Maraviroc to Augment Rehabilitation Outcomes After Stroke

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 MAPK/CREB 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 PI3K/AKT and P44/42 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 two sites, UCLA and Burke Rehabilitation Center in White Plains,
NY, to gather enough entries in a shorter time and to better generalize the results of this
phase II/III 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.

We will look for a behavioral marker of the potential effect of Maraviroc by testing each
subject while on and off the assigned medication with several commonly used
neuropsychological tests of motor and hippocampal learning.

The trial will be registered at ClinicalTrials.gov with ethical approval from the UCLA
medical IRB.

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 the Burke Rehabilitation
Center in NY. The Burke site will have its own IRB review managed by its PI.

On admission to CRI, patients have the option to sign a UCLA-approved consent to be contacted
about research projects that might be applicable to them in the coming 1-2 years. Potential
participants who have signed this will be contacted by a study investigator or the
coordinator who is listed as trained to do so. Dr. Dorsch, who routinely attends on the
stroke rehabilitation unit at CRI, will also approach potential subjects on his service if
they seem appropriate for the trial. In addition, a flyer (submitted) will be provided to
patients with stroke during their inpatient rehabilitation stay who may be interested in the
study, but are not patients of Dr. Dorsch. They can contact the study coordinator if
interested in participation. Some patients may not decide about participation until after
inpatient discharge. They will be further screened after signing a consent by Drs. Dobkin or
Dorsch or a neurologist serving as a rehabilitation fellow who has been added to the IRB
consent process. Potential participants will be shown how their practice will be monitored
with sensors, if they wish.

Randomization:.

Participants will be assigned to the control or experimental group using a 1:1
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 (e.g., adverse drug reaction).

Each site will enter 30-35 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, creatinine/BUN, and MRI/CT
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 the UCLA or Burke pharmacies and
used under an IND and IRB protocol as required by each institution.

Based upon Pfizer's 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, 1.3% 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 John's 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 bilateral ankle sensors that connect to an Android phone and record lower
extremity activity, including walking and cycling. Data includes daily sedentary and active
time, walking speed and distance for each bout, and stance:swing ratios for quality of gait.
Each participant will be supplied with a kit that includes two accelerometer with gyroscope
sensors with Bluetooth and straps for the ankles, two wireless inductive chargers, an Android
smartphone with data plan and app for automatic data upload, and instructions with photos.
Prior to inpatient discharge, the coordinator at each site will show each study subject and
caregiver how to put on and charge the sensors. At their leisure, they can watch a video
about how to use the system. The site coordinator will obtain a template of a 10-m walk to
train the activity algorithm. 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 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 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 (e.g. make sure devices are charged regularly, automatic
data uploads occur without problems, and practice data are processed correctly).

Statistical Analyses:

A recent observational trial (Lohse and Lang, 2016) found that walking speed increases at
0.1m/s per month and the ARAT increases by 2.9 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 -0.206 (m/s), the difference between an assumed
usual care walking speed of 0.51 (SD=0.28) and an assumed intervention group mean walking
speed of 0.716. This assumes a common standard deviation in the two groups and a two group
t-test with a 0.05 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, i.e., 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 both 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 (e.g., 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.

Inclusion Criteria:

- Transfer to inpatient rehabilitation within 4 weeks of stroke onset

- Single ischemic or subcortical hemorrhagic infarct;

- At the time of randomization, hemiparesis with 4/5 or less strength at the hip and
ankle flexors and extensors

- Functional Independence Measure (FIM) score for ambulation ≥3 to walk at least 10
steps;

- Caregiver available for at least two hours a day for practice and transportation when
needed;

- Adequate language skills to read and understand the Informed Consent and retain
information during daily therapies.

Exclusion Criteria:

- Prior stroke with persisting motor impairment or disability;

- Limited resources or illness that will not enable a return to living outside of a
facility;

- Any medical condition that had limited daily physical activity to walking no more than
2 blocks outdoors prior to the stroke (e.g., claudication, congestive heart failure or
lower extremity pain);

- History of dementia or Mini Mental State Examination score <24;

- History of hepatitis or elevated hepatic transaminases or bilirubin;

- History of renal insufficiency or serum creatinine over 1.6;

- Cancer or other chronic illness that makes 3-year survival unlikely or will detract
from the ability to carry out exercise and skills practice.