Sleep SMART Trial - Devin Brown and Ronald Chervin
October 26, 2021ID7074
To CiteDCA Citation Guide
- 00:00To introduce sleep smart,
- 00:02Smart is a randomized clinical
- 00:04trial assessing whether treatment
- 00:06of obstructive sleep apnea shortly
- 00:09after an acute ischemic stroke or
- 00:12high risk TE reduces the risk of
- 00:14cardiovascular events and improves
- 00:16functional outcomes representing sleep.
- 00:18Smart today are Doctor Devin
- 00:20Brown and Doctor Sherman.
- 00:22Dr Brown is a professor of
- 00:24neurology at University of Michigan
- 00:26Medical School Doctor Sherman,
- 00:28who is also a professor for
- 00:29Alaji and a director.
- 00:30Sleep Medicine at University
- 00:32of Michigan Medical school.
- 00:34Thank you very much for joining us today.
- 00:37Thank you so much for the invitation
- 00:39and it's really wonderful to be
- 00:41able to stop by for a visit and talk
- 00:44with you briefly about sleep smart.
- 00:46As we already said,
- 00:47Ron Sherman is also on the line,
- 00:50and so I'm sure he's happy to answer
- 00:52any of your most difficult questions
- 00:55will save those for him for at the end,
- 00:58Sharon's presentation was was very
- 01:00heartwarming at and her house is
- 01:02also quite lovely compared to mine,
- 01:04so apologies for the background.
- 01:07And perhaps for the less
- 01:11heartwarming presentation.
- 01:13And so let's start just by talking a
- 01:15little bit about why in the context
- 01:18of caring for a stroke patient,
- 01:20you would want to even care
- 01:21about obstructive sleep apnea.
- 01:22There are so many other things to
- 01:24consider to worry about to focus on.
- 01:26Why are we obsessed with
- 01:29obstructive sleep apnea,
- 01:30well, obstructive sleep apnea
- 01:32is very common post stroke.
- 01:34It is approaching the prevalence of
- 01:36hypertension, so it's up in the 70s.
- 01:39So when you see a stroke patient,
- 01:41the chances of that person.
- 01:42Obstructive sleep apnea are extremely common.
- 01:46We know that obstructive sleep apnea
- 01:48is an independent risk factor for both
- 01:51incident stroke and recurrent stroke,
- 01:53and it's also an independent risk factor
- 01:55for poor outcomes following ischemic stroke,
- 01:58including both functional
- 02:00and cognitive outcomes.
- 02:03So what are the links there?
- 02:05How does obstructive sleep
- 02:06apnea potentially cause stroke?
- 02:08How does it potentially cause
- 02:10poor outcomes after stroke?
- 02:12Well, there are lots of different.
- 02:13Possibilities first.
- 02:15Sleep apnea causes elaboration of
- 02:18free radicals of khyle 6 E selected.
- 02:23These things can promote Atheros sclerosis.
- 02:25It promotes deleterious cerebral
- 02:27hemodynamics and through
- 02:28multiple different mechanisms,
- 02:30including platelet activation
- 02:32and increased EPO,
- 02:34and decreased fibrinogen increases
- 02:36hypercoagulability and any of these
- 02:38three factors alone or in combination,
- 02:41can increase the risk of
- 02:42both incident and recurrent.
- 02:44Stroke and then following a
- 02:45little bit of a different pathway.
- 02:48Sleep apnea again through all
- 02:50of the different physiologic
- 02:51changes that it can cause.
- 02:53May end up producing angiogenesis,
- 02:55dendritic and axonal
- 02:57sprouting and synaptogenesis,
- 02:59and these factors can result
- 03:02in poorer stroke recovery.
- 03:05So,
- 03:05given that we have both of these two
- 03:07very important potential outcomes,
- 03:10recurrent stroke and stroke recovery,
- 03:12which should we target in a
- 03:15trial looking at treatment of
- 03:17obstructive sleep apnea poststroke?
- 03:19Well,
- 03:20our approach was really that we wanted
- 03:22to have our cake and eat it too,
- 03:24and so this says you can't
- 03:25have your cake and eat it too.
- 03:27That's obviously being stated by
- 03:29somebody who doesn't understand what
- 03:30you're supposed to do with cake,
- 03:32so we took this approach that we wanted to.
- 03:36Test both of our hypotheses that CPAP
- 03:38could improve prevention and it could
- 03:41improve recovery and within sleep.
- 03:43Smart participants are enrolled as if it
- 03:45is a single trial they've taken through.
- 03:47The protocol is if it's a single trial,
- 03:49but then at the time of analysis,
- 03:51which hopefully will come at
- 03:53some point in in several years.
- 03:55It then breaks down into
- 03:57really two separate trials,
- 03:58one where all participants are contributing
- 04:01their data to the prevention outcome,
- 04:03and those include both the high risk Tia.
- 04:06Of which there are very few,
- 04:08and the ischemic stroke patients,
- 04:10and they have to be enrolled
- 04:12within 14 days of symptom onset.
- 04:14But then to answer the recovery aim,
- 04:16we use only a subset of
- 04:18the enrolled participants.
- 04:19Those who had an ischemic stroke
- 04:21within seven days of consent,
- 04:23and those who also have to have had
- 04:26an NIH stroke scale of at least
- 04:27one at the time of enrollment,
- 04:30because, otherwise,
- 04:30how are you going to be able
- 04:32to note that there has been an
- 04:34improvement in in their recovery?
- 04:37So the design of sleep smart is that
- 04:39it is a late phase multicenter trial.
- 04:42The control group is usual care,
- 04:45so it's usual care.
- 04:47Plus automatically adjusting
- 04:48CPAP versus usual care alone.
- 04:51We could have designed this to have an
- 04:53active control will not active control,
- 04:55but a placebo control using sham
- 04:57CPAP and it's something with
- 04:59which we have experienced.
- 05:00But it really would have complicated
- 05:03our design substantially and
- 05:05it would have advocated the.
- 05:07Possibility of are using a run at night,
- 05:09which is a key part of our protocol design,
- 05:12and so in the face of knowing that
- 05:14we are using open label treatment,
- 05:16we used a probe design where the
- 05:19outcome assessors are masked to
- 05:22randomization assignment and
- 05:23then again as I said before,
- 05:24this is really a secondary prevention
- 05:27trial with an embedded recovery trial.
- 05:32This shows how a participant
- 05:34goes through the protocol.
- 05:35So after consent and
- 05:37baseline data collection,
- 05:38the first night is allocated to
- 05:41sleep apnea testing with an ox T3
- 05:44sleep apnea device and then to have
- 05:46qualifying obstructive sleep apnea.
- 05:48The Respiratory Event index has to
- 05:50be at least 10 and half of those
- 05:52events cannot be no greater than
- 05:55half of them can be central events,
- 05:57and then the person moves on to
- 05:59the second night where he or she.
- 06:00Essentially gets a taste of C.
- 06:02Pap gets to try it out in the run and night,
- 06:05and if that subject uses C PAP
- 06:07for release cumulatively 4 hours
- 06:09during that night and also does
- 06:11not exceed 10 for the central
- 06:13apnea index read off of the device.
- 06:16So meaning therefore the person did
- 06:18not have treatment induced central
- 06:20sleep apnea and the participant is
- 06:23willing after that one night of
- 06:25exposure to see PAP to have a 5050
- 06:27chance of intervention versus control group,
- 06:30then that person.
- 06:31Is eligible for randomization and
- 06:33receives again either automatically
- 06:35adjusting CPAP plus best medical
- 06:37therapy versus just best medical
- 06:40therapy alone and then we follow
- 06:42the subjects for three months for
- 06:44the recovery outcomes and then six
- 06:46months for the prevention outcomes.
- 06:51We were asked to cover a couple of
- 06:53different topics during this brief talk,
- 06:55and so I'm going to move on to enrollment
- 06:59criteria and how we we conceptualize those.
- 07:01And we're going to try to highlight some
- 07:03of the questions that were asked of us.
- 07:06So the enrollment criteria really
- 07:08quite broad in sleep smart.
- 07:09We're trying to have a generalizable trial.
- 07:11We're trying to have a treatment
- 07:13that potentially can help the
- 07:15most number of participants.
- 07:17So there the inclusion criteria are really.
- 07:19Very broad.
- 07:20If you've had an ischemic stroke or high
- 07:22risk TA in the prior 14 days in year,
- 07:24at least 18, and you're asleep smart site,
- 07:27you're essentially eligible from the
- 07:30inclusion side of things we have.
- 07:33For what I'm going to describe is 4
- 07:35categories of exclusion criteria.
- 07:37The first are really the general ones,
- 07:39so if you have somebody who's a
- 07:42pregnant woman incarcerated and
- 07:43can't sign our own consent,
- 07:44that somebody who you're
- 07:46going to want to exclude,
- 07:47and if it's somebody who could
- 07:49not perform all of his or her.
- 07:50Activities of daily living
- 07:52prior to the stroke.
- 07:54Then that's also someone
- 07:55who would be excluded.
- 07:57The next category are the
- 07:59CPAP specific related issues.
- 08:01So if you are on currently on mechanical
- 08:03ventilation or if you have a tracheostomy,
- 08:06you're not going to benefit from
- 08:07C PAP and so you're excluded.
- 08:09And then if you've used C PAP
- 08:11in the last month,
- 08:13we have a concern that if your
- 08:14randomized so the control group
- 08:15you're going to go home and use your
- 08:17see PAP and therefore crossover,
- 08:18so you're excluded for that as well.
- 08:21The third category are things that we
- 08:24think potentially could make CPAP riskier.
- 08:26It's very low.
- 08:28Risk treatment,
- 08:29but there there are some factors that
- 08:31may increase risks and so those include
- 08:34things such as bullous lung disease,
- 08:37pneumothorax having hypo tension
- 08:39that's so significant that you're
- 08:41requiring pressers at that time.
- 08:43If you've had massive epistaxis.
- 08:46If you have a possible CSF
- 08:48leak or Numa cephalus,
- 08:49or if you've had any kind of bone
- 08:51off procedure where the bone has
- 08:53not been replaced on the head,
- 08:55then C Pap maybe a little bit more risky.
- 08:58In those participants,
- 08:59and therefore they are excluded.
- 09:00We also have a category for the site P.
- 09:02I feeling like there's some other
- 09:04entity that increases the risk
- 09:06of C PAP and so we allow for of
- 09:08course the judgment of the local
- 09:10teams to decide this is not a good
- 09:13idea for our for our patient.
- 09:15And then the 4th category really is
- 09:17something that makes it really unfeasible.
- 09:20So for instance,
- 09:20if the participant or if the sort of the
- 09:23patient is using oxygen supplementations
- 09:25greater than four liters per minute,
- 09:27you can't believe.
- 09:28That into our CPAP machines,
- 09:29and therefore it's really unfeasible
- 09:31and then if that person is on some type
- 09:34of precautions, contact precaution,
- 09:36respiratory precautions,
- 09:37we don't want to cross contaminate
- 09:40with our equipment and infect
- 09:42another participant so it really
- 09:44becomes unfeasible.
- 09:45Switching gears a little bit,
- 09:47we were asked to talk a little
- 09:49bit about the stroke physicians
- 09:51versus the sleep positions and
- 09:53how those interactions occur.
- 09:55We've had some comments from potential
- 09:59sites where they have said is CPAP
- 10:01really safe for stroke patients?
- 10:04So I'm concerned that if my person
- 10:05if my patient is enrolled and then
- 10:07randomize the intervention group,
- 10:09that CPAP could potentially cause harm
- 10:11that is most commonly said by a sleep.
- 10:14I started a stroke.
- 10:15Position if it is,
- 10:16if it said and on the flip side,
- 10:18there are some sites where they'll
- 10:20come back to us and say how
- 10:21can you withhold CPAP after you
- 10:22know that the patient has been
- 10:24diagnosed with obstructive sleep
- 10:25apnea by randomizing that person
- 10:27to the control group that is more
- 10:30commonly said by a sleep physician.
- 10:33And so overall,
- 10:34we really feel that we are in a
- 10:36position of clinical equipoised with
- 10:37respect to C PAP for stroke patients.
- 10:40We don't know whether CPAP will
- 10:43help harm or essentially do
- 10:45neither for our stroke patients.
- 10:47There have been no definitive
- 10:49randomized controlled trials for stroke
- 10:51patients for stroke outcomes that have
- 10:54shown anything is improved by CPAP.
- 10:56So we feel comfortable with
- 10:57holding it from the control group,
- 10:59and there there's precedence for this.
- 11:01There have been numerous.
- 11:03Randomized controlled trials that
- 11:04have enrolled either patients
- 11:06with cardiovascular disease,
- 11:08such as Save Rick Ads or SIRKAS,
- 11:11or that have enrolled lots of
- 11:14participants with severe sleep apnea,
- 11:16such as apples where patients are
- 11:18randomized to a control group or,
- 11:20in the case of apples, to a sham control.
- 11:25So other investigative teams,
- 11:28other funding agencies,
- 11:30other peer review panels have found
- 11:32this to be completely ethical
- 11:34and not have any concern.
- 11:37There's also the 2017 U.
- 11:39S Preventive Taskforce report that
- 11:41helped inform our our decision making
- 11:45at the time that we were designing
- 11:48sleep smart and and proposing it
- 11:50for the first time that states that
- 11:52there is no established benefit
- 11:53of C PAP for any health outcome.
- 11:55This is just.
- 11:55In the general population,
- 11:56not even specific to stroke aside
- 11:59from the modest improvement in
- 12:01sleep related quality of life,
- 12:02and the more recent U.
- 12:03S preventive taskforce doesn't say
- 12:06anything that would compel us not to
- 12:09randomize participants to a control group.
- 12:11We were also asked to talk a little
- 12:13bit about crossover so crossovers
- 12:15where you have a control person who
- 12:17someone who's randomized to the control
- 12:19group who then wants to use CPAP.
- 12:21So when that does occur and it's
- 12:23not something that we thought
- 12:25would be very common.
- 12:26Based on our preliminary work
- 12:28and based on prior CPAP trials,
- 12:30pilot trials among stroke
- 12:32patients if that does occur,
- 12:34then the clinical team should absolutely
- 12:37feel free to refer the participant
- 12:39for sleep apnea testing for sleep.
- 12:41Get me a treatment in the clinical realm,
- 12:43it usually takes some time for that
- 12:45to be available to the participant,
- 12:47so it may actually.
- 12:50Push the see PAP treatment for clinical
- 12:52care outside of the even six month window.
- 12:54By the time the person is able
- 12:56to get tested and treated and
- 12:58have a C Pap in his or her home,
- 13:00but the research team, we would suggest
- 13:03not help facilitate that process.
- 13:05It is a protocol violation for a
- 13:07control participant to start using
- 13:08C PAP so it has to be reported
- 13:10as such and in the analysis,
- 13:12at least in the intent to treat
- 13:14component which is our primary analysis.
- 13:16The control participant who starts
- 13:18using C PAP will be analyzed.
- 13:20As a control participant.
- 13:23Crossovers from control.
- 13:24Two intervention or to to CPAP use
- 13:27have been very uncommon in in sleep
- 13:30smart so far it's been around 2%.
- 13:35So what about anticipated challenges?
- 13:38Well, we knew that recruitment
- 13:39would be an issue.
- 13:40Recruitment is an issue for every
- 13:43randomized controlled trial.
- 13:44CPAP adherence is an issue
- 13:46for every CPAP related trial,
- 13:49but some of the things that we did
- 13:51not anticipate having difficulty
- 13:52with included a global pandemic.
- 13:55We did not presage that,
- 13:57and having difficulty achieving
- 13:59in window outcome assessments
- 14:01has been much more challenging.
- 14:04Then we had anticipated we have
- 14:06more missing data at the three
- 14:08month TIMEPOINT for the modified
- 14:10Rankin which is our primary for
- 14:12that aim than we had anticipated.
