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Trial record 94 of 163 for:    Recruiting, Not yet recruiting, Available Studies | "Cerebral Palsy"

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

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ClinicalTrials.gov Identifier: NCT03710343
Recruitment Status : Not yet recruiting
First Posted : October 18, 2018
Last Update Posted : October 19, 2018
Sponsor:
Collaborator:
The Hospital for Sick Children
Information provided by (Responsible Party):
Holland Bloorview Kids Rehabilitation Hospital

Brief 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.

Condition or disease Intervention/treatment Phase
Cerebral Palsy Spastic Spastic Cerebral Palsy Cerebral Palsy, Spastic Cerebral Palsy, Mixed Drug: Metformin Drug: Placebo Oral Tablet Phase 2

Detailed Description:

Clinically, children with CP may receive active physiotherapy, and there is support for goal directed physiotherapy with a focus on motor function and active motor learning principles to enhance motor function in children with CP. For this study, the investigators want to do a feasibility study, to see if taking the drug metformin for 16 weeks while doing physiotherapy leads to better gross motor function (i.e. controlled body movements) and thinking skills when compared to doing physiotherapy alone.

Participants in both groups will receive goal-directed, active physiotherapy twice a week during the same 16 weeks 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. Fifty participants with bilateral spastic CP age 5 to 12 with evidence of white matter imaging (WMI) and gross motor function classification system (GMFCS) levels II-V will be recruited for participation. MRI, cognitive testing and questionnaires will be conducted at SickKids where paediatric protocols and processes have been developed.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double blinded. Participants and research personnel will remain masked until the completion of all study participants.
Primary Purpose: Treatment
Official Title: Metformin for Motor and Cognitive Improvement in Children With Cerebral Palsy: A Feasibility Study
Estimated Study Start Date : January 1, 2019
Estimated Primary Completion Date : December 1, 2020
Estimated Study Completion Date : February 1, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Metformin
Metformin oral tablet will be taken by mouth, once or twice a day for 16 weeks.
Drug: Metformin
Participants will be randomized to either the Metformin (Glucophage) or Placebo group at baseline. Participants in both groups will receive active physiotherapy twice weekly during the 16 week intervention. Participants will be followed-up until 40 weeks from baseline.
Other Name: Glucophage

Placebo Comparator: Placebo
The placebo oral tablet will be taken by mouth once or twice a day for 16 weeks.
Drug: Placebo Oral Tablet
Participants will be randomized to either the Metformin (Glucophage) or Placebo group at baseline. Participants in both groups will receive active physiotherapy twice weekly during the 16 week intervention. Participants will be followed-up until 40 weeks from baseline.
Other Name: Placebo




Primary Outcome Measures :
  1. Proportion of eligible patients that are recruited as study participants during the study timeline [Feasibility]. [ Time Frame: 2.5 years ]
    Patients must meet all eligibility criteria in order to be included in the analysis of this outcome measure. A higher proportion of eligible patients recruited is considered to be a better outcome.

  2. Proportion of recruited participants that take 80% of the study anticipated medication (metformin/placebo) during the intervention phase [Feasibility] [ Time Frame: 2.5 years ]
    Pill counts will be conducted to calculate percent adherence to therapy based on number of pills taken vs. anticipated pill consumption during the intervention phase. Higher adherence to therapy is considered to be a better outcome.

  3. Proportion of recruited participants that attend 80% of the 32 rehab sessions during the intervention phase [Feasibility] [ Time Frame: 2.5 years ]
    Rehab sessions will occur twice per week during the treatment phase for a total of 32 sessions. Participants must attend at least 26 of 32 sessions to reach 80% adherence to rehab sessions. Higher adherence to the rehab sessions is considered to be a better outcome.

  4. Proportion of recruited participants that have the Gross Motor Function Measure-66 (GMFM-66) measured at baseline and after 16 weeks of study participation [Feasibility] [ Time Frame: 2.5 years ]
    Participants are instructed to complete two separate GMFM-66 assessments: Baseline and at 16 weeks (after the completion of the treatment phase).

  5. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 2.5 years ]
    Safety will be measured by the Safety Monitoring Uniform Report Form (SMURF). The SMURF consists of semi-structured interview questions that capture participants' perceptions of potential AEs and study procedures. It has been modified to assess AEs that are metformin-specific such as the potential for lactic acidosis, fatigue, difficulty breathing, dizziness, irregular heartbeat, sweating, changes in vision, coordination, confusion and seizures. Participants will be asked to indicate 'Yes' or 'No' to a wide range of potential AEs. Incidence of AEs will be compared between each treatment group (metformin/placebo).


Secondary Outcome Measures :
  1. Gross Motor Function Measure-66 [ Time Frame: Change in Gross Motor Function Measure-66 (GMFM-66) from baseline to 40 weeks ]
    Participant's gross motor function will be measured by the Gross Motor Function Measure-66 (GMFM-66). The GMFM-66 is an interval-level measure of foundational gross motor skills. Participant is measured on a continuum from 0 (low motor ability) to 100 (high motor ability). Two forms of the GMFM: the original 88-item GMFM, which yields a total score and scores in five dimensions (lying & rolling, sitting, crawling & kneeling, standing, walking, running & jumping); and the GMFM-66 (66 of the 88 items) with interval scaling. Individual items on the GMFM are scored on a 4-point ordinal scale; 1 indicates that the child initiates the task (completes < 10% of the activity); 2 indicates that the child partially completes the task (completes from 10 to 99% of the activity); 3 indicates that the child completes the task (100%); and NT indicates that the child was not tested. Scores vary from a minimum of 0 (scores of 0 on all items) to 100 (scores of 3 on all items).

  2. Cambridge Neuropsychological Test Automated Battery (CANTAB) [ Time Frame: Change in CANTAB measures from baseline to 40 weeks ]
    The CANTAB is a computerized test battery capable of capturing multiple data sources. Includes several tasks. Rapid Visual Information Processing: detection of target sequences of digits. Shorter reaction times indicate better information processing. Match to Sample Visual Search: matching test where the participant is shown a complex visual pattern and the participant must identify the matching box. More correct matching and shorter reaction times indicate better information processing. Simple Reaction Time: Measures simple reaction time. Shorter reaction times indicate better alertness and motor speed. Choice Reaction Time: Measures general alertness and motor speed. More correct responses and shorter reaction times indicate better alertness and motor speed.

  3. NIH Toolbox (National Institutes of Health) [ Time Frame: Change in NIH toolbox measures from baseline to 40 weeks ]
    A computerized battery of tests that assesses cognitive function with standardized scores ranging from ages 3-85. Selected tests will assess executive function, processing speed, episodic memory, and working memory. Higher proportion of correct responses and reduced response times indicate better executive functioning, processing speed, episodic and working memory.

  4. Children's Auditory Verbal Learning Test-2 [CAVLT-2] [ Time Frame: Change in CAVLT-2 measures from baseline to 40 weeks ]
    The Children's Auditory Verbal Learning Test-2 [CAVLT-2] provides measures of immediate memory span as well as immediate and delayed recall. This will allow assessment of the extent of deficits within the areas of auditory verbal learning and memory. CAVLT-2 is applicable for children aged 6.6 to 17.11 years of age. As such, for this study, children between 5.0 to 6.5 years of age will not complete the CAVLT-2.

  5. Wechsler Scales of Intelligence [ Time Frame: Change in Wechsler Scales of Intelligence measures from baseline to 40 weeks ]
    The Wechsler Scales of Intelligence provide a brief measure of overall intelligence. WASI-II is applicable for people aged 6.0 to 90.11 years of age. For participants who are 5.0 to 5.9 years of age, the Wechsler Preschool and Primary Scale of Intelligence - Fourth Edition (WPPSI - IV) will be used instead. The WASI groups ability into two areas: Verbal Comprehension Index (VCI), which measures verbal ability, and Perceptual Reasoning Index (PRI), which involves the manipulation of materials or processing of visual stimuli to solve problems. There is also a full-scale IQ score. Both indexes and the IQ score have standard scores with a mean of 100, and scores of 90 to 110 falling into the Average range. The WPPSI - IV measures ability across five areas of cognitive functioning: Verbal Comprehension, Visual Spatial, Fluid Reasoning, Working Memory, and Processing Speed. A full scale IQ composite score is derived from these subtests.


Other Outcome Measures:
  1. Changes in the tissue structure cortical-spinal tract and other relevant white matter tracts as measured by Diffusion Kurtosis Imaging (DKI). [ Time Frame: Change in the tissue structure of cortical-spinal tract and other relevant white matter tracts from baseline to 40 weeks ]
    DKI is a magnetic resonance imaging (MRI) modality that measures water diffusion in the brain and provides information regarding tissue structure. Tractography will be used to identify the cortical-spinal tract and other relevant white matter tracts. Tractography defines white matter tracts based on regions of interest.

  2. Change in spasticity as measured by the Modified Tardieu Scale from baseline to 40 weeks [ Time Frame: Change in MTS measure from baseline to 40 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.

  3. Change in Quality of Life (specific to cerebral palsy) as measured by the Cerebral Palsy-Quality of Life (CP-QOL) from baseline to 40 weeks [ Time Frame: Change in CP-QOL measure from baseline to 40 weeks ]
    Measured by the CP-QOL, a disease-specific QOL measure exclusively for children with CP. Two versions: the CP-QOL-CHILD for children 9-12 , 53 items; a parent-proxy version for parents of children aged 4-12 , 65 items; Items map to these domains: Social Well-being and Acceptance, Participation and Physical Health, Feelings about Functioning, Emotional Well-being and Self-esteem, and Pain and Impact of Disability. Parent proxy version has domains for Access to Services and Family Health. Adolescent version domains: General well-being and participation, Communication and physical health, School well-being, Social well-being, Access to services, Family Health, and Feelings about functioning. Present feelings for each item are valued along a nine-point Likert scale. Higher responses indicating more positive feelings. Item scores are rescaled between 0-100 for analysis and a mean score for each domain.

