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Placebo Controlled Double Blind Crossover Trial of Metformin for Brain Repair in Children With Cranial-Spinal Radiation for Medulloblastoma

This study is currently recruiting participants.
See Contacts and Locations
Verified January 2017 by Donald Mabbott, The Hospital for Sick Children
Sponsor:
Information provided by (Responsible Party):
Donald Mabbott, The Hospital for Sick Children
ClinicalTrials.gov Identifier:
NCT02040376
First received: January 7, 2014
Last updated: January 4, 2017
Last verified: January 2017
  Purpose
A placebo controlled double blind crossover trial of metformin in 30 children treated with radiation for medulloblastoma - the most common malignant brain tumour. The investigators will use tests of thinking and learning and brain imaging techniques to examine whether metformin can enhance cognition or promote brain repair following radiation-induced brain injury.

Condition Intervention Phase
Brain Tumor Treated With Cranial or Cranial-Spinal Radiation Drug: Metformin Drug: Placebo Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Placebo Controlled Double Blind Crossover Trial of Metformin for Brain Repair in Children With Cranial-Spinal Radiation for Medulloblastoma

Resource links provided by NLM:


Further study details as provided by Donald Mabbott, The Hospital for Sick Children:

Primary Outcome Measures:
  • Efficacy of metformin in fostering brain repair [ Time Frame: Change from baseline testing prior to starting pill cycle 1 (1-3 weeks prior to start of first 12 week treatment course) to testing at end of pill cycle 1 (1-2 weeks following completion of the first 12 week treatment course) ]
    The efficacy of metformin in fostering brain repair will be evaluated using both: (a) novel neuro-imaging techniques sensitive to subtle brain changes that may reflect recovery of gliogenesis/neurogenesis, and (b) neuro-cognitive measures sensitive to cognitive morbidity associated with radiation injury.

  • Efficacy of metformin in fostering brain repair [ Time Frame: Change from baseline testing prior to starting pill cycle 2 (1-2 weeks prior to start of second 12 week treatment course) to final testing (1-3 weeks after completion of the second 12 week treatment course) ]
    The efficacy of metformin in fostering brain repair will be evaluated using both: (a) novel neuro-imaging techniques sensitive to subtle brain changes that may reflect recovery of gliogenesis/neurogenesis, and (b) neuro-cognitive measures sensitive to cognitive morbidity associated with radiation injury.


Estimated Enrollment: 30
Study Start Date: March 2014
Estimated Study Completion Date: March 2018
Estimated Primary Completion Date: March 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A (Crossover Group 1)
Subjects assigned to this arm will receive metformin first, followed by a washout period and then placebo.
Drug: Metformin
Metformin and placebo doses will be 500 mg/m2 po daily given in 2 doses for one week and if there are no concerns increased to 1000 mg/m2 po daily given in 2 doses for the rest of the 12 week trial. The investigators will use the closest dose according to body surface area (250-500-750-1000) BID.
Drug: Placebo
Metformin and placebo doses will be 500 mg/m2 po daily given in 2 doses for one week and if there are no concerns increased to 1000 mg/m2 po daily given in 2 doses for the rest of the 12 week trial. The investigators will use the closest dose according to body surface area (250-500-750-1000) BID.
Experimental: Group B (Crossover Group 2)
Subjects assigned to this arm will receive placebo first, followed by a washout period and then metformin.
Drug: Metformin
Metformin and placebo doses will be 500 mg/m2 po daily given in 2 doses for one week and if there are no concerns increased to 1000 mg/m2 po daily given in 2 doses for the rest of the 12 week trial. The investigators will use the closest dose according to body surface area (250-500-750-1000) BID.
Drug: Placebo
Metformin and placebo doses will be 500 mg/m2 po daily given in 2 doses for one week and if there are no concerns increased to 1000 mg/m2 po daily given in 2 doses for the rest of the 12 week trial. The investigators will use the closest dose according to body surface area (250-500-750-1000) BID.

  Eligibility

Ages Eligible for Study:   5 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria: Survivors will be included if they:

  1. Have been treated with cranial or cranial-spinal radiation,
  2. Are between 5 and 21 years of age at time of consent, and
  3. Either declare English as their native language or have had at least two years of schooling in English at the time of their baseline assessment.
  4. Have been diagnosed with a brain tumour requiring treatment with cranial or cranial-spinal radiation at least 2 years ago, is not receiving active treatment and no more than 15 years may have elapsed between treatment with cranial-spinal radiation and time of the trial. Survivors with a shunt will be included in the trial, but will need to be identified prior to study enrollment to discuss any specific considerations for imaging.
  5. Meet criteria for adequate organ function requirements:

    1. Adequate renal function defined as: Creatinine clearance or radioisotope glomerular filtration rate (GFR) > 70ml/min/1.73 m2 or serum creatinine based on age/gender as follows:

      Maximum Serum Creatinine Level (mg/dL)

      5 to < 10 years: Male = 1; Female = 1

      10 to < 13 years: Male = 1.2; Female = 1.2

      13 to < 16 years: Male = 1.5; Female = 1.4

      ≥ 16 years: Male = 1.7; Female = 1.4

    2. Adequate liver function defined as:

    Total bilirubin < 1.5 x upper limit of normal (ULN) for age, and,

    serum glutamate oxaloacetate transaminase (SGOT) (AST) or serum glutamate pyruvate transaminase (SGPT) (ALT) < 3 x upper limit of normal (ULN) for age.

  6. Females of childbearing potential must have a negative pregnancy test result and must agree to use a medically acceptable method of contraception throughout the entire study period and for 30 days after the last dose of study drug.
  7. Informed consent will be obtained from the participants and/or their legal guardians by study team members authorized to consent for this study.

Exclusion criteria: Survivors will be excluded if they

  1. Are receiving palliative care.
  2. Are unable to participate in neuro-imaging without sedation as this is the primary outcome measure for the trial.
  3. Are unable to swallow tablets.
  4. Are unstable and/or insulin-dependent (Type 1) diabetic patients.
  5. Have acute or chronic metabolic acidosis and/or lactic acidosis.
  6. Any female patient or partner who has reached menarche and male patients who are not willing to use an effective method of contraception.
  7. Patient who is pregnant or lactating and does not agree to stop breastfeeding while receiving trial treatment.
  8. Have a history of renal disease or renal dysfunction e.g., as suggested by elevated serum creatinine levels (see 5.a. Inclusion criteria) or abnormal creatinine clearance.
  9. Have a history of congestive heart failure requiring pharmacologic treatment.
  10. Have a known hypersensitivity to metformin hydrochloride.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02040376

Contacts
Contact: Donald Mabbott, PhD 416-813-8875 donald.mabbott@sickkids.ca
Contact: Eric Bouffet, MD 416-813-8221 eric.bouffet@sickkids.ca

Locations
Canada, Ontario
The Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, M5G 1X8
Sponsors and Collaborators
The Hospital for Sick Children
  More Information

Responsible Party: Donald Mabbott, Psychologist, The Hospital for Sick Children
ClinicalTrials.gov Identifier: NCT02040376     History of Changes
Other Study ID Numbers: 1000039383
Study First Received: January 7, 2014
Last Updated: January 4, 2017

Keywords provided by Donald Mabbott, The Hospital for Sick Children:
Paediatrics
Medulloblastoma
Metformin

Additional relevant MeSH terms:
Medulloblastoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neuroectodermal Tumors, Primitive
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on June 23, 2017