Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT): Design, methods, and baseline results

1 Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease leading to dementia and eventually death. The disease is named after Alöis Alzheimer (German physician) who described the characteristic plaques and tangles in the brain of a 50 year old woman dying of the condition in 1906.¹ There is no known cure for the disease. The only treatments are palliative.

AD was the 8^th leading cause of death in 2000; accounting for 49,558 deaths in that year.² It threatens to exact an increasing toll as life expectancy increases. Worldwide, the number of people with AD in 2006 was estimated to be 26.6 million. That number is projected to grow fourfold by 2050 (106.8 million people).³ In the U.S. the projection is as high as 4.58 million people with AD by 2047.⁴ Potential savings with disease delayed or averted are large. Brookmeyer et al estimate that an intervention resulting in a 1-year delay in disease onset would produce an annual savings of about 10 billion dollars 10 years after initiation of such an intervention.

These harsh realities have led various groups to mount randomized trials aimed at assessing the utility of various drugs and regimens in preventing development of the condition. One of those efforts culminated in the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT).

ADAPT was an investigator-initiated, NIH-funded, primary prevention, randomized, placebo-controlled, multicenter trial. It was designed to address the question of whether non-steroidal anti-inflammatory drugs (NSAIDs) could prevent or delay the onset of Alzheimer’s disease (AD), with the secondary objectives of determining whether the study treatments could attenuate cognitive decline associated with aging.

The drugs tested were celecoxib (Celebrex®, Pfizer) and naproxen sodium (Aleve®, Bayer).⁵ This paper describes design, methods, and baseline results of the trial. Particulars of the trial are given in Table 1. Table 2 gives a chronology of the trial.

Table 1.

ADAPT features and operating characteristics

A. Profile

Descriptors: Randomized, multicenter, phase 4, double-masked, placebo-controlled,  primary prevention, trial

Treatment structure: Simple (non factorial), parallel

Treatment groups: 3 (Celecoxib, naproxen, and matching placebos; see Section 3)

Funding source: National Institutes on Aging

Funding mode: Grant, cooperative agreement (U01 AG015477)

Disbursal of funds: Via contracts from the Study Chair's institution with participating  centers

Centers: 8

Field sites/clinics: 6

Baltimore: Johns Hopkins Univ, Sch Med, Constantine Lyketsos, MD

Boston: Boston University, Sch Med, Robert Green, MD

Rochester (NY); Moore Community Hospital, M Saleem Ismail, MD

Seattle*: Univ Washington, Sch of Med, Suzanne Craft, PhD

Sun City (Az); Sun Health Research Institute, Marwan Sabbagh, MD

Tampa*: The Roskamp Institute Memory Clinic, Michael Mullan, MBBS, PhD

Coordinating Center (CC) (Baltimore)

Johns Hopkins University, Sch of Pub Health, Curtis Meinert, PhD

Office of Chair: Univ of Washington (Johns Hopkins Univ, Sch of Pub Health through 28    February 2002); John CS Breitner

Project Office (Bethesda)

National Institute on Aging, Neil Buckholtz, PhD

Start date: 1 March 2000

Achieved sample size: 2,528

B. Recruitment

Approach: Primarily via targeted mailings to selected zip code areas surrounding the field    sites; mailing addresses provided by HCFA/CMS

Enrollment: 1st person randomized 8 March 2000

Enrollment suspended: 17 Dec 200415

No. randomized: 2,528 (see Figure 1)

C. Followup

Design: Common closing date for all regardless of when randomized (28 Feb 2007)

Person years of followup: 4,66015

D. Randomization

Fixed assignment ratio: 1:1:1.5 (Cel:Nap:Plbo)

Stratification: Field site and age (3 age groups)

Assignment issued from CC after eligibility determined

E. Data collection/processing

Paper forms

Data entry at field sites via on-site PC

Data harvest done by CC; monthly

F. Sample size calculation

Outcome measure: AD incidence

Δ = 30% reduction in AD incidence

α = 0.05 (2-tailed)

1 - β = Power = 0.80 for 30% reduction in AD incidence

Calculated sample size: 2,625 dementia-free subjects aged 72 – 88 with a history of  Alzheimer-like dementia in a first degree relative

Assumed period of treatment and followup: 5 yr min; 7 yr max

Assumptions: 5%/yr loss to followup; Loss due to mortality: 4/100 in year 1, and an 8.5%  /yr increase per yr thereafter; loss due to noncompliance to trt  (ie, stop taking assigned trt  and do not take an NSAID on a regular basis; 15% in 1st yr and 5%/yr thereafter); loss of  precision due to use of NSAIDs in placebo-assigned participants (2.5%/yr)

G. Organizational bodies (September 2006)

Steering Committee (SC): 12; Study officers (SO) plus 6 field site directors

Study Officers (SO): 6; Study chair, chair of SC, director & deputy director of CC, field site  director, & project officer

Research Group: ~50; SC, SO, field site coordinators, neuropsych-psychometricians, CC  personnel

H. Treatment effects monitoring (TEMC)

Results by treatment group during trial seen only by the treatment effects monitoring  committee

TEMC members: 5 voting, 3 nonvoting; voting members independent of ADAPT;  appointed by study investigators with advice and consent of sponsor; nonvoting members:  Director of CC, NIA Project Officers, study consultant

Meeting mode and frequency: Face-to-face, every six months; more frequent if necessary

Operating philosophy: Members not masked to treatment assignment; no adjustment for  multiple looks; no preordained stopping rules

^*Added November 2001

Table 2.

