Official Title
Phase III Randomized Double-blind Placebo-controlled Trial of Metformin for Cognitive Recovery and White Matter Growth in Paediatric Medulloblastoma Patients
Summary:
The efficacy of treatment with metformin for promoting cognitive recovery and brain growth in children/adolescents treated for medulloblastoma will be investigated in a multi-site Phase III randomized double-blind placebo-controlled parallel arm superiority trial. Specifically, in children/adolescents aged 7 years to 17 years and 11 months who have completed treatment for medulloblastoma, is oral administration of metformin for 16 weeks associated with greater improvement of cognitive function and brain growth compared to placebo administered for 16 weeks?
Trial Description
A
critical barrier to improving the quality of life of
children/adolescents living with cancer is that our curative therapies,
which include a combination of surgery, chemotherapy and radiation, have
toxic effects on healthy tissue, resulting in long-term problems. This
is evident for children and adolescents who survive medulloblastoma - a
brain tumour requiring aggressive therapy: they experience brain injury
and cognitive impairment. There are few therapies for restoring
cognitive function and promoting brain growth in survivors; however new
work in regenerative medicine offers a possible alternative. The drug
metformin promotes brain growth in animal models by activating neural
stem cells. In a pilot trial with 24 participants, we found that
metformin was safe and tolerable for use in children/adolescents treated
with cranial radiation for a brain tumour and may improve cognition and
promote white matter growth. In this multi-site clinical trial, we will
test the efficacy of treatment with metformin for brain repair and
cognitive recovery in medulloblastoma survivors. If we find that
metformin promotes cognitive improvement and brain growth in paediatric
survivors of medulloblastoma, this may offer a viable therapeutic
approach that may improve quality of life of these cancer patients and
provide a model for treatment of late effects in other paediatric
cancers.
This study is designed
to test the efficacy of metformin in a 16-week multi-centre, phase III,
double-blind, randomized placebo-controlled superiority trial with two
parallel conditions (metformin versus placebo). Participants will be
randomly assigned to one of the two treatments where they will either
complete a 16-week cycle of metformin or a 16-week cycle of placebo.
Participants will be randomized using Research Electronic Data Capture
(REDCap) to ensure allocation concealment. The randomization code will
not be released until the participant has been recruited, consented and
passed screening. Outcome assessments will be conducted at Baseline
(intelligence quotient (IQ) testing will also be conducted at
Screening), immediately following the completion of week 16 treatment,
and 24 weeks following completion of the intervention (Week 40).
The primary endpoint is
cognitive function in children/adolescent survivors of medulloblastoma
at Week 16 compared to Baseline. We hypothesize that 16 weeks of
treatment with metformin will be associated with better cognitive
outcomes than 16 weeks of treatment with placebo. Cognitive outcomes
will be measured using tests of working memory, declarative memory, and
processing speed.
The key secondary
outcome will be diffusion MRI within the corpus callosum at Week 16
compared to Baseline. We hypothesize that 16 weeks of treatment with
metformin will be associated with increased white matter growth in the
corpus callosum compared to 16 weeks of treatment with placebo.
Increased white matter growth will be measured using diffusion MRI
metrics.
Exploratory outcomes have been selected to investigate broader metformin-induced changes in the brain and cognition.
- We hypothesize that 16 weeks of
treatment with metformin will promote global white matter growth in the
brain more so than 16 weeks of treatment with placebo at Week 16
compared to Baseline. White matter growth will be assessed using
diffusion MRI metrics of myelin and fiber structure.
- We hypothesize that 16 weeks of
treatment with metformin will result in greater increases in hippocampal
volume compared to that 16 weeks of treatment with placebo at Week 16
compared to Baseline. Structural MRI measures of hippocampal volume will
be explored.
- We hypothesize that 16 weeks of
treatment with metformin will result in superior performance on measures
of attention and executive functioning compared to 16 weeks of
treatment with placebo at Week 16 compared to Baseline. Tests of
attention and executive functioning will be used.
- We hypothesize that all outcome
measures will continue in the predicted direction at 24 weeks (Week 40)
compared to Baseline following completion of 16 weeks of metformin
compared to 16 weeks of placebo.
- We also hypothesize that 16 weeks of
treatment with metformin will yield better outcomes in females compared
to males for all measures and that these findings will persist at 24
weeks (Week 40) following the intervention compared to Baseline.
- We hypothesize that 16 weeks of
treatment with metformin will result in improved ratings of global
health as reported by the parent/guardian at Week 16 compared to
Baseline.
Metformin is a
well-studied medication with a broad clinical experience in children
including polycystic ovarian syndrome, diabetes, and obesity. The
youngest age of use is 2 years old. The proposed dose and the schedule
of administration of metformin is based on safety and toxicity data
obtained from our pilot trial and previous use in paediatric
populations. One hundred and twenty English speaking and 20 French
speaking participants - aged 7 years to 17 years and 11 months - will be
recruited from up to 17 sites across Canada and Australia.
Analysis of covariance
(ANCOVA) will be used to examine the effects metformin versus placebo
for each outcome in English speaking participants, controlling for
Baseline outcome measurements. For French speaking participants, only
secondary and some exploratory outcomes will be examined to explore the
effects metformin versus placebo controlling for Baseline outcome
measurements. By focusing on a disease that requires some of the most
aggressive therapy used in modern protocols, and by targeting the
patients most vulnerable to the harmful effects of treatment we hope to
provide a model of intervention that can then be applied to other
cancers and actively promote brain health and cognitive recovery.
View this trial on ClinicalTrials.gov
