Metformin for Motor and Cognitive Improvement in Children With Cerebral Palsy: A Feasibility Study

Study Overview
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Brief Summary
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The study design is a single-subject ABA clinical trial that is investigating the feasibility including adherence, safety and tolerability of metformin in children aged 5 to 18 years with cerebral palsy (CP). ABA refers to Phase A1 with no metformin, Phase B with metformin, and Phase A2 with no metformin. Secondarily, the study is exploring whether metformin has possible health benefits for improving motor function and cognition.

Detailed Description
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The trial is designed as a 48 week limited institution two-site single case ABA study feasibility trial. ABA refers to Phase A1 with no metformin, Phase B with metformin, and Phase A2 with no metformin. Primary endpoints are feasibility, including recruitment, adherence to study medication and outcome measure completion, safety and tolerability of metformin. Key secondary endpoints are gross motor function and sustainability of intervention. Exploratory endpoints are cognitive and MRI measures as well as qualitative information regarding barriers to participation. All participants will receive the study drug (metformin) during the 16 week intervention period. This study will be done at two different locations in Toronto 1) Holland Bloorview Kids Rehabilitation Hospital and 2) the Hospital for Sick Children (SickKids). Each participant will be asked to go to both hospitals to do different tests and assessments for the study. Ten participants with physician diagnosis of CP age 5 to 18 with evidence of white matter imaging (WMI) or Grey Matter Imaging (GMI), and gross motor function classification system (GMFCS) levels II-V will be recruited for participation. MRI, cognitive testing and focus groups will be conducted at SickKids where paediatric protocols and processes have been developed.

Official Title
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Metformin for Motor and Cognitive Improvement in Children With Cerebral Palsy: A Feasibility Study

Conditions
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Cerebral Palsy

Intervention / Treatment
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* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria are as follows: Physician diagnosis of cerebral palsy defined as a group of permanent disorders of the development of movement and posture causing activity limitation that is attributed to non-progressive disturbances that occurred in the developing fetal or infant brain. Evidence of WMI or GMI pattern on prior clinical neuro-imaging scanning (MRI) No history of hypoglycemia after 2 years of age No aspiration pneumonias in the last year requiring hospitalization No lower extremity orthopedic surgery in the last six months prior to trial entry No acute or chronic metabolic acidosis and/or lactic acidosis over the lifespan, including a lactate level greater than 2.4 mmol/L at the screening visit. No history of renal disease Age 5 to 18 years, 11 months at the time of enrollment 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 Gross Motor Function Classification System Level of II - V at the time of enrollment Ability to communicate (verbal or non-verbal) pain or discomfort With the exception of physiotherapy, no participation in active gross motor rehabilitation treatment (e.g. receiving lower extremity botulinum toxin injections, engaged in robotic walking therapy) up to 4 months prior to trial entry period and willingness to forgo introducing any new CP treatments during the 16 week trial period Able to consume whole or crushed tablets swallowed orally or through a gastrostomy tube Ability to understand and follow single step instructions/commands (i.e. blinking eyes, opening mouth, and moving head side to side). Meet criteria for normal organ function requirements as described below: Normal renal function defined as: Estimated glomerular filtration rate (eGFR) > 75ml/min/1.73m2 eGFR is calculated using the Schwartz formula: eGFR (mL/min/1.73 m²) = (0.41 × Height in cm) / Creatinine in mg/dL [29, 30] Normal liver function defined as: Total bilirubin < upper limit of normal (ULN) for age SGOT (AST) or SGPT (ALT) < upper limit of normal (ULN) for age Maximum AST Level (U/L) Male Female <12 years <47 <47 ≥ 12 years <35 <30 Maximum ALT Level (U/L) Male Female All Ages <50 <36 Maximum Total Billirubin Level ( μmol/L) Male Female All Ages <20 <20 Informed consent (and assent, where applicable) will be obtained from the participants by study team members authorized to consent for this study Exclusion criteria are as follows: Participants who meet any of the following criteria will not be eligible to take part in the trial: No prior clinically ordered neuro-imaging to allow determination of WMI or GMI Have a known hypersensitivity to metformin hydrochloride Have Diabetes (Type I or II) Have taken oral metformin previously Have been part of another clinical intervention study within the past 3 months prior to study entry Require sedation for blood tests Treatment or planned treatment involving diuretics Current or planned treatment with cationic drugs excreted by the kidneys (e.g. amiloride, cimetidine, digoxin, morphine, nifedipine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin). Current or planned treatment with concomitant medications with potential unacceptable interaction with metformin including topiramate, lamotrigine, levetiracetam, beta blockers, ACE inhibitors, glycopyrrolate, and carbonic anhydrase inhibitors, or at the discretion of the delegated study physician for medications with potential interactions such as sertraline, lansoprazole and omeprazole. Receiving deep brain stimulation or intrathecal baclofen Dosage of oral baclofen and benzodiazepines stabilized for less than 2 months prior to study entry, and/or planning to change the dosage over the treatment period (if applicable) Females who are pregnant, nursing, or planning a pregnancy during the study Pernicious anemia (according to results of the screening visit blood draw) Weight for age percentile less than 5% Uncontrolled seizures with or without medication (defined by a seizure lasting longer than 10 minutes in duration within six months prior to study entry or change in seizure medication due to poor seizure control in the 3 months prior to trial entry). History of congestive heart failure (including the use of diuretics) requiring pharmacologic treatment within two years prior to study entry

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: The trial is designed as a 48 week limited institution two-site single case ABA study feasibility trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>Metformin oral tablet will be taken by mouth or through a gastrostomy tube, once or twice a day for 16 weeks. | Drug: Metformin<br>* Single case ABA study design. Phase B (intervention period) with metformin administered orally (or by gastrostomy tube) for 16 weeks.<br>* Other names: Glucophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The first indicator of feasibility will be assessed | Whether 50% of identified eligible potential participants are consented. | 1.25 years | 
| The second indicator of feasibility will be assessed | Whether 80% of the study medication (metformin) was taken by all enrolled participants | 1.25 years | 
| The third indicator of feasibility will be assessed | Whether the GMFM-66 was performed for 80% of participants at all time points: pre-pre intervention , pre-intervention, post-intervention and at follow up (4 months post-intervention). | 1.25 years | 
| The fourth indicator of feasibility will be assessed | Whether an MRI was performed for 70% of participants at pre-intervention (i.e. beginning of the 16 week-intervention) and post-intervention (i.e. at the end of the 16-week intervention). | 1.25 years | 
| Tolerability and safety | Tolerability and safety of metformin will be evaluated with adverse event reporting and by semi-structured interviews of participants' perceptions of the study procedures known as the Safety Monitoring Uniform Research Form (SMURF) during the 16-week intervention period at all 7 safety visits. | 1.25 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gross Motor Function Measure-66 | Gross motor function as assessed by the Gross Motor Function Measure-66 (GMFM-66). | Change in Gross Motor Function Measure-66 (GMFM-66) from pre-pre Intervention (visit 1) to baseline/pre-Intervention (visit 2) to week 16 of Intervention (visit 9) to 48 weeks | 
| Change in spasticity as measured by the Modified Tardieu Scale from baseline/pre-intervention (visit 2) to 48 weeks | Measured by the Modified Tardieu Scale (MTS), which consists of performing a passive muscle stretch at two velocities, slow and fast. The rater measures the angle of the spastic catch in the fast stretch (defined as R1) and then measures the passive range of motion during the slow stretch (defined as R2) in the ankle plantar flexors and knee flexors bilaterally. The difference between R2 and R1 will be the measure of the dynamic component of spasticity. Results are presented on a scale ranging from 0-4 where decreased scores indicate less resistance, which is considered to be a better outcome. | Change in Modified Tardieu Scale (MTS) measure from baseline/pre-intervention (visit 2) to week 16 of Intervention (visit 9) to 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cerebral Palsy, Pediatric, Motor Function, GMFCS, Cognitive Function, Glucophage, Metformin