Barry R Davis MD PhD University of Texas School of Public Health Houston TX Duke Industry Statistics Symposium A re Pragmatic Trials Ready for Prime Time September 7 2017 Outline Description of ID: 908878
Download Presentation The PPT/PDF document "Challenges of a Large Pragmatic Trial: t..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Challenges of a Large Pragmatic Trial: the ALLHAT Experience
Barry R. Davis, MD, PhDUniversity of Texas School of Public HealthHouston, TX
Duke Industry Statistics Symposium
A
re Pragmatic Trials Ready for Prime Time?
September 7, 2017
Slide2OutlineDescription of ALLHAT
PRECIS-2 for ALLHATExpected ChallengesUnexpected ChallengesSummary
Slide33The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
JAMA. 2002;288:2981-2997
U.S. Department of
Health and Human Services
National Institutes
of Health
National Heart, Lung, and Blood Institute
www.allhat.org
Slide4Enroll broadly representative and heterogeneous patient populations Conducted in typical clinical and health care settingsLarge in sizeTo discern hypothesized differences in effectivenessTo evaluate differences in patient subgroupsAs simple as possible in design and conduct Maximal inclusion, minimal exclusion criteriaMinimally intrusive on routine clinical practice in terms of procedures, data collection
Examples: ALLHAT1 , MI-FREE2Pragmatic Study Characteristics
1
ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic.
JAMA
2002; 288:2981–97;
http://www.ncbi.nlm.nih.gov/pubmed/12479763
2
Choudhry, N.K., et al.
Full coverage for preventive medications after myocardial infarction.
N
Engl
J Med.
2011 Dec 1;365(22):2088–97;http://www.nejm.org/doi/full/10.1056/NEJMsa1107913
Slide5Slide6Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)Practice-based, randomized, multi-center trial
Antihypertensive component42,418 high-risk hypertensives 55+ yearsWhether newer agents reduce incidence of CHD compared to a diuretic
Blinded, no placebo
Slide7Plus:Lipid-lowering component -
1/4 of antihypertensive trial cohort (10,336)moderately hypercholesterolemic patients does reduction of LDL cholesterol reduce all-cause mortality?unblinded (pravastatin vs “usual care”)
Slide8Secondary ObjectivesAll-cause mortalityStroke
Combined CHDCombined CVDCancerMajor subgroupsAge 65+, women, African-Americans, diabetics
Slide9Randomized Design of ALLHAT
High-risk hypertensive patients
Consent / Randomize
Amlodipine
Chlorthalidone
Doxazosin
Lisinopril
Eligible for lipid-lowering
Not eligible for lipid-lowering
Consent / Randomize
Pravastatin Usual care
Follow until death or end of study (4-8 years)
Slide10Infrastructure623 clinical sites in the U.S., Canada, Puerto Rico, and U.S. Virgin Islands42,418 participants in the antihypertensive component
10,355 participants in the lipid componentRandomization began 2/94Follow-up ended 3/02
Slide1111
33
CANADA
CANADA
Quebec
Ontario
Washington
Oregon
Quebec
California
MEXICO
MEXICO
Nevada
Idaho
Montana
North Dakota
South Dakota
Wyoming
Utah
Colorado
Arizona
New Mexico
Texas
Oklahoma
Kansas
Nebraska
Minnesota
Iowa
Wisconsin
Michigan
Michigan
Illinois
Missouri
Indiana
Arkansas
Louisiana
Mississippi
Alabama
Georgia
Tennessee
Kentucky
Ohio
WV
Virginia
N. Carolina
S. Carolina
Pennsylvania
DE
NJ
MD
New York
VT
NH
CT
MA
RI
Maine
New Brunswick
Nova Scotia
Prince Edward
Island
Island of
New Foundland
Puerto Rico
(Area Enlarged)
St. Croix, Virgin Islands
(Area Enlarged)
The Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial
Florida
CTC,
UT
Program Office,
NHLBI
-623 Clinical Centers
-USA, Canada, Caribbean
-Diverse practice settings
-Primary sponsor: NIH-NHLBI
-Concurrent support from the VA
-Assistance from pharmaceutical companies but no role in scientific conduct of trial
Slide12Infrastructure (continued)9 regionsVA sites, Canadian sites
7 geographically distributed50-100 sites per region1-2 Regional MD’s2-4 Regional Study Coordinators
Slide13Role of the Regional TeamsInitial regulatory paperworkTrainingRegular communication with sites
Address questions from site staffSite monitoring visitsSteering Committee, subcommitteesWriting groupsAssist CTC with forms, MOO, proceduresParticipate in planning for Investigators’ MeetingsSite recruitment
Slide14PRECIS-2
Study populationEligibility 5Recruitment 4LocationSetting 5
Organization 5
Methods
Primary Outcome 5
Follow-up 4
Primary Analysis 5
Intervention delivery
Flexibility 4
Adherence 4
Slide15Slide16Expected Challenges Design and analysis
Study protocol, forms, manual of operationsRandomization for two trialsPromote study awareness among physicians & patients at national level
Slide17Expected Challenges (Continued)
Site recruitment and IRB approvalAcquisition and distribution of study drugsLarge meeting coordination and travelRegional administration & communicationsFinancial management
Slide18Minority recruitment goalsSupport center selection and oversight
QC, monitoring, and reportsAssist clinical sites in recruitment and adherenceSteering Committee, Subcommittees, DSMBPublications and presentations
Expected Challenges (Continued)
Slide1919Eligibility Criteria forAntihypertensive Trial
InclusionAged > 55 years
BP
eligibility -
140/90 mm Hg but
180/110 mm Hg at two
visits
1+ major CVD risk factors - MI
or stroke (> 6 months),history of revascularization, documented ASCVD, diabetes,, HDL < 35 mg/dL, LVH (ECG or echo), current cigarette
smoking
ExclusionMI, stroke within 6 months, Symptomatic CHF or ejection fraction < 35%, creatinine 2 mg/dL, requiring diuretics, CCB, ACEI, or alpha blockers for reasons other than hypertension
Slide20Unexpected Challenges Recruitment
Early discontinuation of doxazosin armCancellation of closeout trainingFollow-up specialistsDissemination
Slide21Unexpected Challenge 1 - Recruitment
Go from 270 to 400 sites (to 600) Add cigarette smoking as risk factorLower age cutoff from 60 to 55 Extend recruitment period for 1 yearIncrease $ for randomization
Pressel et al. Controlled Clinical Trials 22:674–686 (2001)
Wright et al. Controlled Clinical Trials 22: 659-673 (2001)
Slide22Pressel et al. Controlled Clinical Trials 22:674–686 (2001)
Wright et al. Controlled Clinical Trials 22: 659-673 (2001)
Unexpected Challenge
1 -
Recruitment
6.
Add Puerto Rico
7. Add field personnel program
8. Extend recruitment period for 6 months to
end
of 1/98
9. Add 9
th
Region – Canada
10. Publicity –
radio
, print, direct mail
Slide23Unexpected Challenge 2 - Early Discontinuation of Trial Arm
1/24/00 – NHLBI Director accepts recommendation to drop arm; futility of primary endpoint & statistical, clinical significance of major secondary endpoint1/28/00 – 1st Transition Committee meeting2/3/00 – Steering Committee and Regions informed
2/11/00 – Closeout materials finalized
Pressel et al. Controlled Clinical Trials 22:29–41 (2001)
Slide24Pressel et al. Controlled Clinical Trials 22:29–41 (2001)
Unexpected Challenge 2 -
Early Discontinuation of Trial Arm
2/16-18/00 – Transition kits to sites
2/18/00 – Paper submitted to
JAMA
Express
3/8/00 – NHLBI press release
3/15 – ACC presentation
4/5 – Paper appears on WWW;
in
print on 4/19
Slide25Unexpected Challenge 3 - Cancellation of Closeout Training Meeting (9/14-15/01) for Investigators
Major investigators meeting in Kansas City to train sites on the closeout procedureCloseout visits to start 10/1/01Events of Sept. 11 resulted in cancellation of meeting (over 1000 people)
Crisis recovery – What do we do about training
?
Slide26CTC, NHLBI, 9 Regions formulated plan in KCSend out training kits, series of conference calls, site visits, local training meetings, one-on-one callsEffort begun immediately61% trained by 9/30/01, 97% by 10/31/01
All sites trained by November 2001
Unexpected Challenge
3 -
Cancellation of Closeout Training Meeting (9/14-15/01) for Investigators
Slide27Unexpected Challenge 4 - Follow-up Specialists to Locate Participants
Losses to follow-up large problem in long-term practice-based large trial – many sites had little experienceNeed database search and follow-up specialistFollow-up specialist protocol Started in 4/2000
Pressel et al. SCT 2002, 2003
Slide28One, then two, then three F/U specialistsIncorporating searches into closeout 10/1/01 – 3/29/02
Pressel et al. SCT 2002, 2003
Unexpected Challenge
4 -
Follow-up Specialists to Locate
Participants
Slide29Unexpected Challenge 5 -Dissemination
Dissemination of results is part of every trialUsually just papers and presentationsUsually more done if industry-sponsoredDissemination to be integral part of ALLHAT
Pressel et al. SCT 2005
Slide30Planning started with Dissemination CommitteeBeyond publication of primary resultsPress conference, training spokespersons, major meetings, work with Publications Committee, work with NHBEP, press kits, web site, lay journals, etc.
Bartholomew et al. Clinical Trials, 2009
Stafford et al., Archives of Internal Med, 2010
Unexpected Challenge
5 -
Dissemination
Slide31SummaryA large pragmatic trial can present several expected and unexpected challengesALLHAT
challenges mostly related to:600+ practice-based sitesNo specific funding except for forms completedCompeting prioritiesOffset by:Relatively simple protocol
Few forms
Few data items collected per visit
Slide32Lessons Learned
Experienced team is a mustAnticipate problemsRely on others inside & outside trial
Involve the investigators and coordinators
Open communications, flexibility