STOP-LEUKEMIA: Repurposing metformin as a leukemia-preventive drug in CCUS and LR-MDS

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rigshospitalet

Participant type

Patients, Healthy volunteers

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

1 Dec 2021 → ongoing

Decision date (initial)

2025-01-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-518436-37-01

EudraCT number

2020-005088-30

ClinicalTrials.gov

NCT04741945

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Prophylaxis, Efficacy, Safety

The purpose 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.

Conditions and MedDRA coding

Myelodysplastic syndromes (MDS), very low- and low-risk

Study design 1 period

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. Work Package (WP) 0: • 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.
2. 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. • 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. • ≥18 years of age. • Written informed consent prior to study procedures. • Willingness to comply with mandatory aspects of the protocol. • Ability to swallow pills.

Exclusion criteria 2

1. 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 magnetic resonance scanning (MRS).
2. 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 <45 mL/min. • Performance status according to the Eastern Cooperative Oncology Group >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).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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.
2. 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.

Secondary endpoints 3

1. 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.
2. 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.
3. 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rigshospitalet

Sponsor organisation

Rigshospitalet

Address

Blegdamsvej 9

City

Copenhagen Oe

Postcode

2100

Country

Denmark

Scientific contact point

Organisation

Rigshospitalet

Contact name

Kirsten Grønbæk

Public contact point

Organisation

Rigshospitalet

Contact name

Kirsten Grønbæk

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications