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    Summary
    EudraCT Number:2020-005088-30
    Sponsor's Protocol Code Number:STOP-LEUKEMIA
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-11-05
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2020-005088-30
    A.3Full title of the trial
    STOP-LEUKEMIA: A pilot study of metformin as a leukemia-preventive drug in patients with CCUS or LR-MDS
    STOP-LEUKEMIA: Et pilotstudie af metformin som et leukæmi-forebyggende lægemiddel hos patienter med CCUS eller lav-risiko MDS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    STOP-LEUKEMIA: A pilot study of metformin as a leukemia-preventive drug in patients with CCUS or LR-MDS
    STOP-LEUKEMIA: Et pilotstudie af metformin som et leukæmi-forebyggende lægemiddel hos patienter med CCUS eller lav-risiko MDS
    A.3.2Name or abbreviated title of the trial where available
    STOP-LEUKEMIA
    A.4.1Sponsor's protocol code numberSTOP-LEUKEMIA
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorKirsten Grønbæk
    B.1.3.4CountryDenmark
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportRigshospitalet
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKirsten Grønbæk
    B.5.2Functional name of contact pointEpi-/Genome lab
    B.5.3 Address:
    B.5.3.1Street AddressOle Maaløes Vej 5
    B.5.3.2Town/ cityCopenhagen N
    B.5.3.3Post code2200
    B.5.3.4CountryDenmark
    B.5.4Telephone number004535455713
    B.5.6E-mailkatja.kaastrup@regionh.dk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Metformin "Medical Valley"
    D.2.1.1.2Name of the Marketing Authorisation holderMedical Valley Invest AB
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Clonal cytopenia of undetermined significance (CCUS) and lower-risk myelodysplastic syndrome (LR-MDS).
    Klonal cytopeni af ubestemt signifikans (CCUS) og lavere-risiko myelodysplastisk syndrom (MDS)
    E.1.1.1Medical condition in easily understood language
    Predispositions to leukemia
    Forstadier til leukæmi
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10028533
    E.1.2Term Myelodysplastic syndrome
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    E.2.2Secondary objectives of the trial
    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).

    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Both sub-studies are also referenced in section E.2.2 as secondary objectives of the trial.

    Sub-study 1
    Title: WP0: Bone Marrow Adipose Tissue, Gut Microbiota and Intestinal Permeability in CCUS and LR-MDS Patients (v5.0 02.10.2022)

    Objectives:
    The aim of WP0 is the comparison between CCUS/LR-MDS patients and healthy controls of biological features which we hypothesize to be of pathogenetic relevance for disease progression and may be possible targets of metformin treatment. The primary objectives of WP0 are to investigate 1) the abundance and properties of BMAT and 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 compare these to the corresponding in patients from visit 1 in WP1.

    Sub-study 2
    Title: WP2: Safety and efficacy of metformin compared to historical placebo controls (v5.0 02.10.2022)

    Objectives:
    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 RCT (NCT03999723).
    E.3Principal 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 <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 hematolytic 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.

    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.
    E.4Principal 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 <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).

    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).
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Visit 1 (baseline) and visit 4 (after 12 months of study treatment) and continuously throughout the trial for safety endpoints and protocol adherence.
    E.5.2Secondary end point(s)
    The secondary endpoints of WP1 are:
    Interim efficacy
    1. The change in variant allele frequency (ΔVAF) 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 size estimation for this, should this be feasible.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The timepoints of evaluation of the secondary endpoints are included in section E.5.2.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Feasibility
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    End of study is defined as LVLS.

    All patients will undergo follow-up yearly for three years after EOS. Follow-up will include information on survival or death, cause of death, and disease progression, if diagnosed following a clinical indication for a bone marrow investigation and do not require physical attendance of the study subjects.

    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-12-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-03-26
    P. End of Trial
    P.End of Trial StatusOngoing
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