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

• ClinicalTrials.gov Identifier: NCT02040376
• Recruitment Status: Completed
• First Posted: January 20, 2014
• Last Update Posted: May 30, 2019
• Sponsor: The Hospital for Sick Children
• Information provided by (Responsible Party): Donald Mabbott, The Hospital for Sick Children

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Brain Tumor Treated With Cranial or Cranial-Spinal Radiation	Drug: Metformin; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (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
• Study Start Date: March 2014
• Actual Primary Completion Date: December 2017
• Actual Study Completion Date: December 2017

Arms and Interventions

Arm	Intervention/treatment
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.

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.

Eligibility Criteria

• 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

Locations

Canada, Ontario

The Hospital for Sick Children

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
• First Posted: January 20, 2014
• Last Update Posted: May 30, 2019
• Last Verified: May 2019

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

Paediatrics; Medulloblastoma; Metformin

Additional relevant MeSH terms:

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