  4. Change in Child-Specific Quality of Life as measured by the KIDSCREEN-10 from baseline to 40 weeks [ Time Frame: Change in KIDSCREEN-10 measures from baseline to 40 weeks ]
    Measured by the KIDSCREEN-10 has ten QOL domains relevant to children with CP including: Physical well-being, Psychological Well-being, Moods and Emotions, Self-Perception, Autonomy, Parent Relation & Home Life, Financial Resources, Peers & Social Support, School Environment, and Bullying. Responses are given using ordinal scales ('not at all', 'slightly', 'moderately', 'very', 'extremely') ('excellent', 'very good', 'good', 'fair', 'poor').

  5. Change in Health-Related Quality of Life as measured by the Health Utilities Index from baseline to 40 weeks [ Time Frame: Change in HUI measure from baseline to 40 weeks ]
    Measured by the Health Utilities Index. Includes eight attributes: Vision, Hearing, Speech, Ambulation, Dexterity, Emotion, Cognition and Pain with each attribute consisting of 5 to 6 levels. Scored by using a multi-attribute utility function to assign weights to each level selected for each attribute. Weights are combined statistically to derive a single total utility. Since the attributes in the HUI are structurally independent, the user can produce attribute scores, in addition to overall utility with scores that range from 0 to 1, with higher scores indicating more utility.

  6. Change in health and social service resource utilization as measured by the Resource Use Questionaire - Cerebral Palsy from baseline to 40 weeks [ Time Frame: Change in health and social service resource utilization from baseline to 40 weeks. ]
    Measured by the Resource Use Questionnaire-CP (RUQ-CP). This instrument is designed to measure family resource use of cerebral palsy-related treatments, services and programs. Categories included are: School Programs; Speech-Language or Communication Services; Occupational Therapy or Physiotherapy; Child-Focused Recreational Activities; Medications; Additional Services; Purchased Materials, Equipment; Time Associated with Treatment and Care; and Government Tax Deductions, Subsidies and Other Financial Supports. The outcome is measured in dollars and subsequently bounded by $0 at the low end and unbounded at the high end. The RUQ-CP provides no guidance regarding better or worse, rather it reports dollars spent where a higher value reflects a greater level of expenditure. Cost categories are summed to form an estimate of total utilization.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   5 Years to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria are as follows:

  1. Bilateral Spastic Cerebral Palsy as defined by the 'European Surveillance of CP' diagnostic flow chart [20] (can have an element of mixed tonal pattern with co- existing dystonia)
  2. Born prematurely < 33 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 last year
  7. No acute or chronic metabolic acidosis and/or lactic acidosis over the lifespan, including a lactate level greater than 2 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 swallow tablets either whole or crushed
  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: normal serum creatinine based on age/gender as follows:

      Maximum Serum Creatinine Level (µmol/L)

      Male:

      3-5 years <52; 6-9 years <62; 10-11 years <72; 12 years - 12 years 11 months <82;

      Female:

      3 to 5 years <52; 6 to 9 years <62; 10 to 11 years <72; 12 years - 12 years 11 months <83;

    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. No 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. No 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 10%
  13. Uncontrolled seizures with or without medication (defined by a seizure within one year prior to study entry or change in seizure medication 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03710343


Contacts
Contact: Daniel Warner, BScH 416-425-6220 ext 6482 dwarner@hollandbloorview.ca

Locations
Canada, Ontario
Holland Bloorview Kids Rehabilitation Hospital Not yet recruiting
Toronto, Ontario, Canada, M4G1R8
Contact: Daniel Warner, BScH    416-425-6220 ext 6482    dwarner@hollandbloorview.ca   
Principal Investigator: Darcy Fehlings, MD, MSc         
The Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Sponsors and Collaborators
Holland Bloorview Kids Rehabilitation Hospital
The Hospital for Sick Children
Investigators
Principal Investigator: Darcy Fehlings, MD, MSc Holland Bloorview Kids Rehabilitation Hospital

Responsible Party: Holland Bloorview Kids Rehabilitation Hospital
ClinicalTrials.gov Identifier: NCT03710343     History of Changes
Other Study ID Numbers: MET-09-2017
First Posted: October 18, 2018    Key Record Dates
Last Update Posted: October 19, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Holland Bloorview Kids Rehabilitation Hospital:
Cerebral Palsy
Spastic
Pediatric
Motor Function
GMFCS
Cognitive Function
Glucophage
Metformin

Additional relevant MeSH terms:
Cerebral Palsy
Paralysis
Muscle Spasticity
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Brain Damage, Chronic
Brain Diseases
Central Nervous System Diseases
Muscular Diseases
Musculoskeletal Diseases
Muscle Hypertonia
Neuromuscular Manifestations
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs