A Phase 2 interventional study of Metformin in Preleukemia, Myelodysplastic Neoplasm and Cytopenia, sponsored by Kirsten Grønbæk. Recruiting at 1 site in Denmark. Open to participants aged 18 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-11-22.
Sponsored by Kirsten Grønbæk · Phase 2, Interventional, and Other
This is a single-arm pilot study of the feasibility and safety of metformin in patients with clonal cytopenia of undetermined significance (CCUS) or lower-risk myelodysplastic neoplasms (LR-MDS).
The research plan is divided into three work packages (WP):
WP0: Bone Marrow Adipose Tissue, Gut Microbiota, and Intestinal Permeability in CCUS and LR-MDS Patients.
The aim of WP0 is to investigate biological features which the investigators hypothesize to be of pathogenetic relevance for MDS progression and may be possible targets of metformin treatment. For this purpose, 20 elderly (≥60 years) healthy controls will be included for comparison to patients with CCUS or LR-MDS from WP1.
The primary objectives are to investigate 1) the abundance and properties of bone marrow adipose tissue (BMAT) and bone marrow (BM) adipocytes, and 2) the gut microbiota and intestinal permeability of patients with CCUS or LR-MDS compared to age-, sex- and body mass index (BMI)-matched healthy controls. Secondary objectives are to characterize DNA methylation and hydroxymethylation (5-mC and 5-hmC) patterns, and hormone and cytokine levels in BM plasma from healthy controls and patients with CCUS or LR-MDS.
WP1: Safety, feasibility, and mechanisms of action of metformin in patients with CCUS or LR-MDS.
In this WP up to 40 patients with CCUS or LR-MDS will receive metformin 2000 mg daily or their maximum tolerated dose (MTD) for 12 months. The aim of WP1 is to investigate safety of metformin and feasibility of the protocol in patients with CCUS or LR-MDS. Potential mechanisms of anti-leukemic action of metformin will also be explored in order to identify a suitable outcome measure and estimate standard deviation of the outcome measure. All in order to inform the design of a future phase 3 RCT of the efficacy of metformin in CCUS and LR-MDS patients. Endpoints of WP1 are specified in the corresponding section.
WP2: Safety and efficacy of metformin compared to placebo. The primary objective of WP2 is to compare 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 pilot study (NCT03999723).
Data and samples from approximately 50 historical controls will be included from the EVI-2 study in which participants were randomized to receive placebo or oral vitamin C supplement for 12 months.
1,312 studies on the registry are indexed under Preleukemia; 58 are open to participants now.
This study's planned enrollment of 40 is above the median of 36 across 1,056 interventional studies indexed under Preleukemia.
Browse Preleukemia studies →Kirsten Grønbæk is the lead sponsor of 2 studies on the registry; 2 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Patients are eligible to be included in WP1 if they meet all of the following criteria:
Inclusion criteria:
A diagnosis of:
Exclusion criteria:
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 screening.
Healthy volunteers are eligible to be included in WP0 if they meet all of the following criteria:
Inclusion criteria:
Exclusion criteria:
2000 mg/day metformin for 12 months.
Drug: Metformin
2000 mg/day metformin for 12 months (1000 mg b.i.d.) with a slow up-titration six weeks prior to full dose treatment.
Safety as assessed by the number of serious adverse events including any suspected unexpected serious adverse reactions
To assess safety of metformin treatment in this off-label indication by the type, grade, and number of adverse events and serious adverse events including any suspected unexpected serious adverse reactions in the patients.
Time frame: From inclusion to 12 months of study treatment
Safety as assessed by median maximum tolerated dose in mg/day
To assess safety of metformin treatment in this off-label indication by median maximum tolerated dose and a description of any changes in individual medication doses.
Time frame: From inclusion to 12 months of study treatment
Feasibility as assessed by rates of recruitment/refusal rates
To assess feasibility of the study protocol in terms of recruitment and refusal rates.
Time frame: From inclusion to 12 months of study treatment
Feasibility as assessed by 12 months follow-up, i.e., study completion, rate
To assess feasibility of the study protocol in terms of rate of study completion. To assess safety of metformin treatment in this off-label indication by the type, grade, and number of adverse events and serious adverse events including any suspected unexpected serious adverse reactions in the patients; drop-out rates; and a description of any changes in individual medication doses including median maximum tolerated dose.
Time frame: From inclusion to 12 months of study treatment
Feasibility as assessed by rate of compliance to protocol procedures
To assess feasibility of the study protocol in terms of rate of adherence to protocol procedures (study medication and study procedures).
Time frame: From inclusion to 12 months of study treatment
Interim efficacy: Mutational burden as assessed by change in variant allele frequency
Change in variant allele frequency (ΔVAF) by next generation sequencing (NGS)
Time frame: From inclusion to 12 months of study treatment
Interim efficacy: Patient-reported outcome measures based on the EORTC QLQ-C30
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).
Time frame: From inclusion to 4 months of study treatment
Interim efficacy: Patient-reported outcome measures based on the EORTC QLQ-C30
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).
Time frame: From inclusion to 12 months of study treatment
Interim efficacy: Patient-reported outcome measures based on the SF-36
Change in patient-reported outcome measures (PROM), based on the validated Short Form 36 Health Survey Questionnaire (SF-36).
Time frame: From inclusion to 4 months of study treatment
Interim efficacy: Patient-reported outcome measures based on the SF-36
Change in patient-reported outcome measures (PROM), based on the validated Short Form 36 Health Survey Questionnaire (SF-36).
