Ignite Creation Date:
2024-05-06 @ 10:09 AM
Last Modification Date:
2024-10-26 @ 12:25 PM
Study NCT ID:
NCT03172026
Status:
TERMINATED
Last Update Posted:
2021-08-03
First Post:
2017-05-25
Brief Title:
Maraviroc to Augment Rehabilitation Outcomes After Stroke
Sponsor:
University of California Los Angeles
Organization:
University of California Los Angeles
Study Overview
Official Title:
Maraviroc to Augment Rehabilitation Outcomes After Stroke
Status:
TERMINATED
Status Verified Date:
2021-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Poor recruitment for each site partly related to Covid epidemic
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
MAROS
Brief Summary:
After stroke the combination of progressive skills practice in an adequate dose exercise for fitness and reduced sedentary time will augment motor and cognitive outcomes Sensorimotor and cognitive improvements after stroke often reach a general plateau by approximately 12 weeks after onset however Drugs that might enhance learning or neural repair as well as other molecular and synaptic adaptations that occur during skills training and fitness exercise might extend that recovery curve although to date only fluoxetine has given any hint of this Most trials have tested agents that modulate neurotransmitters Several very recent preclinical experiments and observational studies in patients after stroke suggest that the commercially available medication Maraviroc a CCR5 antagonist may augment skills learning during rehabilitation training especially during the first three months after onset by affecting CREB and synaptic plasticity
The investigators will carry out a randomized controlled trial of Maraviroc in patients with disabilities severe enough to have required inpatient stroke rehabilitation and based on our preclinical data who can start the drug intervention within 6 weeks of stroke onset The investigators will compare usual post-stroke care plus placebo versus Maraviroc given for 8 weeks in 60 participants However to try to maximize the amount of practice that is most relevant to the primary outcome measurements and determine whether or not Maraviroc can enhance the effects of training as hypothesized all participants will be tele-monitored by mobile health devices and will receive weekly telephonic encouragement based on device data to walk reduce sedentary time and reach and grasp in the home in between usual care therapies Compliance serial motor changes over time and self-management skills in making use of the telerehabilitation devices will be a nested substudy of feasibility of remote monitoring and feedback
The investigators will carry out a randomized controlled trial of Maraviroc in patients with disabilities severe enough to have required inpatient stroke rehabilitation and based on our preclinical data who can start the drug intervention within 6 weeks of stroke onset The investigators will compare usual post-stroke care plus placebo versus Maraviroc given for 8 weeks in 60 participants However to try to maximize the amount of practice that is most relevant to the primary outcome measurements and determine whether or not Maraviroc can enhance the effects of training as hypothesized all participants will be tele-monitored by mobile health devices and will receive weekly telephonic encouragement based on device data to walk reduce sedentary time and reach and grasp in the home in between usual care therapies Compliance serial motor changes over time and self-management skills in making use of the telerehabilitation devices will be a nested substudy of feasibility of remote monitoring and feedback
Detailed Description:
Background
After stroke the combination of progressive skills practice in an adequate dose exercise for fitness and reduced sedentary time will augment motor and cognitive outcomes Sensorimotor and cognitive improvements after stroke often reach a general plateau by approximately 12 weeks after onset however Drugs that might enhance learning or neural repair as well as other molecular and synaptic adaptations that occur during skills training and fitness exercise might extend that recovery curve although to date only fluoxetine has given any hint of this Most trials have tested agents that modulate neurotransmitters Several very recent preclinical experiments and observational studies in patients after stroke suggest that the commercially available medication Maraviroc may augment skills learning during rehabilitation training especially during the first three months after onset by acting on unique molecular components for novel learning
