Real-Life Example of Pragmatic
Clinical Trials in End-Stage Renal
Disease: The TiMe Trial
Michel Chonchol, MD
Professor of Medicine
University of Colorado Denver
Aurora, CO, USA
Randomized Controlled Trials in
Nephrology
Palmer S et al. Am J Kidney Dis 2011; 58:335-337
Clinical Practice Guidelines
KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and
Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)
Strength of recommendation
RECOMMENDATIONS
1 = strong
5D, we suggest lowering elevated phosphorus levels
the normal range (2C).
2 =toward
weak
• 4.1.1In patients with CKD stages 3-5, we suggest maintaining serum phosphorus in the normal range
(2C). In patients with CKD stage
• 4.1.2In patients with CKD stages 3-5D, we suggest maintaining serum calcium in the normal range (2D).
Quality of evidence
mEq/l) (2D).
A= high
4.1.4In patients with CKD stages 3-5 (2D) andB=
5D (2B),
we suggest using phosphate-binding agents in the treatment of
moderate
hyperphosphatemia. It is reasonable that the choice of phosphate binder takes into account CKD stage, presence of other components
of CKD-MBD, concomitant therapies, and side-effect
(not graded).
Cprofile
= low
4.1.5In patients with CKD stages 3-5D and hyperphosphatemia, we recommend restricting the dose of calcium-based phosphate binders
D in=thevery
and/or the dose of calcitriol or vitamin D analog
presencelow
of persistent or recurrent hypercalcemia (1B).In patients with CKD
• 4.1.3In patients with CKD stage 5D, we suggest using a dialysate calcium concentration between 1.25 and 1.50 mmol/l (2.5 and 3.0
•
•
stages 3-5D and hyperphosphatemia, we suggest restricting the dose of calcium-based phosphate binders in the presence of arterial
calcification (2C) and/or adynamic bone disease (2C) and/or if serum PTH levels are persistently low (2C).
• 4.1.6In patients with CKD stages 3-5D, we recommend avoiding the long-term use of aluminum-containing phosphate binders and, in
patients with CKD stage 5D, avoiding dialysate aluminum contamination to prevent aluminum intoxication (1C).
• 4.1.7In patients with CKD stages 3-5D, we suggest limiting dietary phosphate intake in the treatment of hyperphosphatemia alone or in
combination with other treatments (2D).
Learning Health System
Every clinical care encounter is an opportunity for
learning and for producing generalizable
knowledge
• Favorable developments
‒ Consolidation of health systems
‒ Increased use of electronic health records
• Goal is to move beyond observational studies and
conduct clinical trials within the clinical care
setting
NIH Health Care Systems Research
Collaboratory
• “The overall goal …. is to strengthen the national
capacity to implement cost-effective large-scale
research studies that engage health care delivery
organizations as research partners.”
• RFA Requirements
– Conduct a large pragmatic trial demonstration
project
– Perform trial in at least two health care systems
– Rely on hard clinical outcomes and/or patient
reported outcomes
– Ascertain outcomes from clinically available data
Pragmatic Trial
Does this therapy work under usual
care conditions?
Explanatory versus Pragmatic Trials
• Explanatory trials evaluate intervention under ideal,
experimental conditions in order to test a causal
hypothesis (assessment of efficacy)
• Pragmatic trials evaluate intervention under “real-world”
conditions to inform choices between treatment options
(assessment of effectiveness)
• Tradeoff between high internal validity (explanatory) and
high generalizability (pragmatic)
Most trials fall somewhere in between two extremes
(continuum rather than dichotomy)
PRECIS Criteria (Pragmatic-Explanatory Continuum
Indicator Summary)
Explanatory
Pragmatic
Eligibility
Criteria
• Restrictive: highest risk for
outcome, most likely to
respond, most likely to
comply
• All individuals with condition
of interest regardless of risk,
comorbidities, adherence,
language
Intervention
(& comparator)
• Strict implementation
• Expert practitioners
• Close monitoring of dose,
adverse effects with
adjustment or treatment,
respectively
•
•
•
•
Follow-up
• High intensity
• More f/u than usual care
• Data collection for trial
• Low intensity
• No study visits
• Administrative databases
Thorpe KE J Clin Epidemiol 2009
Flexible implementation
No expertise needed
Full range of clinical settings
Comparator is often usual
practice
PRECIS Criteria
Explanatory
Pragmatic
Outcome
• Direct and immediate
consequence of intervention
• May be surrogate of
downstream outcome
• Specialized training for
ascertainment
• May require adjudication
Adherence to
intervention
• Close monitoring of
• Unobtrusive or no
participants and centers
measurement
• Adherence may be
• No strategies to improve
requirement for participation
adherence
• Strategies employed
Analysis
• Intention to treat often
supplemented by per
protocol
• Attempt to answer
narrowest, mechanistic
question
Thorpe KE J Clin Epidemiol 2009
•
•
•
•
Clinically meaningful
Objectively measured
No adjudication
Assessed under usual
conditions
• Pure intention to treat
• Noise is accepted
(embraced?)