Time frame: From inclusion to 12 months of study treatment
Interim efficacy: Patient-reported outcome measures based on the EQ-5D
Change in patient-reported outcome measures (PROM), based on the validated European Quality of Life Five Dimension questionnaire (EQ-5D).
Time frame: From inclusion to 4 months of study treatment
Interim efficacy: Patient-reported outcome measures based on the EQ-5D
Change in patient-reported outcome measures (PROM), based on the validated European Quality of Life Five Dimension questionnaire (EQ-5D).
Time frame: From inclusion to 12 months of study treatment
Interim efficacy: Bone marrow adipose tissue as assessed by MR spectroscopy ratio of adipose tissue and water phase
Change in bone marrow adipose tissue (BMAT) content in bone marrow (BM) measured by MR spectroscopy
Time frame: From inclusion to 4 months of study treatment
Interim efficacy: Bone marrow adipose tissue as assessed by MR spectroscopy ratio of adipose tissue and water phase
Change in bone marrow adipose tissue (BMAT) content in bone marrow (BM) measured by MR spectroscopy
Time frame: From inclusion to 12 months of study treatment
Interim efficacy: Bone mineral density as assessed by DEXA scan measured in grams per cubic centimeter with resulting Z score
Change in bone mineral density (BMD) measured by DEXA scan measured in grams per cubic centimeter with resulting Z score.
Time frame: From inclusion to 12 months of study treatment
Interim efficacy: Body composition as assessed by DEXA scan presented as whole body bone mass and soft tissue composition
Change in body composition measured by DEXA scan presented as whole body bone mass and soft tissue composition with ratios of lean mass, body fat, and bone mass.
Time frame: From inclusion to 12 months of study treatment
Interim efficacy: Gut microbiota composition as assessed by 16S rRNA sequencing
Change in gut microbiota by 16S rRNA sequencing or whole genome sequencing of intestinal bacteria.
Time frame: From inclusion to 4 months of study treatment
Interim efficacy: Gut microbiota composition as assessed by 16S rRNA sequencing
Change in gut microbiota by 16S rRNA sequencing or whole genome sequencing of intestinal bacteria.
Time frame: From inclusion to 12 months of study treatment
Interim efficacy: Small intestinal permeability as assessed by urine-lactulose/mannitol measurement and ion chromatography
Change in small intestinal permeability by functional assessment by urine-lactulose/mannitol measurement and ion chromatography or by indirect assessment by qPCR and 16S rRNA sequencing of whole blood.
Time frame: From inclusion to 4 months of study treatment
Interim efficacy: Epigenetic regulation as assessed by levels of 5-mC and 5-hmC
Change in DNA methylation and hydroxymethylation (5-mC and 5-hmC) patterns in hematopoietic cells by global 5-hmC/5-mC assessment and EPIC arrays.
Time frame: From inclusion to 4 months of study treatment
Interim efficacy: Epigenetic regulation as assessed by levels of 5-mC and 5-hmC
Change in DNA methylation and hydroxymethylation (5-mC and 5-hmC) patterns in hematopoietic cells by global 5-hmC/5-mC assessment and EPIC arrays.
Time frame: From inclusion to 12 months of study treatment
Interim efficacy: Gene expression as assessed by RNA sequencing
Change in RNA expression in hematopoietic cells and BM adipocytes.
Time frame: From inclusion to 4 months of study treatment
Interim efficacy: Gene expression as assessed by RNA sequencing
Change in RNA expression in hematopoietic cells and BM adipocytes.
Time frame: From inclusion to 12 months of study treatment
Interim efficacy: Protein profiles as assessed by proteomics
Change in protein profiles in hematopoietic cells and BM adipocytes by proteomics.
Time frame: From inclusion to 4 months of study treatment
Interim efficacy: Protein profiles as assessed by proteomics
Change in protein profiles in hematopoietic cells and BM adipocytes by proteomics.
Time frame: From inclusion to 12 months of study treatment
Interim efficacy: Response and disease progression as according to the IWG response criteria in myelodysplastic neoplasms
Rates of response and disease progression as according to the International Working Group (IWG) response criteria in myelodysplastic neoplasms.
Time frame: From inclusion to 12 months of study treatment
Interim efficacy: Bone marrow niche factor levels as assessed by ELISA
Change in niche factors in bone marrow by ELISA.
Time frame: From inclusion to 4 months of study treatment
Interim efficacy: Bone marrow niche factor levels as assessed by ELISA
Change in niche factors in bone marrow by ELISA.
Time frame: From inclusion to 12 months of study treatment
Interim efficacy: Cytokine levels as assessed by ELISA
Change in cytokine levels in peripheral blood and bone marrow plasma by ELISA.
Time frame: From inclusion to 4 months of study treatment
Interim efficacy: Cytokine levels as assessed by ELISA
Change in cytokine levels in peripheral blood and bone marrow plasma by ELISA.
Time frame: From inclusion to 12 months of study treatment
Started Dec 2021 (actual). Primary completion is estimated for Feb 2026, 50 months after the start.
Of 104 non-industry phase 2 interventional studies under Preleukemia, half reached primary completion within 64 months of starting (the median), counting those still running; a quarter within 41 and three quarters within 104. This study's planned 50 months is below that.
Counting every sponsor, half of 135 studies reached it within 59 months; a quarter within 37 and three quarters within 91.
How these figures are worked out, and which studies are left out of them.
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Studies of the drug tested here: Metformin
Kirsten Grønbæk