Duke Industry Statistics Symposium Are Pragmatic Trials Ready

Duke Industry Statistics Symposium Are Pragmatic Trials Ready

Duke Industry Statistics Symposium Are Pragmatic Trials Ready for Prime Time? September 7, 2017 Challenges of a Large Pragmatic Trial: the ALLHAT Experience Barry R. Davis, MD, PhD University of Texas School of Public Health Houston, TX Outline Description of ALLHAT PRECIS-2 for ALLHAT Expected Challenges Unexpected Challenges

Summary U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT)

www.allhat.org JAMA. 2002;288:2981-2997 3 Pragmatic Study Characteristics

Enroll broadly representative and heterogeneous patient populations Conducted in typical clinical and health care settings Large in size To discern hypothesized differences in effectiveness To evaluate differences in patient subgroups As simple as possible in design and conduct Maximal inclusion, minimal exclusion criteria Minimally intrusive on routine clinical practice in terms of procedures, data collection Examples: ALLHAT1 , MI-FREE2 ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium channel blocker vs. diuretic. JAMA 2002; 288:298197; http://www.ncbi.nlm.nih.gov/pubmed/12479763 1

Choudhry, N.K., et al. Full coverage for preventive medications after myocardial infarction. N Engl J Med. 2011 Dec 1;365(22):208897;http://www.nejm.org/doi/full/10.1056/NEJMsa1107913 2 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Practice-based, randomized, multi-center trial Antihypertensive component 42,418 high-risk hypertensives 55+ years Whether newer agents reduce incidence of CHD compared to a diuretic Blinded, no placebo

Plus: Lipid-lowering component 1/4 of antihypertensive trial cohort (10,336) moderately hypercholesterolemic patients does reduction of LDL cholesterol reduce allcause mortality? unblinded (pravastatin vs usual care) Secondary Objectives All-cause mortality Stroke Combined CHD Combined CVD Cancer Major subgroups

Age 65+, women, African-Americans, diabetics Randomized Design of ALLHAT High-risk hypertensive patients Consent / Randomize Eligible for lipidlowering Amlodipine

Chlorthalidone Doxazosin Lisinopril Not eligible for lipid-lowering Consent / Randomize Pravastatin Usual care Follow until death or end of study (4-8 years)

Infrastructure 623 clinical sites in the U.S., Canada, Puerto Rico, and U.S. Virgin Islands 42,418 participants in the antihypertensive component 10,355 participants in the lipid component Randomization began 2/94 Follow-up ended 3/02 11 The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

Quebec -Primary sponsor: NIH-NHLBI -Concurrent support from the VA Prince Edward CANADA Island -Assistance from pharmaceutical companies New Brunswick but no role inQuebec scientific conduct of trial -623 Clinical Centers -USA, Canada, Caribbean -Diverse practice settings

CANADA Washington Montana Island of New Foundland North Dakota Maine Ontario Minnesota

Michigan Oregon VT NH Wisconsin Idaho New York South Dakota Michigan

Wyoming Iowa NJ MD Utah California Illinois Indiana

Ohio WV Kansas Colorado Oklahoma DE Program Office, NHLBI

Virginia Missouri Arizona RI Pennsylvania Nebraska Nevada

MA CT Kentucky N. Carolina Arkansas Tennessee S. Carolina MEXICO New Mexico

Texas Louisiana Alabama Georgia (Area Enlarged) St. Croix, Virgin Islands Mississippi MEXICO CTC,

UT Florida Puerto Rico (Area Enlarged) 33 Infrastructure (continued) 9 regions VA sites, Canadian sites 7 geographically distributed 50-100 sites per region

1-2 Regional MDs 2-4 Regional Study Coordinators Role of the Regional Teams Initial regulatory paperwork Training Regular communication with sites Address questions from site staff Site monitoring visits Steering Committee, subcommittees Writing groups Assist CTC with forms, MOO, procedures Participate in planning for Investigators Meetings Site recruitment

PRECIS-2 Study population Eligibility 5 Recruitment 4 Location Setting 5 Organization 5 Methods Primary Outcome 5 Follow-up 4 Primary Analysis 5 Intervention delivery Flexibility 4

Adherence 4 Expected Challenges Design and analysis Study protocol, forms, manual of operations Randomization for two trials Promote study awareness among physicians & patients at national level Expected Challenges (Continued) Site recruitment and IRB approval Acquisition and distribution of study drugs Large meeting coordination and travel Regional administration & communications

Financial management Expected Challenges (Continued) Minority recruitment goals Support center selection and oversight QC, monitoring, and reports Assist clinical sites in recruitment and adherence Steering Committee, Subcommittees, DSMB Publications and presentations Eligibility Criteria for Antihypertensive Trial Inclusion Aged > 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 Exclusion MI, 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 19 Unexpected Challenges Recruitment Early discontinuation of doxazosin arm Cancellation of closeout training Follow-up specialists Dissemination Unexpected Challenge 1 Recruitment 1. 2. 3. 4. 5. Go from 270 to 400 sites (to 600)

Add cigarette smoking as risk factor Lower age cutoff from 60 to 55 Extend recruitment period for 1 year Increase $ for randomization Pressel et al. Controlled Clinical Trials 22:674686 (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 9th Region Canada

10. Publicity radio, print, direct mail Pressel et al. Controlled Clinical Trials 22:674686 (2001) Wright et al. Controlled Clinical Trials 22: 659-673 (2001) Unexpected 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 endpoint 1/28/00 1st Transition Committee meeting 2/3/00 Steering Committee and Regions informed 2/11/00 Closeout materials finalized Pressel et al. Controlled Clinical Trials 22:2941 (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 Pressel et al. Controlled Clinical Trials 22:2941 (2001) Unexpected 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 procedure Closeout visits to start 10/1/01

Events of Sept. 11 resulted in cancellation of meeting (over 1000 people) Crisis recovery What do we do about training? Unexpected Challenge 3 Cancellation of Closeout Training Meeting (9/14-15/01) for Investigators CTC, NHLBI, 9 Regions formulated plan in KC Send out training kits, series of conference calls, site visits, local training meetings, one-on-one calls Effort begun immediately 61% trained by 9/30/01, 97% by 10/31/01 All sites trained by November 2001 Unexpected 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 experience Need database search and follow-up specialist Follow-up specialist protocol Started in 4/2000 Pressel et al. SCT 2002, 2003 Unexpected Challenge 4 Follow-up Specialists to Locate Participants One, then two, then three F/U specialists Incorporating searches into closeout 10/1/01 3/29/02

Pressel et al. SCT 2002, 2003 Unexpected Challenge 5 Dissemination Dissemination of results is part of every trial Usually just papers and presentations Usually more done if industry-sponsored Dissemination to be integral part of ALLHAT Pressel et al. SCT 2005 Unexpected Challenge 5 Dissemination Planning started with Dissemination Committee Beyond publication of primary results Press 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 Summary A large pragmatic trial can present several expected and unexpected challenges ALLHAT challenges mostly related to: 600+ practice-based sites No specific funding except for forms completed Competing priorities

Offset by: Relatively simple protocol Few forms Few data items collected per visit Lessons Learned Experienced team is a must Anticipate problems Rely on others inside & outside trial Involve the investigators and coordinators Open communications, flexibility

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