ADAPT chronology

Event	Date
	D	E
2000 6 SC mtgs
Notice of grant award	28 Feb	2000
1st SC meeting; Sun City	30 Mar	2000
Letter of agreement signed with Bayer	7 Jun	2000
Contract with Health Care Financing Administration – HCFA (subsequently Centers for    Medicare and Medicaid Services – CMS) consummated for Medicare\Medicaid mailing list	8 Aug	2000
Contract with ProClinical consummated for packaging and distribution of drug	19 Oct	2000
Mailing list from HCFA received (1,343,722 records)	25 Oct	2000
Training meeting (Baltimore)	2–3 Nov	2000
Naproxen/matching placebo shipped to ProClinical by Bayer	10 Nov	2000
Medicare beneficiary contact letter approved by CMS	1 Dec	2000
Prototype phone screen & recruitment materials mailed to field sites	01 Dec	2000
Letter of agreement signed with GD Searle/Pharmacia	4 Dec	2000
Celecoxib/matching placebo shipped to ProClinical	8 Dec	2000
2001 5 SC mtgs, 2 SO mtgs, 2 TEMC mtgs, 4 site visits
Contract signed with McKesson BioServices Corp for blood draw kits and labels	1 Feb	2001
Contract signed with Covance for laboratory determination	14 Feb	2001
Drug shipped to field sites from ProClinical	20 Feb	2001
Training meeting (Baltimore)	22–23 Feb	2001
1st Treatment Effects Monitoring Committee (TEMC) (conf call)	27 Feb	2001
First participant randomized	8 Mar	2001
SC conference call; vote on addition of Tampa and Seattle	8 Nov	2001
2002 4 SC mtgs, 6 SO mtgs, 2 TEMC mtgs, 5 site visits
Updated mailing list from CMS received (1,218,796 records)	13 Feb	2002
Paper on ADAPT masking published5	Feb	2002
Updated mailing list from CMS received (1,364,714 records)	26 Apr	2002
Public Citizen letter to Sec'y of HHS requesting ADAPT be stopped45	4 Sep	2002
Letter from ADAPT to Sec'y HHS rebutting Public Citizen letter	30 Sep	2002
NIH response to Public Citizen letter	18 Nov	2002
2003 2 SC mtgs, 5 SO mtgs, 2 TEMC mtgs, 7 site visits
Public Citizen letter to NIH re ADAPT46	13 Apr	2003
NIH response to Public Citizen letter	13 May	2003
2004 4 SC mtgs, 2 SO mtgs, 2 TEMC mtgs, 6 site visits
Competing renewal submission	26 Feb	2004
SC vote to suspend treatment and enrollment (conf call)	17 Dec	2004
NIH press conference re decision to suspend	20 Dec	2004
FDA clinical hold issued	23 Dec	2004
2005 7 SC mtgs, 3 SO mtgs, 2 site visits
FDA Arthritis Advisory Committee and Drug Safety and Risk Management Advisory    Committee meeting re celecoxib	16–18 Feb	2005
Statement from ADAPT read at FDA hearing27	18 Feb	2005
SC vote to make trt suspension of 17 Dec permanent	10 Mar	2005
NIA requests revision to competing renewal of 26 Feb 2004	18 Apr	2005
SC vote to lift results blackout; IND terminated; TEMC dissolved; ADAPT Advisory    Committee created	2 Aug	2005
SC & Research Group (RG) meeting; Seattle; outcome data presented by trt group	6–7 Oct	2005
2006 2 SC mtg, 14 SO mtgs, 6 site visits
Competing renewal resubmitted (application: 2 U01 AG015477–06A1)	1 Mar	2006
ADAPT master data set available for distribution to field sites	3 May	2006
Competing renewal reviewed by NIA study section	12 Jul	2006
Summary statement (2 U01 AG015477–06A1; priority score: 172; 20.3 percentile)	Jul 28	2006
ADAPT AD outcome manuscript submitted to Neurology	22 Oct	2006
ADAPT CV and cerebrovascular safety results published15	17 Nov	2006
2007 18 SO mtgs
Notification of closeout of data collection (PPM 93); 28 Feb 2007	3 Jan	2007
ADAPT AD outcome manuscript accepted for publication in Neurology14	22 Jan	2007
Treatment assignment unmasking (PPM 95)	31 May	2007
Competing renewal resubmitted (application: 2 U01 AG015477–06A2)	5 Jul	2007
ADAPT cognitive decline manuscript submitted to Archives of Neurology	5 Jul	2007
On-site data entry discontinued (PPM 97)	31 Aug	2007
Cessation of clinic funding (PPM 98)	30 Sep	2007
Summary statement for 2 U01 AG015477–06A2 (priority score: 152; 15.1 %ile)	12 Dec	2007
ADAPT cognitive decline manuscript accepted; Archives of Neurology	13 Dec	2007
2008 3 SO mtgs
Paper re lessons from ADAPT published8	Jan	2008
Master data set distributed to ADAPT investigators	20 Feb	2008

2 Funding initiative

Efforts to fund the trial started with a grant application submitted to the NIH in May 1997 and culminated, two submissions later, in funding (Table 3). ADAPT was an investigator-initiated trial funded via a cooperative agreement with the National Institute on Aging (NIA).

Table 3.

Initial funding history

1st submission

Study population: Cache County Utah cohort

Sample size: 3,100

Treatments: Ibuprofen and matching placebo

Primary outcome measure: AD incidence

Enrollment period: 1 yr

Length of followup: 4 yrs

5 yr budget: $10,486,428

Submitted: 30 May 1997

Outcome: Not funded; priority score: 263; percentile rank: 55.2

2nd submission

Study population: Cache County Utah cohort

Sample size: 2,800

Treatments: Ibuprofen and matching placebo

Primary outcome measure: AD incidence

Enrollment period: 1yr

Length of followup: 4 yrs

5 yr budget: $14,087,522

Submitted: 13 February 1998

Outcome: Not funded; priority score: 205; percentile rank: Not available

3rd submission

Study population: 4 field sites (Bal, Bos, Roc, Logan)

Sample size: 2,625

Treatments: Ibuprofen, celecoxib and matching placebos

Primary outcome measure: AD incidence

Enrollment period: 1.5 yrs

Length of followup: 7 yrs

5 yr budget: $25,121,319

Submitted: 1 March 1999

Outcome: Funded; priority score: 166; percentile rank: 12.7

The original proposal was for a trial of ibuprofen and matching placebo. In response to suggestions from the Initial Review Group, the third submission was changed to compare ibuprofen and celecoxib to matching placebos.

The outcome measure remained constant as AD incidence. The period of time anticipated for enrollment increased from 12 months (first and second submissions) to 18 months in the funded proposal and the amount requested (5 yr totals) grew from $10,486,428 in the first submission to $25,121,319 in the funded proposal.

The approach to recruitment also changed. In the first submission recruitment was to take place in Cache County, Utah, building on work done there in another project that had characterized a cohort of nearly 5,000 elderly people.^6,7 As the scope of the proposal was expanded, the approach changed to one involving four enrolling sites (one being in Cache County). Ultimately the Cache County site was dropped in favor of another site.

3 Choice of study treatments and treatment protocol

The study treatments and dosage schedules ultimately chosen are shown in Table 4. The criteria for stopping or interrupting treatment are given in Table 5.

Table 4.

ADAPT treatment regimens

No. enrolled	Treatment	Dosage
719	Naproxen sodium; Nap (Aleve®, Bayer)	220 mg b.i.d. (blue tablet/blue label) and placebo matched to celecoxib (white tablet/white label), given orally; 4 tablets / day
726	Celecoxib; Cel (Celebrex®, Pharmacia)	200 mg b.i.d. (white tablet/white label) and placebo matched to naproxen (blue tablet/blue label), given orally; 4 tablets / day
1,083	Placebo (PLBO)	Placebo matched to naproxen (blue tablet/blue label) and placebo matched to celecoxib (white tablet/white label), given orally; 4 tablets / day

Table 5.

Treatment protocol

Criteria for study treatment termination

• The participant develops serious complications of an ulcer, such as gastrointestinal  bleeding, perforation, or obstruction (mandatory stop)

• Any condition that, in the opinion of the study physician, makes it medically  inappropriate or risky for the participant to continue on study treatment

Criteria for study treatment interruption

• If the participant develops any signs or symptoms suggestive of an ulcer or kidney  disease, the participant is withdrawn from study treatment pending an evaluation by the  study physician and primary care physician (plus a specialist if necessary). The  participant is put back on study treatment at the discretion of the study physician.

• If the participant develops an elevated blood pressure, creatinine, or potassium or a  decreased hematocrit, he or she is referred for evaluation and treatment. The study  physician determines whether it is medically necessary to interrupt study treatment.

• If the participant requires corticosteroids, or warfarin, ticlopidine or any type of anti-  coagulant, study treatment is interrupted for the duration of usage.

• If the participant is taking ≥ 4 doses per week of any of the following, study treatment is  interrupted:

- vitamin E (at doses > 600 IU per day)

- non-aspirin NSAIDs or aspirin (> 81 mg per day)

• The participant enrolls in any trial that is likely to interfere with ADAPT procedures or  affect treatment outcomes

• If the participant develops any condition that in the opinion of the study physician makes  it medically inappropriate or risky to continue treatment, study treatment is interrupted.

The original plan was to test ibuprofen and celecoxib against a matching placebo. That plan was predicated on an assumption that it would be possible to obtain the drugs and matching placebos from the manufacturers. Funding was not adequate to cover purchase of the drugs or the manufacture of matching placebo. Several months of negotiations resulted in a commitment from Monsanto/Searle (manufacturers of Celebrex, later acquired by Pharmacia, and ultimately by Pfizer) to provide celecoxib in unmarked 200 mg “bright stock” capsules, and placebo capsules that were visually indistinguishable. It became clear early on, however, that the leading manufacturer of ibuprofen was not interested in supplying their drug and a placebo. Instead, they offered to supply commercially available drug for overencapsulation, suggesting that the large “overcapsules” could be filled with inert powder to make placebo. The investigators were concerned that the large capsules would be difficult to swallow, and also that they would be fairly easy to disassemble to see if they contained a recognizable dosage of the commercial agent. A consultant suggested that 220 mg naproxen sodium tablets (Aleve®) and matching placebo had been offered for other trials by Bayer, and that the company would probably make them available for ADAPT. Expert consultants saw no reason a priori that naproxen should not be substituted for ibuprofen. The notion of preparing and packaging 3 identical appearing capsules (celecoxib, naproxen, and placebo) was dismissed as being impractical because any change in packaging or formulation would have required extended testing and expense to satisfy the FDA regarding bio-availability and packaging.

4 Eligibility criteria

All trials represent select study populations. The requirement for informed consent alone renders them select, but they must also meet selection criteria. The eligibility and exclusion criteria for ADAPT are given in Table 6.

Table 6.

Inclusion and exclusion criteria

Inclusion criteria

• Age 70 years or older at time of the eligibility evaluation visit

• Family history of one or more 1st degree relatives with Alzheimer-like dementia

• Collateral respondent available to provide information on cognitive status of study    participant and to assist with monitoring of use of study medications, if necessary

• Sufficient fluency in written and spoken English to participate in study visits and    neuropsychological testing

• Willingness to limit use of the following for the duration of treatment:

- vitamin E at doses > 600 IU/day

- non-aspirin NSAIDs or aspirin at doses > 81 mg/day

- histamine H2 receptor antagonists

- Ginkgo biloba extracts

• Intention and ability (in opinion of the study physician) to participate in regular study    visits

• Consent

Exclusion criteria

• History of peptic ulcer complicated by perforation, hemorrhage, or obstruction

• History of peptic ulcer with symptoms within 4 weeks of intended enrollment date

• Concurrent use of warfarin, ticlopidine, or any other type of anti-coagulant

• Use of ≥ 4 doses/wk of any of the following in the 14 days prior to the intended    enrollment date:

- histamine H2 receptor antagonists

- non-aspirin NSAIDs

- aspirin use > 81 mg/day

• Concurrent use of systemic corticosteroids

• Clinically significant hypertension, anemia, liver disease, or kidney disease (per    guidelines in ADAPT Handbook)

• History of hypersensitivity or anaphylactoid response to sulfonamide antibiotics (eg,    Bactrim, Septra, Gantrisin, Gantanol, Urobak), or to aspirin or other NSAIDs (eg,    ibuprofen, dicofenac, celecoxib, naproxen)

• Plasma creatinine ≥ 1.5 mg/dL

• Enrollment in any trial likely to interfere with ADAPT procedures or treatments

• Cognitive impairment or dementia according to criteria specified in ADAPT    Neuropsychology Manual

• Current alcohol dependence or abuse

• Any condition that, in the opinion of the study physician, makes it medically    inappropriate or risky for participant to enroll in ADAPT

The approach to enrollment in ADAPT can be characterized as a "risk concentration design", i.e., one in which persons were screened to select those considered to be at increased risk for outcomes of interest.⁸ The efficiency of the design depends on the degree of risk concentration accomplished by the selection factors.

ADAPT attempted “risk concentration” for AD using two known risk factors, age and family history of dementia or AD. Clearly, the incidence of AD increases with age, so part of the debate had to do with where to set the lower age cutoff (there was no upper age cutoff in ADAPT). The higher the cutoff the higher the likely incidence, but the greater the difficulty in achieving the specified sample size. The grant application as submitted proposed a lower age cutoff of 72 years, but that was later lowered to 70 to increase the pool of potential recruits.

A family history of age-related dementia has been shown to be a risk factor for AD in various studies.^9,10,11,12 Hence its use in ADAPT was as a screening variable to select people at increased risk.

Several of the exclusions (principally the first five proscriptions in the list of exclusions in Table 6) were imposed to reduce the risk of gastro-intestinal (GI) bleeds, inasmuch as conventional NSAIDs, including naproxen, carry known risks for such bleeding. Another obvious exclusion was use of " ≥ 4 doses/wk of non-aspirin NSAIDs" since such use might well be dangerous if in conjunction with naproxen or celecoxib. The exclusion basically had the effect of excluding people with arthritis or other conditions likely to render them as “obligate” NSAID users. Because arthritis is more common in women than men¹³ this exclusion, no doubt, biased the available pool toward men instead of women.

5 Outcome measures

Clearly, the choice of outcome measures is an important design decision in any trial. More often than not the so called primary outcome measure is also the design variable – the variable used in the sample size calculation. Investigators in ADAPT, from the outset, wanted a "clinically relevant" measure. The argument was between a measure of cognitive decline and actual diagnosis of AD. Ultimately they settled on AD even though it was obvious that the former would have produced a smaller sample size requirement. The concerns were, first, that the observational evidence base spoke much more strongly to a “protective” effect against AD dementia than to any such effect against cognitive decline. Second was a concern that the relevance of benefit in a less steep cognitive decline with age would be more difficult to translate into clinical relevance than measurable differences in AD incidence. But it was also clear that the trial would be strapped for power using AD unless it could follow large numbers of people for long periods of time – 7 years as the trial was designed. The availability of support for such a long time required an act of faith on the part of the investigators inasmuch as NIH grant funding is made available in five year intervals. A strong probability of re-funding was essential because, even if the trial succeeded in recruiting the large number of participants needed, there was little probability of demonstrating a difference with treatment – if indeed one existed at all – after the first funding cycle (2000 – 2005).

Having settled on AD as the primary outcome measure, with cognitive decline as a secondary outcome, the next problem was to develop a reasonable estimate of AD incidence in a placebo-assigned group of people aged 70 or over having a first degree relative with age-related dementia or AD. As is often the case in trials, especially in prevention trials, the investigators were forced to make an "educated guess" from published observational studies. The figures for AD incidence used were 2.5/100 for year 1; 2.75/100 for year 2; and 3.03/100 for year 3 but, as also is often the case, they proved to be overestimates.⁸ The observed incidence rate per 100 person years for all treatment groups combined was 0.7.¹⁴ Undoubtedly the low rate is reflective of a “healthy volunteer effect”, but it was almost certainly a consequence also of the eligibility criterion that participants have no detectable cognitive disorder at entry into the study.

6 Sample size specifications

The particulars for the sample size calculation underlying the trials are given in Panel F of Table 1. Relying on the assumptions stated in Table 1, the planned sample size was 2,625. Loss due to mortality was predicted at 4/100 in year 1 with an 8.5% annual increment thereafter. Probably as another reflection of the “healthy volunteer effect,” the actual observed mortality three year rate was only 1.27/100.¹⁵

7 Recruitment design

The primary difficulty in a prevention trial such as ADAPT lies in identification of people at risk of the disease of interest – AD. The usual approaches to recruitment common in trials, enrolling people already diagnosed with disease, do not work in primary prevention trials. People do not usually recognize themselves as being at risk for the disease or condition of interest. They have to be identified in some way. In ADAPT, the primary means of identification was by mass mailings to people aged 70 or over. The mailings were directed to eligible beneficiaries of Medicare using addresses supplied under an agreement between the NIA and HCFA (Health Care Financing Administration), renamed CMS (Centers for Medicare and Medicaid Services).

The mailing lists comprised eligible Medicare beneficiaries who lived in areas around the field sites, as determined by zip code. All told, there were about 3.5 million mailings. This number includes 1.2 million re-mailings to people previously contacted in the initial waves of mailings. Use of the HCFA/CMS lists obligated investigators to initiate the mailing program with a letter on Government letterhead advising recipients that their names and addresses had been given to people running ADAPT, and stating explicitly that recipients were under no obligation to participate in the study (letter on ADAPT website, www.jhucct.com/adapt).

Mailings were done by a mailing service (Alliance Mass Mailing, Forest Hill, Maryland) in waves over the course of enrollment. The general approach was to start with a mailing to a few thousand people per field site and then increase the number as field sites became proficient at screening and enrollment. The first mailings occurred in late April 2001 and the last ones in early December 2004. See Figure 1 for enrollment over time.

Figure 1.

Enrollment over time

The yield from these mailings ranged in the neighborhood of 0.8 per 1,000 mailings and around half that fraction for re-mailing to previous recipients of letters.

The vast number of people enrolled came from the HCFA/CMS mailings. Less than 5% came via other means including (depending on the field site), use of voter registration lists, local newspaper and radio ads, presentations to church groups and civic organizations, and presentations at area academic institutions, hospitals and nursing homes.

See the ADAPT website (www.jhucct.com/adapt) for prototype copies of consent forms.

8 Randomization, masking, followup, and data collection designs

Randomization was controlled by the coordinating center. Field sites requested assignment after keying essential data necessary for assignment plus data to determine eligibility and absence of excluding conditions. Randomization was in permuted blocks of sizes 7 or 14 arranged (randomly ordered) within three age strata − 70–74, 75–79, and 80+ − within field site. Participants were counted as enrolled in the treatment group to which assigned on release of the assignment to a field site.

Treatments were administered in double-masked fashion. Masking was accomplished by use of placebos matching the celecoxib and naproxen treatments. See Martin et al⁵ for details on the masking. People removed from treatment by study personnel during the trial remained masked to assignment. The mask for participants and study personnel remained in place until June 2007 when it was lifted via mailings to study participants revealing assignment.

Followup was independent of treatment, that is, all persons were followed via regular study visits and telephone contacts even if they were no longer adherent to the assigned study treatment. All persons were followed to a common closing date, 28 February 2007.

The data collection schedule is outlined in Table 7. Data collection was via paper forms keyed by study personnel at the field sites via dedicated PCs. Harvests of data were done monthly by coordinating center personnel.

Table 7.

Data collection schedule

	EL* visit− 1	EN* visit 0	Followup contacts (mos from EN visit)
			1	3	6	9	12	15	18	21	24…
Type of visit/contact
Eligibility	✓
Enrollment		✓
Cognitive assessment							✓				✓
Interval			✓		✓				✓
Telephone				✓		✓		✓		✓
Procedures
Consent	✓	✓
Physical exam	✓						✓				✓
Med history	✓		✓	✓	✓	✓	✓	✓	✓	✓	✓
Neurological exam	✓						✓				✓
Laboratory tests	✓		✓		✓		✓		✓		✓
Blood sample		✓
Review of compliance			✓	✓	✓	✓	✓	✓	✓	✓	✓
Review of med use	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓
Review of adverse events			✓	✓	✓	✓	✓	✓	✓	✓	✓
Dispensing study drug		✓			✓		✓		✓		✓
Neuropsychological tests
Modified Mini-Mental	✓	✓					✓				✓
Digit span		✓					✓				✓
Generative Verbal Fluency		✓					✓				✓
Rivermead Memory Test		✓					✓				✓
Hopkins Verbal Learning	✓	✓					✓				✓
Visuospatial Memory Test	✓					✓				✓
Self-rating Memory Functions		✓					✓				✓
Geriatric Depression Scale		✓					✓				✓
Dementia Severity Rating	✓	✓					✓				✓

^*EL = eligibility; EN = enrollment

The list of study instruments used in ADAPT is given in Table 8.

Table 8.

Data collection instruments

Neuropsychological tests

Modified Mini-Mental State Examination-Epidemiological (3MS-E) [Teng & Chui,     1987]28

Digit Span [Wechsler, 1981]29

Generative Verbal Fluency

Narratives from the Rivermead Behavioral Memory Test [Wilson et al, 1989]30

Hopkins Verbal Learning Test - Revised (HVLT-R) [Brandt, 1991]31

Brief Visuospatial Memory Test - Revised [Benedict, 1996]32

Self-rating of Memory Functions (self-administered) [Squire et al, 1979]33

Geriatric Depression Scale (self-administered) [Yesavage et al, 1983]34

Dementia evaluation battery

Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) battery [Morris et     al, 1989]35

Trail Making Test [Reitan, 1986]36

Logical Memory [Wechsler, 1987]37

Benton Visual Retention Test (BVRT) [Benton, 1974]38

Controlled Oral Word Association Test (COWA) [Benton, 1988]39

Symbol Digit Modalities Test (SDMT) [Smith, 1982]40

Shipley Vocabulary [Zachary, 1991]41

Self-Rating of Memory Functions [Squire et al, 1979]33

Collateral respondent questionnaires

Dementia Severity Rating Scale (DSRS) (self-administered) [Clark & Ewbank, 1996]42

Dementia Questionnaire (DQ-cr) [Silverman et al, 1986]43

Neuropsychiatric Inventory (NPI) [Cummings et al, 1994]44

9 Baseline data

Table 9 provides a description of the study population as enrolled. Data summarized in the table were collected during the eligibility and enrollment visits (see Table 7 for data collection schedule). The median age at entry was 74. Ages at enrollment ranged from 70 – 90.

Table 9.

Baseline results

	Total		Cel		Nap		Plbo
	No.	%	No.	%	No.	%	No.	%	p
Randomized	2,528		726		719		1,083
Age
70–74	1,402	55.5	402	55.4	401	55.8	599	55.3
75–79	796	31.5	228	31.4	228	31.7	340	31.4
80–84	286	11.3	84	11.6	76	10.6	126	11.6
> 85	44	1.7	12	1.7	14	1.9	18	1.7
	2,528	100.0	726	100.1	719	100.0	1,083	100.0
Gender									0.69
Male	1,368	54.1	384	52.9	389	54.1	595	54.9
Female	1,160	45.9	342	47.1	330	45.9	488	45.1
	2,528	100.0	726	100.0	719	100.0	1,083	100.0
Race/ethnic origin									0.06
White	2,451	97.0	698	96.1	698	97.1	1,055	97.4
African-American	44	1.7	15	2.1	16	2.2	13	1.2
Hispanic	18	0.7	10	1.4	2	0.3	6	0.6
Other	15	0.6	3	0.4	3	0.4	9	0.8
	2,528	100.0	726	100.0	719	100.0	1,083	100.0
Education									0.21
< High school	102	4.0	28	3.9	35	4.9	39	3.6
HS graduate	503	19.9	151	20.8	126	17.5	226	20.9
Some college	695	27.5	201	27.7	204	28.4	290	26.8
College degree	484	19.1	139	19.1	122	17.0	223	20.6
Post-graduate ed	744	29.4	207	28.5	232	32.3	305	28.2
Marital status									0.44
Married	1,817	71.9	510	70.2	539	75.0	768	70.9
Widowed	461	18.2	143	19.7	116	16.1	202	18.7
Separated	13	0.5	3	0.4	2	0.3	8	0.7
Divorced	171	6.8	50	6.9	42	5.8	79	7.3
Never married	65	2.6	20	2.8	20	2.8	25	2.3
Not reported	1	0.0	0	0.0	0	0.0	1	0.1
Alcohol drinks/wk									0.89
0	919	36.4	266	36.6	258	35.9	395	36.5
1–6	901	35.6	261	36.0	257	35.7	383	35.4
7–12	457	18.1	132	18.2	137	19.1	188	17.4
13–21	251	9.9	67	9.2	67	9.3	117	10.8
Hx smoking									0.07
Never	1,123	44.4	337	46.4	338	47.0	448	41.4
Past	1,331	52.7	364	50.1	362	50.4	605	55.9
Current	74	2.9	25	3.4	19	2.6	30	2.8
Hx peptic ulcer									0.97
Yes	112	4.4	32	4.4	33	4.6	47	4.3
No	2,416	95.6	694	95.6	686	95.4	1,036	95.7
Hx stroke									0.54
Yes	29	1.1	11	1.5	7	1.0	11	1.0
No	2,499	98.9	715	98.5	712	99.0	1,072	99.0
Hx transient ischemia		100.0	726	100.0	719	100.0	1,083	100.0	0.64
Yes	88	3.5	23	3.2	23	3.2	42	3.9
No	2,440	96.5	703	96.8	696	96.8	1,041	96.1
Hx coronary artery bypass		100.0	726	100.0	719	100.0	1,083	100.0	0.82
Yes	106	4.2	29	4.0	33	4.6	44	4.1
No	2,422	95.8	697	96.0	686	95.4	1,039	95.9
Hx angina									0.83
Yes	110	4.4	34	4.7	29	4.0	47	4.3
No	2,418	95.6	692	95.3	690	96.0	1,036	95.7
Hx congestive heart disease		100.0	726	100.0	719	100.0	1,083	100.0	0.22
Yes	22	0.9	10	1.4	5	0.7	7	0.6
No	2,506	99.1	716	98.6	714	99.3	1,076	99.4
Hx myocardial infarction									0.12
Yes	130	5.1	39	5.4	27	3.8	64	5.9
No	2,398	94.9	687	94.6	692	96.2	1,019	94.1
Hx emphysema or COPD									0.27
Yes	86	3.4	23	3.2	31	4.3	32	3.0
No	2,442	96.6	703	96.8	688	95.7	1,051	97.0
Hx osteoarthritis	2,528	100.0	726	100.0	719	100.0	1,083	100.0	0.61
Yes	751	29.7	209	28.8	209	29.1	333	30.7
No	1,777	70.3	517	71.2	510	70.9	750	69.3
Hx rheumatoid arthritis	2,528	100.0	726	100.0	719	100.0	1,083	100.0	0.59
Yes	50	2.0	16	2.2	11	1.5	23	2.1
No	2,478	98.0	710	97.8	708	98.5	1,060	97.9
Hx other non-aspirin NSAID (any dose) or aspirin (>81mg/day)									0.72
Yes	435	17.2	121	16.7	120	16.7	194	17.9
No	2,093	82.8	605	83.3	599	83.3	889	82.1
Histamine H2-receptor use									0.06
Yes	64	2.5	11	1.5	25	3.5	28	2.6
No	2,464	97.5	715	98.5	694	96.5	1,055	97.4

The gender mix was 54:46 male to female. The corresponding mix in the U.S. (2000 Census data) is 39:61. The under-representation of women relative to their numbers in the general population is likely the result of the exclusion of people requiring regular treatment for the pain of arthritis – a condition more common in women than men.¹³

The population enrolled was predominantly white (97%) in spite of efforts to recruit minorities.

Over 3/4ths of the enrolled population had some college education with over 40% having earned a college degree – roughly twice the percentages in the corresponding U.S. population for people aged 70 −74.¹⁶

Nearly 3/4ths of the population enrolled were married on entry. About 7% reported being divorced, about the same as for similarly aged people in the U.S. population (http://www.census.gov/acs/www/; accessed 31 March 2008).

About 70% of the enrolled population consumed 6 or fewer drinks per week.

Less than 3% were cigarette smokers on entry. The corresponding figures for the U.S. population for people aged 65 and over was 8.3% as per the National Health Interview Survey, January-June 2007 (http://www.cdc.gov/nchs/data/nhis/earlyrelease/200712_08.pdf; accessed 31 March 2008). Forty-four percent reported never having smoked cigarettes.

About 17% of the enrollees reported having used non-aspirin NSAID (any dose) or aspirin (>81mg/day) aspirin in the past.

