Transcript Poster P16 - Society for Clinical Trials

Jennifer Gassman, Dana Miskulin, Philip Zager, David Ploth, Manisha Jhamb, Lavinia Negrea, Mahboob Rahman, Cynthia Kendrick, Karen Brittain, Susan Sherer
Reason why those eligible to enter Baseline
were not randomized
Introduction
Screening
Baseline
The optimal blood pressure target for patients on hemodialysis
is unknown. The Blood Pressure in Hemodialysis (BID) Pilot
randomized clinical trial is an NIDDK/Dialysis Clinic, Inc., multicenter pilot study in which hypertensive hemodialysis patients
are randomized to a standardized pre-dialysis Systolic BP of
110-140 vs.155-165 mmHg.
126 participants on three-times-weekly dialysis were
randomized at 21 dialysis units (with a census of 1600 patients)
associated with five clinical centers (University of New Mexico;
Tufts University; Medical University of South Carolina; University
of Pittsburgh; and Case Western Reserve University/University
Hospitals) and followed for one year. The Data Coordinating
Center is in the Department of Quantitative Health Sciences at
the Cleveland Clinic. The goals of the BID Pilot Study were to
assess the feasibility and safety of randomizing participants to
the systolic blood pressure treatment arms and to inform the
design of a full-scale trial. Outcomes included protocol
adherence, achievement of randomized SDUSBP goals by 2week running means, and changes in LV mass by cardiac MRI.
BID recruitment was expected to be challenging, and study
coordinators kept standardized local logs of reasons by stage of
recruitment, with reasons for Stage 1 “Why not asked?” tracked
for local dialysis unit patients apparently eligible who were not
approached, and Stage 2 “Why refused?” tracked for those
approached who refused consent.
281 of 387 patients approached consented and enrolled in the
BID Study Baseline, which included
 Standardized Blood Pressure measured (pre-cannulation)
before each dialysis session
 At least one day with Home Blood Pressure measured 3x
morning and 3x afternoon
 At least one 24-hour Ambulatory Blood Pressure Measurement
 Cardiac MRI
 Demonstration of hypertension (with back titration of
antihypertensives until running mean systolic >155 mmHg)
Only 126/281 (45%) of those who enrolled in Baseline were
randomized. Stage 3 Recruitment tracking included collecting
Baseline dropout data on reasons enrolled patients were not
randomized. Three-stage recruitment tracking helped identify
barriers at each stage of the challenging recruitment process.
BID Study enrollment took place over four years, from
December 2011 to January 2015. Study Coordinators at the five
participating clinical centers logged Stage 1 reasons why
patients were not approached and kept local tallies that showed
that 387 participants were approached by the study coordinators
and asked to consent to the BID Pilot Study.
Of those approached for consent, 125 refused, and study
coordinators kept local Stage 2 tallies of reasons for refusal.
(These data could not be entered in the study database for
individual because the patients had not consented.) Local tallies
were summarized quarterly and presented annually at Steering
Committee meetings. Reasons patients couldn’t be approached
or wouldn’t consent were discussed and evaluated, with a mind
toward a future Phase III randomized clinical trial. Major
reasons that patients refused to consent for the BID Pilot Study
included perception of study being burdensome, n=34 (27%),
unwillingness to participate in research, n=14 (11%), and
reluctance to change medications/goals, n=10 (8%).
A total of 281 patients consented and enrolled in the BID Pilot
Study Baseline, during which SDUSBP was measured prior to
each dialysis session. Participants did home blood pressure
measurements weekly (3x morning and 3x afternoon) and did at
least one 24-hour Ambulatory Blood Pressure measurements.
Stage 1. Local Site Tally
Reasons some candidates were not approached
Only dialyzes twice a week
Will soon be doing PD/ nocturnal/ home dialysis
Will soon receive a transplant
Patient is concerned about his arm or vascular access
Known to be substance abuser
Known to be non-compliant to dialysis treatments or time
Known to be non-compliant to fluid intake
Known to be non-compliant to antihypertensive meds
Can’t measure his/her BP in his/her upper arm
SDU BP < 140 mmHg on no meds or minimal meds
Blood Pressures not under 140 but seem too low
Too large to fit in an MRI machine
Metal in body precludes measurement of MRI
Other contra indication to MRI (list it)
Seems to have very frequent hospitalizations
Thought to have a short life expectancy (list why)
Blind
Other comorbidity (list)
Cognitive impairment
Speaks a language our site does not support (list language)
Patient known to not to want to participate
Primary care doc/nephrologist known not to want pt to participate
Patient has no family support
Enrolled or about to enroll in another intervention study
Plans to switch to a non BID unit nearby (list unit)
Plans to move to a new city
Incarcerated
Nursing Home
Medications were back-titrated until a 2-week running mean
pre- dialysis standardized systolic BP>155 mmHg was
demonstrated. 126 participants were found to be eligible (verified
through an online “ready to randomize” program that checked all
baseline requirements against the study’s Oracle database at the
Cleveland Clinic) and were randomized.
