METFORMIN HYDROCHLORIDE for Li-Fraumeni syndrome

Stratification factors

• Biological sex (documented for randomization)

Inclusion criteria

• {"criterion_text":"- Male, female, inter/diverse participants (biological sex will be documented for randomization) aged ≥ 10 years\n- LFS diagnosis confirmed by detection of a TP53 germline or postzygotic somatic P/LP variant\n- Capable of understanding the consent process and participation in the trial\n- Signed written informed consent by participant and both parents/ legal representatives (if applicable)"}

Exclusion criteria

• {"criterion_text":"- Currently taking metformin\n- Evidence of significant renal impairment, eGFR < 45ml/min/1.73m² or conditions like dehydratation, severe infections or shock that could affect renal function\n- Liver failure, cirrhosis and/or aspartate transaminase or alanine transaminase >2.5 x upper limit of normal (ULN)\n- Elevated risk of lactic acidosis such as current moderate to severe alcohol use disorder (AUD), congenital lactic acidosis, concurrent intake of carbonic anhydrase inhibitor (e.g. acetazolamide), acute metabolic acidosis\n- Hypersensitivity to any of the components of the IMP metformin used and contained excipients\n- Unwillingness or inability of participant to take part in the cancer surveillance programme (incl. WB-MRI)\n- Participation in another clinical trial with investigational drugs within five times the half-life of the investigational drug or relevant metabolites at the time of enrolment\n- Metformin intake for more than 3 consecutive months within 2 years before randomization\n- Current cancer diagnosis (detected previously or at baseline screening) , if feasible, rescreening should be offered at a later suitable date\n- Current completion of cancer therapy < 6 months before randomization, if feasible, rescreening should be offered at a later suitable date\n- Current type 2 DM\n- Female participants who are pregnant or breastfeeding before randomization; if feasible, re-screening should be offered at a later suitable date. Exemptions during trial participation are detailed in table 5 in chapter 13.9.\n- Gastro-intestinal condition (such as Short-Bowel Syndrome) that could affect uptake of metformin\n- Concurrent illness that could result in life expectancy of <5 years\n- History of one or more of the following cardiac conditions: a. Grade II severity according to the New York Heart Association Functional Classification (defined as symptomatic at less than ordinary levels of activity). b. Ischemic cardiac event including myocardial infarction within 3 months prior to randomization c. Uncontrolled cardiac disease, including unstable angina pectoris, uncontrolled hypertension (i.e., sustained systolic BP > 160mmHg or diastolic BP > 90mmHg); or other known acute cardio-respiratory illness like respiratory failure or recent myocardial infarction that could lead to tissue hypoxia"}

Primary endpoints

• {"endpoint_text":"- Cancer-free survival (CFS) as time between randomization and “cancer” event defined as histologically confirmed cancer diagnosis established during trial participation or death from any cause","definition_or_measurement_approach":"Time between randomization and a “cancer” event defined as histologically confirmed cancer diagnosis established during trial participation or death from any cause."}

Secondary endpoints

• {"endpoint_text":"- Tumor-free survival (TFS) as time between randomization and a “tumor” event including diagnosis of histologically confirmed cancer or clinically or radiologically detected benign or premalignant lesion identified during trial participation or death from any cause","definition_or_measurement_approach":"Time between randomization and a “tumor” event including histologically confirmed cancer or clinically/radiologically detected benign or premalignant lesion identified during trial participation or death from any cause."}
• {"endpoint_text":"- Time from randomization to death from any cause during trial participation","definition_or_measurement_approach":"Time from randomization to death from any cause during trial participation."}
• {"endpoint_text":"- Number and type of emerging cancers, including size, stage and histological grade at diagnosis","definition_or_measurement_approach":"Counting and classification of emerging cancers with documentation of size, stage and histological grade at diagnosis."}
• {"endpoint_text":"- Treatment-emergent (serious) adverse events (AEs, SAEs)","definition_or_measurement_approach":"Recording of treatment-emergent adverse events and serious adverse events according to standard safety reporting."}
• {"endpoint_text":"- Levels of metformin adherence described by the aggregated MARS-5 scores","definition_or_measurement_approach":"Measurement of metformin adherence using aggregated MARS-5 questionnaire scores."}
• {"endpoint_text":"- Change of QoL, FOP, levels of depression and anxiety and distress during the trial","definition_or_measurement_approach":"Assessment of change in quality of life (QoL), fear of progression (FOP), depression, anxiety and distress during the trial using validated instruments (specific instruments not listed in JSON)."}
• {"endpoint_text":"- Change in QoL, FOP, levels of depression and anxiety and distress from baseline to last visit","definition_or_measurement_approach":"Comparison of QoL, FOP, depression, anxiety and distress scores from baseline to last visit."}
• {"endpoint_text":"- Correlation of baseline weight, BMI and lifestyle factors (e. g. smoking) with outcome","definition_or_measurement_approach":"Correlation analyses of baseline weight, BMI and lifestyle factors (e.g., smoking) with trial outcomes."}

Methods

• Recruitment materials and arrangements documented (K1_Recruitment arrangements).
• Printed brochure materials (K2_Recruitment material_Broschure_geschwarzt).
• Digital recruitment via website and Instagram (K2_Recruitment material_Webseite_Instagram).
• Target audience: adolescents and adults with Li-Fraumeni syndrome (LFS); country-specific (Germany) recruitment documents and local trial sites listed.

Germany

Earliest CTIS Part Ii Submission Date

19-08-2025

Latest Decision Or Authorization Date

27-08-2025

Processing Time Days

8

Number Of Sites

3

Number Of Participants

330

Primary sponsor

Full Name

Medizinische Hochschule Hannover

Organisation Type

Educational Institution

Country Of Registered Address

Germany

Third parties

• {"country":"Germany","full_name":"Medizinische Hochschule Hannover","duties_or_roles":"Sponsor duties (code: 13); contact email: deZwaan.Martina@mh-hannover.de","organisation_type":"Educational Institution"}
• {"country":"","full_name":"German Cancer Aid (Deutsche Krebshilfe)","duties_or_roles":"Source of monetary support (listed under sourceOfMonetarySupport)","organisation_type":""}