- 14:14We did try in the design of sleep smart
- 14:17to prepare for some of these challenges.
- 14:20So for instance we built in telephone
- 14:23outcome assessments from the onset
- 14:25that was always allowable and sleep
- 14:27smart even pre COVID and most of our
- 14:30outcomes can be assessed by telephone.
- 14:32There are only a few secondary outcomes.
- 14:34Exploratory outcomes that cannot,
- 14:36but most of them can.
- 14:37We really tried to be very careful and
- 14:40intentional about the selection of our
- 14:43outcome assessments to make them as
- 14:45short as possible and when possible,
- 14:47to allow something to be conducted by phone.
- 14:51We also created a lot of tools for
- 14:54site teams to be able to reach out to
- 14:56participants in case there were any
- 14:58issues trying to achieve outcome assessments.
- 15:01So we built in a place in the
- 15:03back of the consent form.
- 15:04For instance,
- 15:05where lots of contact information,
- 15:07alternative contact information
- 15:08for the subject,
- 15:10alternative contact information for partners,
- 15:12friends,
- 15:13family members could be
- 15:14documented and then referred to.
- 15:16We created several letter templates
- 15:18for sites to use to reach out to
- 15:21subjects about scheduled appointments.
- 15:23Missed appointments unable to reach
- 15:25those types of things we've developed.
- 15:28A slide set that sites can
- 15:31use to help educate teams.
- 15:34Clinical teams,
- 15:35including nurses about sleep
- 15:37smart and we created a document
- 15:41that provides our sort of answers
- 15:44to potential difficult patient
- 15:46questions at the time of enrollment,
- 15:49and we also of course,
- 15:50built in Tele Med telemedicine
- 15:52approach to outpatient.
- 15:53Management of CPAP,
- 15:55which in COVID has been very advantageous.
- 16:01But despite the challenges,
- 16:02there remain lots of hope.
- 16:04There's hope because the of the vaccine,
- 16:07which hopefully will assist teams and
- 16:11getting back to their usual state when
- 16:13it comes to coordinator coverage.
- 16:15Respiratory therapy support,
- 16:16but mostly our hope comes from
- 16:19our sites and the sites have been
- 16:21doing a fantastic job despite the
- 16:23pandemic in the face of a pandemic,
- 16:26we are really grateful to every site.
- 16:28There are some sites,
- 16:30as you see who are randomized.
- 16:32In the 50s and the 60s,
- 16:34number of participants,
- 16:35which is fantastic.
- 16:37I would like to give a little
- 16:39shout out to two of your sites.
- 16:40North Shore with 16 and Yale
- 16:44with nine Randomizations.
- 16:46We're very grateful to you
- 16:47for all of your work.
- 16:49You also have Hartford and Staten Island,
- 16:52and we are grateful for those sites as well.
- 16:57And then just looking at by RCC
- 16:59and you see that some are CC's
- 17:02are just going gangbusters.
- 17:04Some are not participating in sleep
- 17:06smart that is very few of them.
- 17:08And then I've outlined Yale doing very
- 17:12well here somewhere in the middle.
- 17:16And so I thank you very much for again,
- 17:18the invitation and for your attention.
- 17:22And again, Ron is is available to answer
- 17:24any difficult question that that you have.
- 17:30Thank you very much for that Devin.
- 17:32Uhm, I just had a question
- 17:35about a trial powering.
- 17:37Whether it was parked for both
- 17:39the cardiovascular events as
- 17:40well as the recovery outcomes.
- 17:43Yeah, no, that's a good question.
- 17:45So we did look at power calculations
- 17:48for both and we anticipate that a
- 17:51certain percentage of the total will
- 17:54be available for the recovery outcome.
- 17:57And it turns out that we are we have a
- 18:00higher proportion than we had anticipated,
- 18:02so we we think that those two are
- 18:04kind of going to ride along together
- 18:06and that by the end we should have
- 18:08a sufficient number in both groups.
- 18:11Fantastic in such an innovative
- 18:13innovative trial design. Thank you.
- 18:24Alright, I think those are the questions.
- 18:26Well, thank you so much for joy.