The C-C chemokine receptor 5 CCR5 is a seven-transmembrane G protein-coupled receptor that mediates HIV virus cellular entry Individuals who are homozygous for a 32 base pair deletion in the CCR5 gene CCR5D32 and subsequently do not express functional CCR5 are highly protected from infection with R5 HIV-1 The receptor is expressed in microglia astrocytes and neurons in many regions of the brain Dr Alcino Silva at UCLA postulates that this receptor is involved in learning and memory In a series of elegant experiments he showed 1 CCR5 deficiency results in enhancements in hippocampal learning and memory and in experience-dependent sensory plasticity and 2 CCR5 overexpression leads to learning and memory deficits Decreasing the function of CCR5 increases MAPKCREB signaling long-term potentiation hippocampus-dependent memory and neocortical experience-dependent plasticity Ligand binding to CCR5 is known to modulate several parallel signaling cascades implicated in learning and memory including the suppression of adenyl cyclase as well as the activation of the PI3KAKT and P4442 MAPK signaling These findings support the application of brain permeable CCR5 antagonists not only as a combination drug in antiretroviral therapy but also as a treatment for cognitive deficits caused by HIV In addition the studies suggest that the receptor is a novel target to augment learning and memory in those with cognitive and motor deficits in relation to training
Several preclinical models of stroke and traumatic brain injury from Drs ST Carmichael Alcino Silva and Esty Shohami suggest that the FDA-approved CCR5 reversible co-receptor antagonist Maraviroc may lead to better motor outcomes when combined with training presumably due to enhanced learning Stroke induces CCR5 expression in neurons in the first month after onset in a mouse model Carmichael Knockdown of CCR5 in the motor cortex of adult mice improves recovery after stroke Carmichael and Silva et al Maraviroc also improves motor recovery in this model An Israeli post stroke observational trial TABASCO Einor Ben Assayag et al enabled a test of the effects of a naturally occurring loss of function mutation in CCR5 CCR5 delta32 About 15 of the Ashkenazi Jewish population carries the deletion CCR5 rs333 - 32 This group in TABASCO had better outcomes for walking speed and the Berg Balance Scale A Washington University observational study that included some subjects with this deletion also looked positive for better outcomes but was more equivocal based on differences in stroke type Neither gene association study has been published yet
Maraviroc is the only CCR5 antagonist currently approved by the United States Food and Drug Administration the European Commission Health Canada Maraviroc Selzentry Pfizer is a small molecule currently approved for treatment of patients infected with R5-tropic HIV-1 It is metabolized by CYP3A4 The dose may have to be adjusted when given with CYP3A4 inducers or inhibitors primarily drugs that are also used for HIV therapy but also for several anticonvulsants None of the subjects in the proposed trial will be entered if on these medications The drug has a good pharmacokinetic profile with relatively low protein binding and high bioavailability when given at standard doses twice a day It is moderately lipophilic so it can penetrate the blood-brain barrier At a single dose of 300 mg time to maximum concentration occurred by two hours post-treatment in humans The terminal half-life is 14-18 hours so a single dose used during the time of training in the proposed protocol should be adequate rather than the BID treatment for AIDS Despite low CSF concentrations the drug suppresses CSF viral load It potently inhibits downstream CCR5 signaling and does not induce CCR5 internalization suggesting that the drug is a functional CCR5 antagonist
Aims
Given the potential for Maraviroc to augment rehabilitation training the investigators will carry out a trial of Maraviroc in patients with disabilities severe enough to have required inpatient stroke rehabilitation and based on our preclinical data who can start the drug intervention within 6 weeks of stroke onset The stud design is a parallel group randomized controlled pilot trial at 3 sites the Department of Neurology at the UCLA Bruce Dobkin MD the Burke Neurological Institute in White Plains NY Tomoko Kitago MD and the Department of Neurology at the Yale University Lauren Sansing MD to gather enough entries in a shorter time and to better generalize the results of this phase IIIII pilot trial Usual post-stroke care plus placebo will be compared to Maraviroc given for 8 weeks in 60 participants up to 66 to account for dropouts The primary outcome measurements will be gains in walking and functional use of the affected upper extremity continuously monitored remotely as well as formally assessed at 4 and 8 weeks after initiating the drug and at 6 months primary endpoint post stroke onset To try to maximize the amount of practice that is most relevant to the primary outcome measurements and determine whether or not Maraviroc can enhance the effects of training as hypothesized all participants will be monitored by mobile health devices and will receive weekly encouragement based on device data to walk reduce sedentary time and reach and grasp in the home in between usual care therapies The amount of use of these telerehabilitation devices will be a nested substudy of feasibility
Hypothesis 1 Subjects who take Maraviroc plus outpatient and home-based rehabilitation therapy managed remotely will improve significantly more in the primary outcomes of walking speed and upper extremity function by the Action Research Arm Test ARAT compared to the placebo drug group at the 6-month post stroke assessment
Hypothesis 2 The feasibility of home-based telerehabilitation practice will be revealed by the finding that at least 75 of all participants will have achieved compliance for at least 150 minutes of walking and 100 minutes of reach and grasp practice weekly
Methods
Consent Process
Participants will be identified from the inpatient stroke rehabilitation admissions to the UCLA affiliated California Rehabilitation Institute CRI and from referrals to Burke and to Yale The Burke site will have its own IRB review managed by its PI
On admission to CRI patients have the option to sign a consent to be contacted about research projects that might be applicable to them Potential participants who have signed this will be contacted by a study investigator In addition a flyer submitted will be provided to patients with stroke during their inpatient rehabilitation stay who may be interested in the study
Randomization
Participants will be assigned to the control or experimental group using a 11 computer-generated randomized allocation schedule in the REDCap clinical database Assignment for both research sites occurs automatically upon the entry of eligibility criteria
All members of the research team and the subjects will be blinded as to allocation The study statistician and the rest of the Safety Committee will have access to the assignment if necessary eg adverse drug reaction
Each site will enter 20-25 subjects approximately half into each of the trial arms Entries will be accomplished within 30 months with follow-up assessments and data analyses by the end of 36 months
Baseline Studies
Age gender body mass index ethnicity living place work status caregiver support date of stroke date of transfer for inpatient rehabilitation lesion type TOAST and location personal risk factors for stroke medications and FIM for level of pre-stroke walking and ADLs will be collected Other measures will include the National Institutes of Health Stroke Scale NIHSS British Medical Council manual muscle exam for eligibility motor FIM score 10-m walking speed 6-min walking distance and Action Research Arm Test ARAT The investigators will record the average two blood pressures and heart rates on the day of entry and the most recent HbgA1c and lipid panel liver function tests creatinineBUN and MRICT imaging results from the inpatient rehabilitation medical record If liver function tests or creatinine cannot be found the tests will be obtained at the outpatient research site as a cost to the study Drs Dobkin and Dorsch will review each imaging study to localize the relevant stroke lesion by consensus An email address and phone number for the patient and a close contact will be kept separate from the clinical database by the coordinator
Interventions
Maraviroc Medications are often in flux during inpatient rehabilitation so Maraviroc or placebo will be started within two weeks of discharge which most often will occur from 4-6 weeks after stroke onset A 1-month supply of capsules will be handed to participants after the Consent has been signed baseline measurements obtained and randomization assigned usually on the same day The second 1-mo supply will be provided during a scheduled interim measurement assessment at UCLA near the end of the 4th week on medication Pill counts will be taken on the returned bottle Participants will take either Maraviroc or a placebo at a dose of 300 mg at 6-8AM The capsules will be supplied by each sites pharmacy and assigned based on a randomization schema
Based upon Pfizers reports on premarketing and post marketing studies of Maraviroc and our review of the literature no dose adjustment is necessary in patients with even mild-to-moderate renal impairment The drug does not affect the QT interval At high doses 600mg or more it may induce orthostatic hypotension so it is recommended that users who also take an anti-hypertensive medication be asked about symptoms of orthostatic hypotension Of note 8 of patients in active and placebo drug groups described orthostatic symptoms in a large trial In HIV trials 13 of subjects had cardiovascular events more than in the placebo group but the link to the drug was unclear and symptoms occurred only in those with known cardiac disease Also no greater incidence of infection rash or other CNS symptoms was noted in these subjects An occasional Stevens-Johnson syndrome and drug rash with eosinophilia and systemic symptoms did occur seen only in post marketing surveillance not in controlled trials so complaints of rash fever joint or muscle aches blisters facial edema etc will be part of our weekly phone call surveillance plan Participants will be told to stop their medication immediately should such symptoms occur and their physician notified Of note St Johns wort should not be used with the medication since it decreases the concentration of Maraviroc
The drug is metabolized by the liver so using it in persons with more than mild hepatic disease especially in the presence of a CYP3A inhibitor would have to be closely monitored our participants will be free of hepatic as well as renal impairment The recommendation from the FDA is to obtain liver function tests prior to starting the drug and again should symptoms such as rash or hepatitis occur This rather rare adverse reaction tends to occur at about one month after starting the medication in less than 4 on the drug or placebo so the investigators will obtain a bilirubin and transaminases at the planned 1-month follow up
Adverse events related to the medication assignment to rehabilitation practice or to other causes will be adjudicated by the Safety Committee with input from the PI
Rehabilitation therapy All participants will have routine outpatient or home health physical and occupational therapy after inpatient discharge as prescribed by their physicians
Each group will be contacted weekly by phone to help maintain interest in the trial count the number of usual care physical and occupational therapy completed assure use of the assigned medication ask about possible adverse reactions and to encourage them to be active The coordinator will obtain this information and provide the feedback using a standard script and checklist
A unique aspect of this trial is a telerehabilitation component that aims to give feedback to all participants to practice with the affected arm and walk daily All participants will be asked to wear a FitBit ankle sensor connected to the cloud Data includes daily sedentary and active time At the weekly call participants will be reminded to try to build up to walking at least 3 times a day for at least 10 minutes per bout and reduce sedentary time Behavioral modification techniques that the investigators have been using successfully based on sensor data will be employed
Participants will also be given a LEAP Motion Controller device that sits in the bottom of a 12x18 box covered by a clear plastic lid This simple system enables us to monitor practice of reaching and grasping with the affected upper extremity in the home At the weekly call they will be encouraged to perform 20-30 minutes daily of reach grasp and pinch actions with small common items and practice bringing the affected hand to the mouth Items will be moved from one corner of the rectangular top to another in a fixed sequence A unique feature of this trial is that telerehabilitation data will provide ground truth about how much participants practiced which may enable a dose-response and responder-nonresponder analysis For example if a subject is taking the active medication but never practices outcomes may be less positive than for the person who does practice as prescribed
A data manager at UCLA will review all incoming data for completeness and quality as well as ensure proper use of the systems eg make sure devices are charged regularly automatic data uploads occur without problems and practice data are processed correctly All feedback will be provided by the UCLA staff
Statistical Analyses
An observational trial Lohse and Lang 2016 found that walking speed increases at 01ms per month and the ARAT increases by 29 points monthly within the time frame of this trial
For the walking speed outcome the evaluable sample size of 30 in each group will have 80 power to detect a difference in means of -0206 ms the difference between an assumed usual care walking speed of 051 SD028 and an assumed intervention group mean walking speed of 0716 This assumes a common standard deviation in the two groups and a two group t-test with a 005 two-sided significance level The estimates for the mean and standard deviation for walking speed come from the LEAPS RCT Duncan N Engl J Med 2011 The investigators plan to enroll 66 patients to account for an expected 10 drop-out rate The t-test used for the power calculation is a simplification of the mixed effects analysis plan for the primary endpoints
For the ARAT sum score analysis is based on a statistical power of 80 with an alpha of 5 for detecting a meaningful difference of 6 points ie a 10 change which has been suggested by several completed trials In a stroke trial the standard deviation was 8 points measured at 2 weeks post stroke Again a sample size of 60 plus 10 dropout rate should suffice
Primary Analyses As appropriate t-tests Wilcoxon rank sum or chi-square tests will be employed to evaluate differences in baseline clinical characteristics between trial participants Using the mixed effects model for Hypothesis 1 should provide greater power than the t-test as it will account for the repeated observations of the endpoints over time For Hypothesis 2 the investigators will look at one aspect of the feasibility of home-based practice as the ratio of those who achieve at least 150 minutes of weekly walking composed of bouts that exceed 5 minutes and 100 minutes of weekly upper extremity practice using the LEAP with the whole group as the denominator The investigators anticipate that 75 will achieve this by the end of the intervention based upon our preliminary studies using these devices in a chronic hemiparetic stroke population
Secondary Analyses Secondary outcomes listed in the Table will be evaluated using t-tests Wilcoxon rank sum tests or chi-square tests as appropriate One planned secondary analysis will compare outcomes based on on whether or not participants can extend their wrist and at least 3 fingers at least 5 degrees at time of randomization to assess for possible differences in drug responses between those with higher compared to lower levels of initial motor control Another will compare outcomes in those who achieve the practice goals of Hypothesis 2 to those who do not in relation to drug assignment
Safety Committee
A Safety Committee will serve the research sites It will include the study statistician a physician and an allied health clinician with training in stroke rehabilitation It will meet before the start of the trial every 6 months after the first 10 subjects have completed the 2-month drug intervention and as needed eg serious adverse reaction
Confidentiality
All data will be entered from both sites into the RedCap database that will be monitored at UCLA by the study statistician for completeness All materials related to the trial for UCLA entries will be stored in a locked cabinet in a locked room by the coordinator
After stroke the combination of progressive skills practice in an adequate dose exercise for fitness and reduced sedentary time will augment motor and cognitive outcomes Sensorimotor and cognitive improvements after stroke often reach a general plateau by approximately 12 weeks after onset however Drugs that might enhance learning or neural repair as well as other molecular and synaptic adaptations that occur during skills training and fitness exercise might extend that recovery curve although to date only fluoxetine has given any hint of this Most trials have tested agents that modulate neurotransmitters Several very recent preclinical experiments and observational studies in patients after stroke suggest that the commercially available medication Maraviroc may augment skills learning during rehabilitation training especially during the first three months after onset by acting on unique molecular components for novel learning
The C-C chemokine receptor 5 CCR5 is a seven-transmembrane G protein-coupled receptor that mediates HIV virus cellular entry Individuals who are homozygous for a 32 base pair deletion in the CCR5 gene CCR5D32 and subsequently do not express functional CCR5 are highly protected from infection with R5 HIV-1 The receptor is expressed in microglia astrocytes and neurons in many regions of the brain Dr Alcino Silva at UCLA postulates that this receptor is involved in learning and memory In a series of elegant experiments he showed 1 CCR5 deficiency results in enhancements in hippocampal learning and memory and in experience-dependent sensory plasticity and 2 CCR5 overexpression leads to learning and memory deficits Decreasing the function of CCR5 increases MAPKCREB signaling long-term potentiation hippocampus-dependent memory and neocortical experience-dependent plasticity Ligand binding to CCR5 is known to modulate several parallel signaling cascades implicated in learning and memory including the suppression of adenyl cyclase as well as the activation of the PI3KAKT and P4442 MAPK signaling These findings support the application of brain permeable CCR5 antagonists not only as a combination drug in antiretroviral therapy but also as a treatment for cognitive deficits caused by HIV In addition the studies suggest that the receptor is a novel target to augment learning and memory in those with cognitive and motor deficits in relation to training
Several preclinical models of stroke and traumatic brain injury from Drs ST Carmichael Alcino Silva and Esty Shohami suggest that the FDA-approved CCR5 reversible co-receptor antagonist Maraviroc may lead to better motor outcomes when combined with training presumably due to enhanced learning Stroke induces CCR5 expression in neurons in the first month after onset in a mouse model Carmichael Knockdown of CCR5 in the motor cortex of adult mice improves recovery after stroke Carmichael and Silva et al Maraviroc also improves motor recovery in this model An Israeli post stroke observational trial TABASCO Einor Ben Assayag et al enabled a test of the effects of a naturally occurring loss of function mutation in CCR5 CCR5 delta32 About 15 of the Ashkenazi Jewish population carries the deletion CCR5 rs333 - 32 This group in TABASCO had better outcomes for walking speed and the Berg Balance Scale A Washington University observational study that included some subjects with this deletion also looked positive for better outcomes but was more equivocal based on differences in stroke type Neither gene association study has been published yet
Maraviroc is the only CCR5 antagonist currently approved by the United States Food and Drug Administration the European Commission Health Canada Maraviroc Selzentry Pfizer is a small molecule currently approved for treatment of patients infected with R5-tropic HIV-1 It is metabolized by CYP3A4 The dose may have to be adjusted when given with CYP3A4 inducers or inhibitors primarily drugs that are also used for HIV therapy but also for several anticonvulsants None of the subjects in the proposed trial will be entered if on these medications The drug has a good pharmacokinetic profile with relatively low protein binding and high bioavailability when given at standard doses twice a day It is moderately lipophilic so it can penetrate the blood-brain barrier At a single dose of 300 mg time to maximum concentration occurred by two hours post-treatment in humans The terminal half-life is 14-18 hours so a single dose used during the time of training in the proposed protocol should be adequate rather than the BID treatment for AIDS Despite low CSF concentrations the drug suppresses CSF viral load It potently inhibits downstream CCR5 signaling and does not induce CCR5 internalization suggesting that the drug is a functional CCR5 antagonist
Aims
Given the potential for Maraviroc to augment rehabilitation training the investigators will carry out a trial of Maraviroc in patients with disabilities severe enough to have required inpatient stroke rehabilitation and based on our preclinical data who can start the drug intervention within 6 weeks of stroke onset The stud design is a parallel group randomized controlled pilot trial at 3 sites the Department of Neurology at the UCLA Bruce Dobkin MD the Burke Neurological Institute in White Plains NY Tomoko Kitago MD and the Department of Neurology at the Yale University Lauren Sansing MD to gather enough entries in a shorter time and to better generalize the results of this phase IIIII pilot trial Usual post-stroke care plus placebo will be compared to Maraviroc given for 8 weeks in 60 participants up to 66 to account for dropouts The primary outcome measurements will be gains in walking and functional use of the affected upper extremity continuously monitored remotely as well as formally assessed at 4 and 8 weeks after initiating the drug and at 6 months primary endpoint post stroke onset To try to maximize the amount of practice that is most relevant to the primary outcome measurements and determine whether or not Maraviroc can enhance the effects of training as hypothesized all participants will be monitored by mobile health devices and will receive weekly encouragement based on device data to walk reduce sedentary time and reach and grasp in the home in between usual care therapies The amount of use of these telerehabilitation devices will be a nested substudy of feasibility
Hypothesis 1 Subjects who take Maraviroc plus outpatient and home-based rehabilitation therapy managed remotely will improve significantly more in the primary outcomes of walking speed and upper extremity function by the Action Research Arm Test ARAT compared to the placebo drug group at the 6-month post stroke assessment
Hypothesis 2 The feasibility of home-based telerehabilitation practice will be revealed by the finding that at least 75 of all participants will have achieved compliance for at least 150 minutes of walking and 100 minutes of reach and grasp practice weekly
Methods
Consent Process
Participants will be identified from the inpatient stroke rehabilitation admissions to the UCLA affiliated California Rehabilitation Institute CRI and from referrals to Burke and to Yale The Burke site will have its own IRB review managed by its PI
On admission to CRI patients have the option to sign a consent to be contacted about research projects that might be applicable to them Potential participants who have signed this will be contacted by a study investigator In addition a flyer submitted will be provided to patients with stroke during their inpatient rehabilitation stay who may be interested in the study
Randomization
Participants will be assigned to the control or experimental group using a 11 computer-generated randomized allocation schedule in the REDCap clinical database Assignment for both research sites occurs automatically upon the entry of eligibility criteria
All members of the research team and the subjects will be blinded as to allocation The study statistician and the rest of the Safety Committee will have access to the assignment if necessary eg adverse drug reaction
Each site will enter 20-25 subjects approximately half into each of the trial arms Entries will be accomplished within 30 months with follow-up assessments and data analyses by the end of 36 months
Baseline Studies
Age gender body mass index ethnicity living place work status caregiver support date of stroke date of transfer for inpatient rehabilitation lesion type TOAST and location personal risk factors for stroke medications and FIM for level of pre-stroke walking and ADLs will be collected Other measures will include the National Institutes of Health Stroke Scale NIHSS British Medical Council manual muscle exam for eligibility motor FIM score 10-m walking speed 6-min walking distance and Action Research Arm Test ARAT The investigators will record the average two blood pressures and heart rates on the day of entry and the most recent HbgA1c and lipid panel liver function tests creatinineBUN and MRICT imaging results from the inpatient rehabilitation medical record If liver function tests or creatinine cannot be found the tests will be obtained at the outpatient research site as a cost to the study Drs Dobkin and Dorsch will review each imaging study to localize the relevant stroke lesion by consensus An email address and phone number for the patient and a close contact will be kept separate from the clinical database by the coordinator
Interventions
Maraviroc Medications are often in flux during inpatient rehabilitation so Maraviroc or placebo will be started within two weeks of discharge which most often will occur from 4-6 weeks after stroke onset A 1-month supply of capsules will be handed to participants after the Consent has been signed baseline measurements obtained and randomization assigned usually on the same day The second 1-mo supply will be provided during a scheduled interim measurement assessment at UCLA near the end of the 4th week on medication Pill counts will be taken on the returned bottle Participants will take either Maraviroc or a placebo at a dose of 300 mg at 6-8AM The capsules will be supplied by each sites pharmacy and assigned based on a randomization schema
Based upon Pfizers reports on premarketing and post marketing studies of Maraviroc and our review of the literature no dose adjustment is necessary in patients with even mild-to-moderate renal impairment The drug does not affect the QT interval At high doses 600mg or more it may induce orthostatic hypotension so it is recommended that users who also take an anti-hypertensive medication be asked about symptoms of orthostatic hypotension Of note 8 of patients in active and placebo drug groups described orthostatic symptoms in a large trial In HIV trials 13 of subjects had cardiovascular events more than in the placebo group but the link to the drug was unclear and symptoms occurred only in those with known cardiac disease Also no greater incidence of infection rash or other CNS symptoms was noted in these subjects An occasional Stevens-Johnson syndrome and drug rash with eosinophilia and systemic symptoms did occur seen only in post marketing surveillance not in controlled trials so complaints of rash fever joint or muscle aches blisters facial edema etc will be part of our weekly phone call surveillance plan Participants will be told to stop their medication immediately should such symptoms occur and their physician notified Of note St Johns wort should not be used with the medication since it decreases the concentration of Maraviroc
The drug is metabolized by the liver so using it in persons with more than mild hepatic disease especially in the presence of a CYP3A inhibitor would have to be closely monitored our participants will be free of hepatic as well as renal impairment The recommendation from the FDA is to obtain liver function tests prior to starting the drug and again should symptoms such as rash or hepatitis occur This rather rare adverse reaction tends to occur at about one month after starting the medication in less than 4 on the drug or placebo so the investigators will obtain a bilirubin and transaminases at the planned 1-month follow up
Adverse events related to the medication assignment to rehabilitation practice or to other causes will be adjudicated by the Safety Committee with input from the PI
Rehabilitation therapy All participants will have routine outpatient or home health physical and occupational therapy after inpatient discharge as prescribed by their physicians
Each group will be contacted weekly by phone to help maintain interest in the trial count the number of usual care physical and occupational therapy completed assure use of the assigned medication ask about possible adverse reactions and to encourage them to be active The coordinator will obtain this information and provide the feedback using a standard script and checklist
A unique aspect of this trial is a telerehabilitation component that aims to give feedback to all participants to practice with the affected arm and walk daily All participants will be asked to wear a FitBit ankle sensor connected to the cloud Data includes daily sedentary and active time At the weekly call participants will be reminded to try to build up to walking at least 3 times a day for at least 10 minutes per bout and reduce sedentary time Behavioral modification techniques that the investigators have been using successfully based on sensor data will be employed
Participants will also be given a LEAP Motion Controller device that sits in the bottom of a 12x18 box covered by a clear plastic lid This simple system enables us to monitor practice of reaching and grasping with the affected upper extremity in the home At the weekly call they will be encouraged to perform 20-30 minutes daily of reach grasp and pinch actions with small common items and practice bringing the affected hand to the mouth Items will be moved from one corner of the rectangular top to another in a fixed sequence A unique feature of this trial is that telerehabilitation data will provide ground truth about how much participants practiced which may enable a dose-response and responder-nonresponder analysis For example if a subject is taking the active medication but never practices outcomes may be less positive than for the person who does practice as prescribed
A data manager at UCLA will review all incoming data for completeness and quality as well as ensure proper use of the systems eg make sure devices are charged regularly automatic data uploads occur without problems and practice data are processed correctly All feedback will be provided by the UCLA staff
Statistical Analyses
An observational trial Lohse and Lang 2016 found that walking speed increases at 01ms per month and the ARAT increases by 29 points monthly within the time frame of this trial
For the walking speed outcome the evaluable sample size of 30 in each group will have 80 power to detect a difference in means of -0206 ms the difference between an assumed usual care walking speed of 051 SD028 and an assumed intervention group mean walking speed of 0716 This assumes a common standard deviation in the two groups and a two group t-test with a 005 two-sided significance level The estimates for the mean and standard deviation for walking speed come from the LEAPS RCT Duncan N Engl J Med 2011 The investigators plan to enroll 66 patients to account for an expected 10 drop-out rate The t-test used for the power calculation is a simplification of the mixed effects analysis plan for the primary endpoints
For the ARAT sum score analysis is based on a statistical power of 80 with an alpha of 5 for detecting a meaningful difference of 6 points ie a 10 change which has been suggested by several completed trials In a stroke trial the standard deviation was 8 points measured at 2 weeks post stroke Again a sample size of 60 plus 10 dropout rate should suffice
Primary Analyses As appropriate t-tests Wilcoxon rank sum or chi-square tests will be employed to evaluate differences in baseline clinical characteristics between trial participants Using the mixed effects model for Hypothesis 1 should provide greater power than the t-test as it will account for the repeated observations of the endpoints over time For Hypothesis 2 the investigators will look at one aspect of the feasibility of home-based practice as the ratio of those who achieve at least 150 minutes of weekly walking composed of bouts that exceed 5 minutes and 100 minutes of weekly upper extremity practice using the LEAP with the whole group as the denominator The investigators anticipate that 75 will achieve this by the end of the intervention based upon our preliminary studies using these devices in a chronic hemiparetic stroke population
Secondary Analyses Secondary outcomes listed in the Table will be evaluated using t-tests Wilcoxon rank sum tests or chi-square tests as appropriate One planned secondary analysis will compare outcomes based on on whether or not participants can extend their wrist and at least 3 fingers at least 5 degrees at time of randomization to assess for possible differences in drug responses between those with higher compared to lower levels of initial motor control Another will compare outcomes in those who achieve the practice goals of Hypothesis 2 to those who do not in relation to drug assignment
Safety Committee
A Safety Committee will serve the research sites It will include the study statistician a physician and an allied health clinician with training in stroke rehabilitation It will meet before the start of the trial every 6 months after the first 10 subjects have completed the 2-month drug intervention and as needed eg serious adverse reaction
Confidentiality
All data will be entered from both sites into the RedCap database that will be monitored at UCLA by the study statistician for completeness All materials related to the trial for UCLA entries will be stored in a locked cabinet in a locked room by the coordinator
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None