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Trials of hypertension prevention phase I design
Trials of Hypertension
Prevention
Phase I Design Suzanne Satterfield, MD, Jeffrey A. Cutler, MD, Herbert G. Langford, MD, William B. Applegate, MD, Nemat 0. Borhani, MD, Erica Brittain, PhD, Jerome D. Cohen, MD, Lewis H. Kuller, MD, Norman L. Lasser, MD, Albert Oberman, MD, Bernard Rosner, PhD, James 0. Taylor, MD, Thomas M. Vogt, MD, W. Gordon Walker, MD, and Paul K. Whelton, MD, for the Trials of Hypertension Prevention Collaborative Research Group Phase I of the Trials of Hypertension Prevention (TOHP) wus a Nutionul Heurt, Lung, and Blood Institute-sponsored, 3-yeur, natlonul, multicenter, randomized, controlled trial designed to test the feasibility and efjicay of three life-style (weight loss, sodium restriction, and stress management) and four nutntlon supplement (calcium, mugnesium, fish oil, and potassium) interventions aimed at lowering diastoltc blood pressure in those whose blood pressure wus initially in the high normal range (80 to 89 mm Hgj. A total of 2 182 eo 1un teers were recruited and allocated to the various treatment urms, such that each hypothesis was tested with a power of 85%) or higher to detect a diastolic blood pressure treutment effect of 2 mm Hg. The four nutrition supplement interventions were delivered in a double-blinded f us h’ron und the three life-style interventions, single (observed) -blinded. Phase I tL)as designed to provide u rigorous test of short-term lowering of blood pressure for each of the seven treatments chosen and proslides the basis for planning of a subsequent long-term trial of hypertension prevention. Ann Eptdemiol I99 I ; I :455471. KEY WORDS:
Hypertension.
prevention.
nonpharmuco&c
interzbenrion.
INTRODUCTION Phase I of the Trials of Hypertension ter, randomized of several (DBP)
nonpharmacologic
in the high
cooperative
Prevention
trial of 3-years’ duration normal
agreements
interventions range
testing
(TOHP)
aimed at lowering
(80 to 89 mm Hg).
with the National
was a US national,
the feasibility
Heart,
The
multicen-
and short-term
efficacy
diastolic
pressure
blood
trial was funded
Lung, and Blood Institute
through (NHLBI)
From the Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (S.S., J.O.T.); D’IVISIO~ of Epldemwlogy and Clinical Applications, National Heart, Lung, and Blood Institute. Bethesda, MD (J.A.C., E.B.); Department of Medune. University of Mississippi, Jackson, MS (H.G.L.); Department of Preventive Medicine, UnlversltyofTennessee, Memphis, TN (W.B.A.); Department of Community Medicme, University of Cahfomia, Davis, CA (N.O.B.); St. LOUIS University School of Medicine, St. Louis, MO (J.D.C.); Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Plrtsburgh, PA (L.H.K.); New Jersey Medical School, Newark, NJ (N.L.L.); Division of General and Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL (A.O.); Department of Preventive Medicine, Harvard Medical School, Boston, MA (B.K.); East Boston Neighborhood Health Center, East Boston, MA (J.O.T.); Kaiser Permanente Center for Health Research, Portland, OR (T.M.V.); and The Johns Hopk Ins University School of Hyg:lene and Public Health, Baltimore, MD (W.C.W., P.K. W. ). This article IS dedicated by the Trials of Hypertension Prevention (TOHP) investigators to the memory of Herbert Langford, MD, who died on January 26, 199 I and served as Chairman of Phase I. Address reprint requests to: Suzanne Satterfield, MD, TOHP Coordinating Center, Brigham and Women’s Hospital, 55 Pond Avenue, Brookhe, MA 02146. Received Aprd 30, 1990; rewsed February 12, 199 1. c 1991 Elsev~er Science Publishmg Co., Inc.
1047.279719l/$fi7.50
456
Satterfield et al.
AEP Vol. I,No.5 August 1991: 455-471
TOHPPHASEI DESIGN
as the first phase
for a larger
trial of hypertension
prevention.
Ten
clinical
centers
across the United States and a coordinating center, which included central laboratories and a nutrient data center, were selected by peer review. A lo-month planning phase
was initiated
randomization completed
in Septemher
wab completed
on January
1986. R ecruitment by October 4, 1988.
12, 1990, and the average
began on August 3, 1987, and End point data collection was
period of follow-up
was approximately
18 months.
BACKGROUND Approximately
20% of the adult population
(BP) (l),
pressure myocardial been
a major risk factor
infarction
and congestive
demonstrated
in descriptive
cohort,
in many
specific
determinants
environmental factors,
countries
including
diet,
recognized
that altered
1988 reports
of the Joint of High
interventions
especially
for whom Recent
treatment
reports
Evidence
that
trials
(HCP)
small
and the Dietary
trials randomized
of whether
previously
tervention
or follow-up
determine
if hypertensives
macologic
treatment
sample
can
Detection,
and
care limit
the
1984 and
Evaluation
and
the use of nonpharmacologic with very mild hypertension, risks than
Study
tested
lower
benefits
(11,
12).
interventions
might
in individuals
at risk
BP derives
size of middle-aged
of these include
diastolic Program
(14,
15). Both
to a nonpharmacologic
objective
without
with
from
Control
(DISH)
hypertensives The
primarily
subjects
the Hypertension
in Hypertension
intervention.
HCP
Both
of hypertension
could be maintained
alone.
and
life-style
(13-16).
well-controlled
without
genetic that
of hypertension
nonpharmacologic
therapy
Intervention
and While
it is also increasingly
(8-10).
on the
the development
The most important
both
and costs of medical
of individuals
nonpharmacologic
of relatively
hypertension.
toxicity,
may pose greater
of this disorder
(2-4).
has accrued
H owever,
have recommended
medication
in preventing
development
understood,
have
case-control
and sex groups
drug therapy
in the treatment
with
relationships
both
in the treatment
(5-7).
Committee
Pressure
blood
including
role.
of life, potential
raised the question
also be of value for future clinical
Blood
disease,
These
evidence
therapy
antihypertensive National
has elevated
heart
studies,
yet fully
well established
quality
of lifelong
(2-4).
age, race,
Substantial
may play a major
the usefulness Treatment
most
of pharmacologic
has been
failure
BP are not
play a role.
The effectiveness its complications
heart
States
and coronary
as well as analytic
and across
of high
factors
in the United
for stroke
of both
medication
the effectiveness
trials
inwas to
but with nonphar-
of a combined
reduction
calories, sodium, and alcohol intake in previously well-controlled hypertensives After 4 years, 39% of the active, compared to only 5% of the control group, normotensive
without
and sodium
restriction
rates,
weight
normal
with
weight
antihypertensive separately
loss in overweight
(15). Recently,
medication.
DISH,
in mild hypertensives, subjects
and
which
reported sodium
the Trial of Antihypertensive
tested
weight
the highest
reduction
of
(14). were loss
success
in subjects
of
Interventions
and Man-
agement in overweight mild hypertensives reported the greatest reduction weight loss was combined with antihypertensive medication (16). In the last 10 years, a few trials tested the benefit of nonpharmacologic
in BP when interven-
tions in populations with BP in the normal range. One of the most recent of these, a 5-year trial of 201 overweight subjects with BP in the high normal range used a multifactorial intervention that combined weight loss, alcohol reduction, sodium
Satterfield et al. TOHP: PHASE I DESIGN
AEP Vol. I, h’u. 5 August 1991: 455-471
reductron,
and exercise
loss. The other
(17). BP reduction
relatively
macologic
treatment
Prevention
Trial
population
and achieved
goals of sodium
was related
particularly
large trial (841 participants)
in a population (HPT)
(18).
with BP in the normal
Thus trial was successful
its goal in weight
reduction
or potassium
BP was seen in the weight
testing
loss (net weight
efficacy style
prevention
of various
trials.
net decline
in
(1.8 mm Hg DBP, and 2.4 mm Hg systolic
BP
sodium
chosen
reduction,
The
supplement
in reducing
Although
some
in reducing
in a large cohort.
Randomized
but there
The four nutritional calcium
(32-34),
randomized these The
decision
intervention intervention
The
weight
trials
suggested
no trials selected
(3%37),
a nutrition
in previous
included
and
supplementation
rather
out in hyperten(24-28).
potassium While
showed
(29-3
some would
dietary
l),
previous lower BP,
inconsistent
than
studies
of moderate
individuals
of these supplements
short-term,
loss,
this conclusively
were carried
and fish oil (38-41).
and
life-style
weight
the efficacy
in nonhypertensive
that administration
to be small
life-
loss was the intervention
trial established
for evaluation
three
were
the
three
results. counseling
strategy was based on the knowledge that adherence to dietary counseling is often disappointing (18) and on our desire to provide an optimal test
of the hypothesis. ability
tested.
trial,
of TOHP
trials of stress management
magnesium
to choose
Of these,
BP (22, 23), no previous
supplements
tended
were
first phase
controlled
have been
trials suggested
studies
any of the previous
BP had been most firmly established
small,
sodrum reduction sive subjects,
in the
than
for use in a larger
interventions
for evaluation
largest
aim of the trial was to determine
regimens
and stress management.
whose effectiveness (19-21).
Since the primary
nonpharmacologic
and four nutrition
interventions
a normotensive
loss, 7.7 lbs), but not its
(SBP) after 3 years of follow-up). The first phase of TOHP was larger (2182 participants) hypertension
of weight
of nonphar-
range was the Hypertension in recruiting
supplementation.
loss groups
to degree
the efficacy
457
to achieve
However, similar
our choice
changes
of supplement
by dietary
dosage
was predicated
on an
counseling.
OBJECTIVES The overall
objective
nutritional
and behavioral
among
individuals
The
specific
of the first phase of the TOHP interventions
with high normal aims originally
was to determine
were feasible
and effective
levels of DBP (defined
2.
To evaluate
BP
were:
the level of adherence
with the interventions
centers
to recruit
over a 27- to 36-
period.
3. the trend
To determine
the efficacy of these nonpharmacologic
in DBP change
over time
4. To assess the feasibility prevention. 5. training
selected
in lowering
as 80 to 89 mm Hg).
1. To assess the ability of each of the ten participating clinical and randomize at least 200 participants over a period of 9 months. month
whether
in a favorable
of proceeding
interventions
in altering
direction.
with a full-scale
trial of hypertension
To develop and evaluate the organizational components, logistical support, materials, and study forms for the implementation of a long-term, full-scale,
nonpharmacologic
trial.
In actuality, recruitment lasted for 13 months rather than 9, follow-up was phased out rather than continued to a common termination date, 5 months were reserved for
458
Satterfield et al. TOHP: PHASE I DESIGN
AEP Vol. I, No. 5 August 1991: 4.55-471
Randomization (2.182)
Lifes;**
)
Supple yams
stage 1
I
I
I
Weight Loss
I
I
I
I
Calcium
Magnesium
Sodium
Stress
Control
(327)
(242)
(589)
(237)
(308)
I Control
(2271
(234)
(19) stage 2 I
I
Fish Oil
Potassium
I
(178)
Control (1751
(175)
1 Randomization scheme for phase I of the Trials of Hypertension Prevention. The total numher randomized, 2182, includes 18 participants randomized directly into stage 2 of the supplements intervention. (See text for complete discussion of randomization.)
FIGURE
transition
to phase
II. As a resclt,
the follow-up
period
was 18 months
rather
than
27
to 36 months.
DESIGN
This trial tested (Figure
a broad range of interventions
1). The allocation
style and supplement of its promise allocations
hypothesis,
to the life-style allocations
to provide
with a particular
to the supplement
and
intervention
test of each life-
restriction
investigations.
were 300 participants
management,
size of 2182 subjects
a reliable
focus on sodium
results from earlier
interventions
loss, 225 in stress
in a fixed sample
was designed
but lack of conclusive
315 in weight projected
scheme
in sodium
560 in the control
because
The projected restriction, group.
were 234 to each active
The
supple-
ment
and 232 to the placebo group. The allocation schemes with the actual numbers randomized in phase I of TOHP are shown in Tables I and 2. All of the clinics tested a subset of the interventions.
Three
clinics
clinics
restriction subjects),
tested only life-style
participated (327
in both subjects),
and four tested
interventions,
arms of the trial. six tested
the
two tested Six clinics
value
of a weight
the value of a stress management
(see Table I). Each clinic provided one common interventions. This control group was allocated
only supplements, tested
and five
the value of sodium
loss intervention
intervention
(308
(242 subjects)
control group for both of its life-style a larger number of participants (589
subjects) than the active treatment groups because the weight reduction group could only be compared to the high weight subset of control participants (256 subjects) and not the entire group of controls.
459
Satterheld et al.
AEP Vol. I, No. 5 August 1991: 455-471
TOHP:
TABLE 1 randomized
Allocatic:n of TOHP participants, into
life-style
Weight reduction
66
60 63
69
45
49 47 63
42
Seven
of the ten clinics
and two tested
participants
participated
supplements
were allocated
m the nutritional
diglycine/d,
5013 placebo
or magnesium
potassium
as Chelazomes), placebo);
of participants
the eligibility
stage
1, medical
tested
both life-style
fatty
history
regarding
and supplement
assigned
placebo)
and
the failure
trial,
control
to receive
magnesium
placebo
(either
group calcium
(360 mg OS-Cal
175 were randomized
to
178 to receive
175 to receive
placebo
2). The somewhat
of some
stage
(either smaller
1 participants
in stage 2, such as compliance
disorders,
interventions
arm of the
as Promega),
(see Table
for inclusion bleeding
stage,
acidsid,
as K-DurZO),
necessary
or a common
and 234 to receive
in stage 2 reflects
criteria
supplements
500), 227 to receive
in the second
mg of omega-3
or olive oil as Promega
meet
Life-style control
stages of the supplements
were randomly
as O&al
(60 mEq of potassium/d,
K-Dur placebo number
(3000
In both
to one of the two supplements
calcium/d,
of magnesium
fish oil
of suhlecta
Stress management
exclusively.
(see Figure 1). In the first stage, 137 subjects
( 1000 mg of elemental
receive
numbers
66 32 3118
33 3.27
trial,
(actual
interventions)
Sodium reduction
Clinic
by clinic
PHASE I DESIGN
and BP. The
maintained
five clinics
separate
control
to in that
groups
for each arm of the trial. Both the life-style ment
TABLE 2 supplement
procedure,
Allocation
of TOHP
and the supplement
eligibility
participants,
and exclusion
arms of the trial shared criteria,
by clonic (actuC~l numbers
and parallel
of subjects
a common
recruit-
data collection
sched-
randomired
mtcl
interventions)
Stage 1 Calcium
Magnesium
27
?i?
il 23 I7 21 _
48 22 I4 22
92 11 ?3i
11 ZZi
Stage 2 Placebo
Potassium
Fish oil
Placebo
460
TABLE
AEP Vol. 1. No. 5 August 1991: 455-471
Satterfield et al. TOHP: PHASE 1 DESIGN
3
Sample
size and power” DBP Size of comparison
Intervention
A for 80% power
Active
Control
327 308 242 237 227 lit?
417 256 323 ‘34 234 175
Iii
iii
ules.
However,
substantially
(mm
the
Hg)
consisted
required
life-style
to implement
The supplement tirst stage, numbers pants
period
of intense
through
run-in
tish oil, potassium,
SAMPLE
SIZE
AND
changes
period
and then
the
interventiona
Life-style
with
individual
intervention,
mainte-
and placeho-controlled.
to be as similar
participants
or placebo.
were
design.
were randomized
At the end of 6 months,
of approximately
the same participants
10 weeks,
This
as possible.
which
were rerandomlzed
In the in equal partici-
doubled
as a
to receive
or placebo.
POWER
The sample control
period,
calcium,
a washout
period,
were designed
run-In
magnesium,
.Y! .‘)I .KI .K
followed t7y a less intensive period of follow-up.
were double-hlinded
which
after a 6- to 8-week to receive
went
second
interventions
of two stages,
98
.93 .‘I3
arm of the trial had an open
of an initial
Power for A=3mmHg
Hs)
2.12 2.42 2.44 !.iL? ?.iY 2.Y7 2.w
.Y4 .86 .K6
and group counseling, lasting from 2 to 3 months nance period for the remainder of the 18smonth arm consisted
(mm
.YY .Y6 .Y6 .Y4
methodologies The
A for 80% power
Power for A= 2mmHg
1.32 I.51 1.52 I.@ 1.61 I.84 1.85
different.
interventions
SBP
sizes and corresponding
comparisons
are presented
m mean BP represent
calculated
using the following
power estimates fc>r each of the intervention and fc>r determining 3. Th e p ower calculations
in Table
two-sided
tests with ;I significance
level of .05 and were
formula:
where: ] = the area to the left of [ ] on the standard
@[
normal
curve
CY = 0.05 Z,_,r:J
=
1.96
d = th e expected son groups
difference
in BP change
between
the intervention
CJ = standard error of change in BP; 6.17 for supplements for change in DBP, and 9.98 for supplements and change
in SBP
11, = the number
m the active
intervention
group
and compari-
and 6.36 for life
Satterfield et al.
AEP Vol. 1, No. 5 August 1991: 455-471
461
TOHP: PHASE I DESIGN
no = the number
in the corresponding
control
group
The variances of the change in mean BP from baseline to termination were estimated based on data from the Hypertension Detection and Follow-up Program (HDFP) (42, 43) and on tracking correlations for a population in Wales (44) and another industrial population (45) (details are provided in Appendix 2). Since both baseline and termination BPS were averages of nine measurements, taken at three visits with three readings per visit, the variability of the BP measure was minimized, thus favorably affecting the power of the trial to detect true differences. Original power estimates, based on projected sample sizes, provided for at least 94% power to detect a 2-mm Hg change in DBP and at least 91% power to detect a 3 -mm Hg change in SBP. In addition, the projected sample sizes allowed for detection of changes of 1.6 mm Hg in DBP and 2.5 mm Hg in SBP with 80% power. As shown in Table 3, with the actual numbers randomized, all tests had at least 86% power to detect a 2-mm Hg change in DBP and at least 80% power to detect a 3-mm Hg change in SBP.
SCREENING AND RANDOMIZATION
Screening The aim was to screen men and women aged 30 to 54 years who had no evidence of medically diagnosed hypertension, gross obesity, or other exclusion criteria (Table 4). The most important eligibility criterion was BP. At each visit, three BP measurements were recorded. The cumulative average of the readings for DBP had to fall within the following predetermined ranges for participants to proceed to the next screening visit (SV): SV 1: DBP 75 to 97 mm Hg (average of three readings). SV 2: DBP 77 to 94 mm Hg (average of six readings). SV 3: DBP 80 to 89 mm Hg (average of nine readings). Thus, for a participant to be declared eligible at the end of the third screening visit, the average of all nine DBP measurements obtained at screening visits 1, 2, and 3 had to be within the range of 80 to 89 mm Hp. During screening visits, participants were weighed and body mass index (BMI), defined as kg/m2, was used to determine eligibility. Those participants who had a BMI greater than 36.14 (approximately 160% of ideal body weight) were excluded. Those eligible for inclusion were further classified into high- (BMI of 26.08 to 36.14 for men and 24.26 to 36.14 for women) and low-weight strata (BMI < 26.08 for men; ~24.26 for women) for randomization. Compliance was an eligibility criterion, assessed in the following ways: (1) ability to complete and return a satisfactory 24-hour urine collection and food frequency questionnaire (all subjects), and (2) ability to take 66% or more of prescribed nutrition supplement pills during a 6-week placebo run-in phase (supplements only). Final decisions on eligibility were made at the status review visit (SRV).
Randomization The preliminary steps of the randomization procedure varied according to the types of intervention offered at a given clinic. Those clinics conducting only life-style interventions proceeded immediately to randomization, while those conducting only
462
AEP Vol. 1, No. 5 August 1991: 455-471
Satterfield et al.
TOHP:
PHASE I DESIGN
TABLE 4
Exclusion
criteria
1. Evidence of current hypertension, as defined by nine baseline DBP readings averaging 90 mm Hg or greater, or current use (within the previous 2 months) of antihypertensive medications. 2. Diastolic BP < 80 mm Hg, based on the average of nine readings. 3. Gross obesity, BMI 2 .0514 lb/in’ (36.14 kg/m*). 4. History of any cardiovascular disease, including myocardial infarction, angina, intermittent claudication, congestive heart failure, and stroke. 5. History of diabetes mellitus, defined by self-report or ever use of insulin or oral hypoglycemic agents. 6. History of chronic renal failure and/or kidney stones. 7. Recent history of psychiatric disorders, defined by hospitalization within the previous 5 years for such a condition or current use of antipsychotic or antidepressant medications. skin cancer) in past 5 years. 8. History of malignancy (other than nonmelanoma 9. Serious physical handicaps, including severe arthritis, blindness, or other handicap, that would contraindicate participation in any of the TOHP interventions. 10. Current alcohol intake of more than 21 drink&k. disease, such as peptic ulcer, diverticulitis, ulcerative colitis, 11. History of chronic gastrointestinal inflammatory bowel disease, or other conditions judged by study clinician to be a contraindication to admission to TOHP. 12. Any other serious or life-threatening illness that requires regular medical treatment. 13. Current use (within the past 2 months) of medications that could interfere or interact with study interventions, including diuretics, beta-blockers, and anticoagulants. 14. Serum cholesterol level 2 260 mg/dL, as determined by local laboratory. 15. Serum creatinine level 2 1.7 mg/dL for men or 1.5 mg/dL for women. 16. Casual serum glucose 2 200 mg/dL. 17. Unexplained hyperkalemia. 18. Hypercalcemia, as determined by local laboratory. 19. Unwillingness to discontinue use of preparations of any of the micronutrient supplements being tested in TOHP. 20. Unwillingness to discontinue a dietary regimen incompatible with TOHP interventions, such as a medically supervised diet or a formal weight loss program. 21. For women, current pregnancy or intent to become pregnant during the study period. 22. Current participation in other ongoing clinical trials or prior participation in an active intervention group in the Hypertension Prevention Trial. 23. Participation of another household member in TOHP; TOHP employees; persons living with TOHP employees. 24. Plans to move out of the study area (generally defined as ~50 miles from the study site), such that it would be difficult to come to the study site. 25. Unwillingness to accept randomization into any study group. 26. Inability to cooperate as assessed by clinic staff. 27. Inability or unwillingness to give informed consent.
supplement
interventions
delayed randomization
until after the completion
of the
run-in period to test compliance with pill taking. Clinics conducting both types of interventions utilized a preliminary allocation to one of these two tracks, after which randomization proceeded as at the single-track clinics. Participants in the low-weight stratum were excluded from participation in the weight loss and exercise program or serving as its control but were randomized to all other treatment and control groups. Those
in the high-weight
and controls.
stratum were randomized to all TOHP
The coordinating
center
verified the eligibility
treatment
groups
of the participant
for
randomization on the basis of the data collected at the three screening visits and notified the respective clinical center prior to the date of the SRV. During the SRV, once the participant was also determined eligible on the basis of compliance, the clinic notified the coordinating center by telephone and obtained a randomization assignment. Clinics were also provided with sealed envelopes containing randomization
463
Satterfield et al. TOHP: PHASE I DESIGN
AEP Vol. 1, No. 5 August 1991: 455-471
TABLE 5
TOHP phase I data collection
schedule for life-style interventions
Screening visit
1.
Months of follow-up 3
6
12
L
I
L
L
L
L
L
2
3
BP Weight Demographic Physical activity Health experience Prescription drug
L
General well-being
L
Occupational
Rand
18 L
L
L
L
L L
L
L L
L
L
L
S
S
data S
Hassles scale Cardiovascular
reactivity
Anthropometric Food frequency
L
24-hr recall
L
Blood
L
24-hr urine
L
S
S
S
W
W
W L
L
-
L
L
L
L
L = all life-style participants; S = stress and sample of other life-style participants at stress clinics; W = weight and sample of other high-weight participants; Blood = glucose, cholesterol, creatinine, potassium, and calcium (lo. tally for eligibility); 24-hr urine-sodium, potassium. and creatinine.
assignments possible.
considered
for use when Once
telephone
the assignment
contact
with
was communicated
the coordinating
to the participant,
center
was not
he or she was
officially randomized.
FOLLOW-UP The follow-up visit schedule was, of necessity, relatively complex due to the varied interventions and the differential length of follow-up for life-style and supplement interventions. The data collection schedule for life-style interventions is summarized in Table 5 and the corresponding schedule for nutrition supplement participants, in Table 6. The most important follow-up measure was BP. All follow-up BP values were calculated as an average of nine observations, three readings taken at each of three visits 7 to 30 days apart. For life-style participants, nine BP measurements were taken at baseline, 12, and 18 months, and for supplement participants, nine readings were taken at baseline and 6 months for each stage of the supplement intervention. Interim BP measurements, consisting of three readings taken on one visit, were taken at 3 and 6 months for life-style participants and at 3 months for supplement participants. These interim measures were used primarily for safety monitoring. The final 18-month visits for the life-style arm of the trial were completed by January 12, 1990; the mean follow-up was 75 weeks. Other trial-wide follow-up measurements included pulse rate, body weight measurements, medical histories, physical activity questionnaires, the Psychological General Well-Being Scale, demographic and participant contact information, and urine samples (see Tables 5 and 6). Additionally, for supplements, information on side
464
Satterfield et al. TOHP: PHASE I DESIGN
TABLE
6
TOHP
AEP Vol. 1, No. 5 August 1991: 455-471
phase 1 data collection Stage
schedule for supplements
interventions
1
Stage New baseline
Screening visit 1 BP
s
Weight Demographic Physical actlvlty Health expenence PrescriptIon drug
S S
General
2
6 mo
3 mo
Rand
s
s
S
s
2
1
Rand
s s s
s
3
6
mo
mo
S S
S
S
S S
S S
S
S
data
S S
24-hr
S
recall
Blood
S S S S
S urine
Side effects
3
S
S
Food frequency
24-hr
Washout 10 wk
S
well-being
Occupational
3
2
S assess.
S S
S
Pill count
S
effects
was obtained,
Table
6).
ASCERTAINMENT
and pill count
data were collected
SF
S
S
S S
as a compliance
measure
(see
OF END POINTS
Primary
End Points
The primary
end point
of this trial was change
of the fifth Korotkoff
sound),
end point
in SBP (defined
was change
Initially,
uniform
recertification random
SF
from baseline
training
was performed
as the appearance
and certification at 6-month
zero sphygmomanometer.
To minimize
When
possible,
tion visits as compared
Intermediate
separate
facilities
to intervention
as the disappearance
visits.
The other
of the first Korotkoff
of BP observers
intervals.
ment allocation. Persons certified to measure aspects of the trial, nor were they allowed assignment.
in DBP (defined
to final follow-up
were required,
BP recordings
bias, observers
major sound).
were made
were blinded
and with
BP were not involved with intervention access to data that would reveal group or entrances
were used for data colllec-
visits.
End Points
Intermediate end points tions. Twenty-four-hour
were selected to evaluate implementation of specific intervenurine samples were used to monitor sodium reduction, as well
as magnesium, calcium, and potassium supplementation. For the sodium intervention group, five 24-hour urine samples were obtained-two before randomization and three after randomization. from all other
a
to treat-
life-style
Twenty-four-hour participants
urine
samples
to assess confounding.
for sodium
were also collected
In addition,
food frequency
TOHP: PHASE I DESIGN
questionnaire
and 24-hour
all life-style placebo
dietary
participants.
controls,
four 24-hour
hour urine samples tion.
For the
composition The loss.
group
determined
Psychological specific
included
General
Lazarus’ Hassles
group,
for the
Well-Being Scale.
These
acid
three
24-
phospholipid for 50% of the
a trial-wide
group
was weight
measurements,
which
loss intervention, group
measure,
reactivity
were
80% of the
in other intervention
management
Cardiovascular
were
groups.
scores
on the
and the intervention
to mental
stressors
was also
from all participants in the stress manageand 20 %I of those in other interventions
controls,
also offered
fatty
reduction
and girth individuals
stress
data were obtained
which
plasma
and was determined
to the weight
Scale,
80% of their life-style
in the four centers
before randomization and two after randomiza-
for the weight
skinfold
randomized
points
from
as well as their
controls.
end point
and 20% of high-weight
end
used as a measure. ment
fish oil and their
controls,
Intermediate
end point
were obtained
and their controls,
before randomization
fish oil supplement,
for all participants
high-weight
participants
receiving
end points
intake
participants
were obtained-two
intermediate
Secondary
calcium
urine samples
as the intermediate
receiving primary
of sodium
and
For potassium
were obtained-one
served
participants
recall estimates
For magnesium
and two after randomization.
QUALITY
465
Satterfield et al.
AEP Vol. 1, No. 5 August 1991: 455-471
strebs management.