Features of Pragmatic Trials
• Evaluate “simple” interventions
• Require large sample
• Often use cluster randomization
• Use simplified approach to consent
• Use electronic health records (recruitment, data
collection, communication, monitoring)
• Relatively inexpensive
Pragmatic Trials are Not New
1950s: Polio vaccine
1980s - 1990s: Acute
treatment for MI
Hemodialysis is an Ideal Setting for
Pragmatic Trials
• Highly accessible study population with
frequent clinical encounters
• Highly granular and uniform data
collection as part of routine clinical care
• Infra-structure allows for centralization of
activities and ability to conduct trial in
large number of facilities across a large
geographic area
Dialysis Facility is the Principal Source of
Health Care for Many Patients with ESRD
• Patients have frequent contact with multidisciplinary team members
• Dialysis facilities perform/provide laboratory
studies, blood pressure measurements, QOL
assessments, vaccinations, nutritional
supplements, pharmacy services
• Burdensome for patients to go elsewhere for care
• Primary care providers often relinquish care to
nephrologists and dialysis unit personnel
Nespor SL ASAIO 1992; Holley JL AJKD 1993; Bender FH AJKD 1996;
Zimmerman DL, NDT 2003; Shah N, Int Urol Nephrol 2005; Nissenson AR AJKD 2012.
Dialysis is Already a Learning Health System
• United States Renal Data System (USRDS)
• Dialysis Outcomes and Practice Patterns
Study (DOPPS)
• Dialysis provider organization data
• Quality improvement initiatives
But very little data from randomized clinical trials!
Hemodialysis Session Length
in the 9-15 hr/wk range in 3/week
schedules
(Rationale behind the TiMe Trial)
Dialysis Session Length for a 3/week
Schedule
• Dialysis used to be given for 6-8 hours per session, 3x/week
• NCDS study suggested that Kt/V was a key measure of
adequacy
• More efficient dialyzers, higher blood flow rates
• Kt/V > 1.2 can be given to small patients and women over
about 3.0 hours
• Is session length per se important beyond Kt/V?
• KDOQI – at least 3 hours; European BPG – at least 4 hours
• What is the evidence for session length per se in the 9-15
hr/week range and how strong is it?
“Physiologic” Rationale to Increase
Time per se
• Urea not representative uremic solute
• Phosphate, middle molecules, protein-bound
substances may depend more on weekly time
• Urea not a good model solute
• Surface-area scaling results in longer dialysis times for
small patients and women
• Volume control and ultrafiltration rate depend on
time.
• Shorter time patients may be more volume
overloaded
• Shorter-time patients may have higher UF rate
Lines of Evidence for Benefits of
Longer Session-Length
• Randomized trials (NCDS)
• Cross-country comparisons (US vs.
Europe vs. Japan)
• Within-country observational datasets
• Volume overload and hard outcomes
• High UF rates and hard outcomes
Time in 3/week Dialysis
Markedly different in Japan vs. Europe vs. N. America
Tentori et al, NDT, 27:4180, 2012
Is The Session Length Data From Japan Based On
Biology?
Shinzato T et al, NDT, 1996;2139-2151
Should minimum td > 4 hours?
Miller et al, AJKD, 2009
Is There Something Special About 4.0
Hours? What About 3.5?
Flytheet al, Kidney Int. 2013; 83:104-113
Time > 4 hrs and Survival
3 Different Methods; 3 Different Answers
Brunelli et al, Kidney Int. 2010; 77:630-636
Dose-targeting bias
Daugirdas, Kidney Int 2013;83:9-13
High UF Rate and Mortality
Flythe J et al, Kidney Int., January, 2011
Movilli E et al, NDT 2007, 22:3547.
Summary
• Some evidence from randomized trials (primary
analysis of NCDS that time per se may be important)
• May be due to surface-area-related scaling of solute
removal
• May be due to better volume control
• Observational data is all over the map; country bias,
dose-targeting bias (DTB), confounding with body size
• Results in the US are not consistent; more prominent
effect at 4 hours than at 3.5, suggesting DTB.