10 Postscripts

The impetus for ADAPT was driven by observational data suggesting that use of NSAIDs may reduce the incidence of AD and age-related dementia.¹⁷ By the time the trial was funded, NSAIDs capable of inhibiting activity of the COX-2 enzyme – an enzyme responsible for pain and inflammation – were available¹⁸ (NDA application 20–998; FDA approval 31 December 1998; http://www.fda.gov/cder/foi/nda/98/20998AP_appltr.pdf; accessed 31 Mar 2008). As is often the case, the newest drug is the one viewed as having the most promise. The promise in this case came from the hope that this class of drugs would have less GI toxicity than non-selective COX-2 NSAIDs. That promise is what ultimately led investigators to include a member of that class in ADAPT – celecoxib. But that decision was also the source of difficulties in ADAPT. These difficulties started in September of 2002 with a petition to the Secretary of Health and Human Services (HHS) that ADAPT be stopped because of generic concerns regarding the safety and adequacy of celecoxib. That petition was ultimately rejected, but concerns regarding the safety of the COX-2 inhibiting drugs were raised anew when Merck decided to withdraw another COX-2 inhibitor, rofecoxib (Vioxx®) from the market in September of 2004 because of newly revealed cardiovascular risks. That decision prompted the need for a letter to participants in ADAPT informing them of the withdrawal and that one of the drugs in ADAPT was a member of the COX-2 inhibiting class of drugs. The ADAPT Treatment Effects Monitoring Committee (TEMC) routinely reviewed both safety and efficacy data at its regular meetings, including its meeting of 10 December 2004. On all occasions the TEMC recommended continuation of the trial without modification. The recommendation made on 10 December was based on data gathered through 1 October 2004, but it was also clear that they saw little prospect for continuing much beyond its spring meeting unless signs of benefit started to appear.

Seven days after the meeting, on the morning of Friday 17 December a Study Officer (Director of the Coordinating Center) was informed by telephone by a representative of Pfizer, the supplier of celecoxib for ADAPT, that it was going to announce later that day that a placebo-controlled trial of celecoxib for prevention of colon polyps was being stopped because excess cardiovascular risk in the celecoxib-treated group.¹⁹ That information was relayed by the director of the ADAPT coordinating center to the ADAPT steering committee later that day in a conference call. It was during that conference call that the investigators voted to suspend treatments pending further review. The option of suspending the celecoxib treatment and continuing the naproxen treatment and its placebo was considered but rejected, since doing so would have required unmasking treatment assignments. As it turned out, even if the investigators had decided to continue the treatments, they would have been ordered six days later to suspend them when the FDA issued clinical holds on all Celebrex prevention trials (www.fda.gov/bbs/topics/ANSWERS/2004/ANS01336.html; accessed 3 April 2008; investigators notified of hold by phone 23 December 2004; see ADAPT website for letter; www.jhucct.com/adapt). The hold for ADAPT was to remain in effect until the FDA was satisfied with revision of the investigator brochure and consent documents, re-consent procedures for people already enrolled, and revision of the protocol to "ensure adequate monitoring and assessment of cardiovascular events across treatment arms".

ADAPT policy was to publish results leading to any major protocol change. Hence, once investigators voted to make the suspension permanent (see Table 2 for dates), they set about preparing a paper summarizing the cardiovascular data accumulated in ADAPT. As it turned out, it would take repeated tries with various journals before results were published (see Table 10). The reasons for rejection were that the differences, though in the wrong direction, were not "statistically significant" and hence not "believable", that the results were based on raw counts without independent reading, and that the results were somehow tainted because the decision to stop was not the product of a formal recommendation from the ADAPT TEMC. Some of these issues are raised in an accompanying commentary to the ADAPT publication by Nissen and in a reply to those comments by ADAPT investigators.^20,21

Table 10.

Efforts to publish ADAPT cardiovascular and cerebrovascular data

Event	Date
	D	E
Study treatment suspended	17 Dec	2004
Treatment suspension made permanent	31 Mar	2005
Submission of safety manuscript to New Engl J Med	5 May	2005
Rejection by New Engl J Med	25 May	2005
Submission of safety manuscript to JAMA	13 Oct	2005
Rejection by JAMA	9 Nov	2005
Submission of safety manuscript to Arch Int Med	21 Nov	2005
Rejection by Arch Int Med	1 Dec	2005
Submission of safety manuscript to Lancet	22 Dec	2005
Request for revisions from Lancet	16 Jan	2006
Submission of revised manuscript to Lancet	2 Feb	2006
Rejection by Lancet	20 Mar	2006
Submission of safety manuscript to BMJ	30 Apr	2006
Rejection by BMJ	18 May	2006
Submission of safety manuscript to PloS Clinical Trials	25 Jun	2006
Request for revisions from PLoS Clinical Trials	25 Jul	2006
Publication of Salpeter et al meta-analysis22	Jul	2006
Submission of revised manuscript to PloS Clinical Trials	15 Aug	2006
Second request for revisions from PLoS Clinical Trials	5 Sep	2006
Submission of second revision to PLoS Clinical Trials	11 Sep	2006
Acceptance of safety manuscript by PLoS Clinical Trials	29 Sep	2006

Interestingly, results from ADAPT along with results from several other studies were published in 2006 prior to our own publication in a paper by Salpeter et al.^22,23,24,25

A meta-analysis involving cardiovascular safety data from ADAPT and five other celecoxib-placebo controlled trials was published in early 2008.²⁶