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

• Status: Recruiting
• Trial end date: 2022-06-01
• Target enrollment: 0
• Participant gender: All

Summary

This study will focus on the feasibility of Metformin use in children with cerebral palsy (CP) on improving gross motor function. The study design is a phase II, double blind, randomized control feasibility trial. Participants will be placed randomly into one of two groups based on chance (50/50). The 2 groups are: 1) metformin and 2) placebo.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Holland Bloorview Kids Rehabilitation Hospital
• Collaborator: The Hospital for Sick Children
• Treatments: Metformin

Criteria

Inclusion Criteria are as follows:

1. Bilateral Spastic Cerebral Palsy as defined by the 'European Surveillance of CP' diagnostic flow chart (can have an element of mixed tonal pattern with co- existing dystonia)

2. Born prematurely < 37 weeks gestation

3. Evidence of WMI on prior clinical neuro-imaging scanning

4. No history of hypoglycemia after 2 years of age

5. No aspiration pneumonias in the last year requiring hospitalization

6. No lower extremity orthopedic surgery in the six months prior to trial entry

7. 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.

8. No history of renal disease

9. Age 5 to 12 years, 11 months at the time of enrollment

10. 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

11. Gross Motor Function Classification System Level of II - V at the time of enrollment

12. Ability to communicate (verbal or non-verbal) pain or discomfort

13. 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

14. Willing to forgo external active physiotherapy treatments focused on enhancing gross motor function during the 16 week intervention period. Physiotherapy activities are considered to be any one-on-one physiotherapy sessions with a physiotherapist or physiotherapy assistant or a group physiotherapy program (be it private or public funding) where the child is practicing specific functional mobility skills, working towards an identified goal, repetitively in a concentrated period (45-60 minutes) with progression of the skill difficulty during or between sessions to improve performance of that skill.

15. Able to consume whole or crushed tablets swallowed orally or through a gastrostomy tube

16. Ability to understand and follow single step instructions/commands (i.e. blinking eyes, opening mouth, and moving head side to side)

17. Meet criteria for normal organ function requirements as described below:

1. Normal renal function defined as: Estimated glomerular filtration rate (eGFR) > 75mL/min/1.73m2

2. 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 <12 years: <47 Male ≥ 12 years: <35

Female <12 years: <47 Female ≥ 12 years: <30

Maximum ALT Level (U/L)

Male, All Ages: <50 Female, All Ages: <36

Maximum Total Billirubin Level ( μmol/L)

Male, All Ages: <20 Female, All Ages: <20

18. 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:

1. No prior clinically ordered neuro-imaging to allow determination of WMI

2. Have a known hypersensitivity to metformin hydrochloride

3. Have Diabetes (Type I or II)

4. Have been part of another clinical intervention study within the past 3 months prior to study entry

5. Treatment or planned treatment involving diuretics

6. Current or planned treatment with cationic drugs excreted by the kidneys (e.g. amiloride, cimetidine, digoxin, morphine, nifedipine, procainamide, quinidine, quinine, ranitidine, triamterence, trimethoprim and vancomycin).

7. Treatment or planned treatment with concomitant medications with potential unacceptable interaction with metformin including topirimate, 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.

8. Receiving deep brain stimulation or intrathecal baclofen

9. 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)

10. Females who are pregnant, nursing, or planning a pregnancy during the study

11. Pernicious anemia (according to results of the screening visit blood draw)

12. Weight for age percentile less than 5%

13. Uncontrolled seizures with or without medication (defined by a seizure longer than 10 minutes in duration within six months prior to trial entry or a change in seizure medication due to poor seizure control in the 3 months prior to trial entry)

14. History of congestive heart failure (including the use of diuretics) requiring pharmacologic treatment within two years prior to study entry