Clinical trial NCT03710343: Metformin for Motor and Cognitive Improvement in Children With Cerebral Palsy: A Feasibility Study
Official title: Metformin for Motor and Cognitive Improvement in Children With Cerebral Palsy: A Feasibility Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Cerebral Palsy
Keywords: Cerebral Palsy
Pediatric
Motor Function
GMFCS
Cognitive Function
Metformin
Lead sponsor: Holland Bloorview Kids Rehabilitation Hospital
Sponsor class: OTHER
Collaborators: name: The Hospital for Sick Children
First posted: 2018-10-18
Enrollment: 3
Sex: ALL
Minimum age (years): 5
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: The trial is designed as a 48 week limited institution two-site single case ABA study feasibility trial.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion criteria are as follows:

1. 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."
2. Evidence of WMI or GMI pattern on prior clinical neuro-imaging scanning (MRI)
3. No history of hypoglycemia after 2 years of age
4. No aspiration pneumonias in the last year requiring hospitalization
5. No lower extremity orthopedic surgery in the last six months prior to trial entry
6. 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.
7. No history of renal disease
8. Age 5 to 18 years, 11 months at the time of enrollment
9. 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
10. Gross Motor Function Classification System Level of II - V at the time of enrollment
11. Ability to communicate (verbal or non-verbal) pain or discomfort
12. 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
13. Able to consume whole or crushed tablets swallowed orally or through a gastrostomy tube
14. Ability to understand and follow single step instructions/commands (i.e. blinking eyes, opening mouth, and moving head side to side).
15. Meet criteria for normal organ function requirements as described below:

Normal renal function defined as: Estimated glomerular filtration rate (eGFR) \> 75ml/min/1.73m2

1. eGFR is calculated using the Schwartz formula: eGFR (mL/min/1.73 m²) = (0.41 × Height in cm) / Creatinine in mg/dL \[29, 30\]
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 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:

1. No prior clinically ordered neuro-imaging to allow determination of WMI or GMI
2. Have a known hypersensitivity to metformin hydrochloride or any of the excipients
3. Have Diabetes (Type I or II)
4. Have taken oral metformin previously
5. Have been part of another clinical intervention study within the past 3 months prior to study entry
6. Require sedation for blood tests
7. Treatment or planned treatment involving diuretics
8. 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).
9. 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.
10. Receiving deep brain stimulation or intrathecal baclofen
11. 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)
12. Females who are pregnant, nursing, or planning a pregnancy during the study
13. Pernicious anemia (according to results of the screening visit blood draw)
14. Weight for age percentile less than 5%
15. 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).
16. History of congestive heart failure (including the use of diuretics) requiring pharmacologic treatment within two years prior to study entry

Primary outcomes:
measure: The first indicator of feasibility will be assessed
timeFrame: 1.25 years
measure: The second indicator of feasibility will be assessed
timeFrame: 1.25 years
measure: The third indicator of feasibility will be assessed
timeFrame: 1.25 years
measure: The fourth indicator of feasibility will be assessed
timeFrame: 1.25 years
measure: Tolerability and safety
timeFrame: 1.25 years
Secondary outcomes:
measure: Gross Motor Function Measure-66
timeFrame: 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
measure: Change in spasticity as measured by the Modified Tardieu Scale from baseline/pre-intervention (visit 2) to 48 weeks
timeFrame: Change in Modified Tardieu Scale (MTS) measure from baseline/pre-intervention (visit 2) to week 16 of Intervention (visit 9) to 48 weeks
Other outcomes:
measure: Cambridge Neuropsychological Test Automated Battery (CANTAB)
timeFrame: Change in CANTAB measures at different from from baseline/pre-intervention (visit 2) to week 16 of Intervention (visit 9) to 48 weeks
measure: NIH Toolbox (National Institutes of Health)
timeFrame: Change in NIH toolbox measures from from baseline/pre-intervention (visit 2) to week 16 of Intervention (visit 9) to 48 weeks
measure: Children's Auditory Verbal Learning Test-2 [CAVLT-2] or Rey Auditory Verbal Learning Test [RAVLT] (depending on age of participant)
timeFrame: Change in CAVLT-2 measures from from baseline/pre-intervention (visit 2) to week 16 of Intervention (visit 9) to 48 weeks
measure: Wechsler Abbreviated Scale of Intelligence Second Edition [WASI-II] or Wechsler Preschool and Primary Scale of Intelligence - Fourth Edition [WPPSI - IV], depending on the age of the participant.
timeFrame: Change in Wechsler Scales of Intelligence measures from baseline/pre-intervention (visit 2) to week 16 of Intervention (visit 9) to 48 weeks
measure: Changes in the tissue structure cortical-spinal tract and other relevant white matter tracts or grey matter tracts as measured by Diffusion Kurtosis Imaging (DKI).
timeFrame: Change in the tissue structure of cortical-spinal tract and other relevant white matter tracts or grey matter tracts from from baseline/pre-intervention (visit 2) to 32 weeks
Locations:
city: Toronto
country: Canada
facility: Holland Bloorview Kids Rehabilitation Hospital
state: Ontario
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: Holland Bloorview Kids Rehabilitation Hospital
name: Darcy Fehlings, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References: