Cerebral Palsy
Conditions
Keywords
Cerebral Palsy, Pediatric, Motor Function, GMFCS, Cognitive Function, Metformin
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.
Interventions
DRUGMetformin
Single case ABA study design. Phase B (intervention period) with metformin administered orally (or by gastrostomy tube) for 16 weeks.
Sponsors
Holland Bloorview Kids Rehabilitation Hospital
The Hospital for Sick Children
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The trial is designed as a 48 week limited institution two-site single case ABA study feasibility trial.
Eligibility
Sex/Gender
ALL
Age
5 Years to 18 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The first indicator of feasibility will be assessed | 1.25 years | Whether 50% of identified eligible potential participants are consented. |
| The second indicator of feasibility will be assessed | 1.25 years | Whether 80% of the study medication (metformin) was taken by all enrolled participants |
| The third indicator of feasibility will be assessed | 1.25 years | 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). |
| The fourth indicator of feasibility will be assessed | 1.25 years | 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). |
| Tolerability and safety | 1.25 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gross Motor Function Measure-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 | Gross motor function as assessed by the Gross Motor Function Measure-66 (GMFM-66). |
| Change in spasticity as measured by the Modified Tardieu Scale from baseline/pre-intervention (visit 2) to 48 weeks | Change in Modified Tardieu Scale (MTS) measure from baseline/pre-intervention (visit 2) to week 16 of Intervention (visit 9) 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. |
Countries
Canada
Contacts
PRINCIPAL_INVESTIGATORDarcy Fehlings, MD, MSc
Holland Bloorview Kids Rehabilitation Hospital
Outcome results
None listed