from visit 1 to visit 2 and 4, respectively. 9. The change in small intestinal permeability from visit 1 to visit 2. 10. The change in DNA methylation and hydroxymethylation (5-mC and 5-hmC) patterns, RNA expression and protein profiles in BM and/or PB cells, which may include adipocytes, MSCs, T cells, CD34+ cells and negative fraction from visit 1 to visit 2 and 4, respectively. 11. The change in disease status as according to the International Working Group (IWG) response criteria in myelodysplasia from visit 1 to visit 4. 12. The change in inflammatory markers, hormones and niche factors in PB and BM plasma from visit 1 to visit 2 and 4, respectively. 13. Health-relevant general changes in markers of organ function and serum biochemistry measures including iron and vitamin status, in PB and BM from visit 1 to visit 2, 3, and 4, respectively. The secondary objectives are aimed at exploring potential mechanisms of anti-leukemic action of metformin in patients with CCUS or LR-MDS in order to select appropriate endpoints for the larger future RCT and to inform the sample siz | — |
Countries
Denmark
Contacts
Public ContactEpi-/Genome lab
Kirsten Grønbæk
Outcome results
None listed