Of the 155/281 (55%) participants who entered Baseline but
were not randomized, the most common reason noted was the
combination of unwillingness to back-titrate and/or inability to
achieve the lower limit of the control arm SDUSBP goal (155 mm
Hg) despite back-titration, which occurred in 65/155 (42%)
participants. Detailed reasons are shown below, with major
reasons summarized on the right.
Stage 3. Local Site Tally
Reasons approached candidates did not consent
Likes current BP control and meds, does not want to change them
Not willing to do MRIs
Not willing to do another requirement (keep track of requirement)
Concerned about arm / vascular access
Do not trust doctors, research, “feels like a human guinea pig”
Other specific reason does not want to participate (track reason)
Significant others do not support patient participating
Primary care Dr, other nephrologist do not support participating
Says that study requirements overall are just too much for him/her
Not ready at this time / Thinking about it / Will approach later
The BID Pilot Study
is supported by
NIDDK R01DK083424 and
Dialysis Clinic, Inc.
Stage 3 “Baseline Dropout” Results
Primary reason patient not randomized
Final baseline BP not in range, too low
Final baseline BP not in range, too high
Patient arm(s) can no longer be used to measure BP
Excessive intradialytic hypotension
Excessive post-HD hypotension
Unable to sustain BP>155 mmHg SDUBPM
Patient arms med condition related to past vascular accesses
Patient size prevented fitting into the MRI machine
Unable to have baseline MRI, other reason
Patient had an acute MI during baseline
Patient had unstable angina during baseline
Patient admitted to acute or chronic car
Alcohol or substance abuse detected
Other medical reason
Team decision: patient would not adhere to BP meds
Team decision: patient would not adhere to protocol
Patient changed mind, dislikes in-center BP measurement
Patient changed mind, dislikes cardiac MRI
Patient changed mind, dislikes home BP measurements
Patient changed mind, protocol burdensome
Patient changed mind, other reason
Family/significant other do not support
Patient switched to in-center nocturnal
Patient changed mind, doesn't want to be randomized
Patient could/would not do required baseline home measures
Patient could/would not do required ABPM
Patient switching to non-BID dialysis unit
Patient will receive a living donor kidney
n
(% of 155)
60 (38.7%)
2 (1.3%)
1 (0.6%)
1 (0.6%)
1 (0.6%)
4 (2.6%)
2 (1.3%)
1 (0.6%)
5 (3.2%)
1 (0.6%)
2 (1.3%)
1 (0.6%)
1 (0.6%)
6 (3.9%)
1 (0.6%)
8 (5.2%)
9 (5.8%)
2 (1.3%)
1 (0.6%)
16 (10.3%)
10 (6.5%)
1 (0.6%)
1 (0.6%)
6 (3.9%)
1 (0.6%)
5 (3.2%)
4 (2.6%)
2 (1.3%)
Number
(percent)
Inability to achieve the lower limit of the high
SDUSBP goal (155 mm Hg) despite back titration
65 (42%)
Participant changed his or her mind
38 (25%)
Judged unlikely to achieve goals
9 (6%)
Contraindication to MRI
6 (4%)
Could not perform required procedures
6 (4%)
Other
31 (20%)
Total
155
Discussion and Future Plans
Recruitment was challenging in BID, with less than half of those
enrolling in Baseline proceeding to randomization. Cumulative Stage
3 reasons for baseline dropouts were included in each weekly report
and were presented along with quarterly Stage 1 “Why not asked?”
and Stage 2 “Why refused” reasons on coordinator calls and at
Steering Committee and DSMB calls/meetings. Study coordinators
kept track of the patients at dialysis units associated with their
clinical centers, and patients who had previously been considered
ineligible were reconsidered if reasons for exclusion changed.
Investigators used recruitment tracking data to brainstorm ways
to improve approach, consent, and randomization rates during the
Pilot Study and to plan design changes enabling higher recruitment
yields for a subsequent full-scale study. The BID Study’s sample size
goal of 120 randomized patients was exceeded, with a total of 126
randomized. BID Follow up ended in early 2016. Two-week running
means of 144 ± 17.5 mm Hg vs. 155 ± 15.4 mm Hg (mean ± SD)
were achieved at day 330, showing a separation of 11 mmHg.
Retention was excellent. The goal for completing standardized predialysis blood pressure measurements was exceeded. The goal for
obtaining ambulatory blood pressure measurements was at target.
Fewer home blood pressure measurements than expected were
successfully completed, a result similar to that seen in the Frequent
Hemodialysis Network Nocturnal Study. BID investigators are
currently working on the results paper and writing a protocol for a
full-scale Phase III trial. The Phase III trial will not require cardiac
MRI and will feature a simplified protocol. BID investigators are
enthusiastic, energized by the success of the BID Pilot Study in
showing feasibility and by the results of the SPRINT Study.