TiME Trial Team
Academic
Investigators
Fresenius
TiME
University of
Pennsylvania
DaVita
NIDDK, OD
TiME Trial: Team Effort from the Start
• Trial question
• Trial design
• Grant application
• Protocol development
• Trial conduct
Time to Reduce Mortality in End-stage
Renal Disease (TiME) Trial
Hypothesis
Thrice weekly hemodialysis with session durations
of at least 4 hours and 25 minutes improves
outcomes compared with usual care.
TiME Trial Design
Usual Care
Facilities
Enroll and
Randomize
Facilities
(session duration
not driven by
trial)
Enroll and
follow incident
patients
Intervention
Facilities
≥4.25 hour
sessions
Primary
outcome:
All-cause
mortality
Secondary
outcomes:
Hospitalizations
& Quality of Life
Follow-up Period: 2-3 years
Rationale for Cluster Randomization
• Logisitical efficiencies around recruitment
• As importantly, greater ability to implement
intervention if it is a facility approach
Eligibility Criteria
Facility
• Willingness of nephrologists and facility
leadership
• Capacity to accommodate 4 hr, 25 minute
treatments for incident patients
Patient
• Age >18 years
• Ability to provide consent for dialysis care
Sample Size and Power
• 402 facilities, 6432 patients (approximately 50%
from each dialysis provider organization)
• Average of 16 patients per facility
• 80% power for HR 0.85
• Assumptions
• Mortality rate 18% per year
• Intra-class correlation for mortality of 0.03
• 5% loss to f/u per year
Stratified Randomization
• Central venous catheters
• Black race
>20% vs ≤20%
>50% vs ≤50%
Data Acquisition
• Clinical and administrative data transmitted
electronically from individual facilities and
centralized laboratory to dialysis providers’ data
warehouses
• De-identified data elements transmitted from
dialysis provider data warehouses to Data
Coordinating Center (Penn)
Pragmatic Features of the TiME Trial
• All patients starting dialysis are eligible unless they
are not competent to sign consent to clinical care
• Intervention is delivered by clinical providers
• Outcomes:
• ascertained from routine clinical data
• derived from data elements common to all sites
• Adherence to intervention at the patient level will be
promoted using systems already in use
• Highly centralized implementation approach
• Single IRB of record
• Testing effectiveness rather than efficacy
Approach to Consent
• Patients starting dialysis at participating facilities
are given a brief information document with:
‒ Purpose of the trial
‒ Effect of trial on patient’s session duration
‒ Toll-free telephone number to obtain additional
information from the research team and to opt-out of
participation
• Trial information and toll-free telephone number
to contact research staff are posted in patient
care areas of participating dialysis facilities
throughout the duration of the trial.
Why Use Opt-Out Approach?
• Goal is to evaluate effectiveness rather than efficacy
• Implementation of intervention will be more
successful if facility-wide approach
• Consent requirement will result in imbalance in
patient characteristics between treatment groups
since randomized assignment is known prior to
enrollment
Criteria for Waiving Consent
1. The research involves no more than minimal
risk to the subjects
2. The waiver or alteration will not adversely
affect the rights and welfare of the subjects
3. The research could not practicably be carried
out without the waiver or alteration
4. Whenever appropriate, the subjects will be
provided with additional pertinent information
after participation.
Key Factors for Minimal Risk Determination
• Physician and patient autonomy are maintained
• Research does not change care for patients in
Usual Care arm (which is hypothesized to have inferior
outcomes)
Challenges
• Ethical and regulatory hurdles regarding consent
approach
• Multiple layers of buy-in required
• Facility personnel education
• Potential for contamination across Intervention
and Usual Care facilities
• Changing practices over conduct of trial
• Patient acceptance
• Physician acceptance
Ethical and Regulatory Vetting
• IRB
• Collaboratory / NIH
• OHRP
• FDA
• CMS
Down side of using waiver of consent
• Less able to push adherence to intervention at patient level
Update
Year 1






IRB approval
Office of Human Subjects Protections review
FDA review, exempt from IDE regulations/oversight
Contracts signed
DSMB review
IT systems established
Years 2 - 5
 Facility enrollment and randomization
 Patient enrollment and follow-up
Many Unanswered Questions in Dialysis
about Fundamental Aspects of Care
• Duration of hemodialysis sessions?
• Dialysis solution potassium concentration?
• Blood pressure target?
• Phosphorus target?
• Hemoglobin target?
• Preventive health care?
• Anticoagulation for atrial fibrillation?