CONTROL Extensive
efforts were made to control
tee of the trial,
the Data Collection
to review quality control to requiring sessions,
reports
centers.
In addition,
Assurance
and performance
digit
preference,
collection
produced
met regularly
centers.
staff in training
data
rates were regularly
subcommit-
Committee,
of the clinical
of all data collection
monitoring
and follow-up
of study data. A standing
and Quality
procedures
the participation
compliance,
the quality
error
rates,
and distributed
two site visits were made to each clinic
In addition
and certification protocol
to the clinical
to assess compliance
with
the protocol.
STUDY
ORGANIZATION The
ten clinics
involved
more, Maryland;
nia, Davis, California; chusetts;
University
Memphis, Portland, Center
of
Oregon;
Jackson,
New Jersey Medical Pennsylvania;
Health
School,
Hospital,
Balti-
ofCalifor-
East Boston,
University
Massa-
of Tennessee,
New Jersey; University
Center
St. Louis,
Women’s
University,
University
Center,
Newark,
Kaiser Permanente
and
Hopkins
Alabama;
Mississippi;
and St. Louis University, at Brigham
at Johns
Birmingham,
East Boston Neighborhood
Pittsburgh,
was located
were located
Alabama.
of Mississippi,
Tennessee;
Pittsburgh,
in TOHP
Uni+ersity
for Health
Missouri. Harvard
The
of
Research,
Coordinating
Medical
School,
Boston, Massachusetts, as was the special laboratory responsible for analyses for stage 2 of the supplement arm. The Nutrition Data Center was located at Tufts University, Boston,
and the central
Minnesota,
Minneapolis,
An Executive
laboratory
for clinical
studies
was located
at the Unilrersiry
of
Minnesota.
Comnnttee
\vas formed,
and consisted
of the chairpersons
of four
subcommittees (Design and Analysis, Data Collection and Quality Assurance, Interventions, and Publications and Presentations), the NHLBI Project Officer, the Coordinating Center Director, and the Study Chairman. The Executive Committee’s function
466
Sacterfield et al.
AEP Vol. 1, No. 5 August 1991: 455-471
TOHP: PHASE I DESIGN
was to resolve any operational problems arising between Steering Committee meetings. The Study Chairman, elected by the Steering Committee, served as Chairman of both the Steering Committee and the Executive Committee. The trial was directed by a Steering Committee composed of one representative from each of the clinics as well as from the Coordinating Center and NHLBI. Each unit had one vote, usually cast by the principal investigator. Six subcommittees reported regularly to the Steering Committee: Design and Analysis, Eligibility and Recruitment, Interventions, Data Collection and Quality Assurance, Publications and Presentations, and Clinic Coordinators. The Data and Safety Monitoring Committee (DSMC) was an external advisory group, appointed by the NHLBI, with the advice of the Steering Committee. The committee reviewed the initial study protocol and monitored study data for treatment effects, either beneficial or harmful, which might warrant alteration or early termination of one or more interventions. The DSMC was also responsible for making specific recommendations to the Steering Committee and NHLBI regarding continuation of the trial, with or without changing the protocol, and for advising on whether to proceed with phase II of TOHP.
SUMMARY Phase I of TOHP was a 3-year, national, multicenter, randomized, controlled trial designed to test the feasibility and short-term efficacy of three life-style and four nutrition supplement single-factor interventions aimed at lowering BP in those with an initial pressure in the high normal range. Following a uniform recruitment, screening, and randomization process, participants were treated and followed for an average of either 18 (life-style interventions) or 6 (nutrition supplement interventions) months. The primary end point was DBP, but careful measurements of SBP and interventionspecific intermediate end points were also obtained. Extensive precautions were taken to ensure the collection of high quality data and the careful monitoring of progress during the trial. Phase I provides a rigorous evaluation of short-term BP lowering for each of the seven treatments tested and provides the basis for planning of a subsequent longer-term trial of hypertension prevention. Phase I of the Trials of Hypertension Prevention was supported by cooperative agreements HL37849, HL37852, HL37853, HL37854, HL37872, HL37884, HL37899, HL37904, HL37906, HL37907 and HL37924 from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The investigators are grateful to Marion Laboratories (Kansas City, MO), Schering-Plough (Miami, FL), and WarnerzLambert (Morris Plains, NJ) for donating pills and calendar packs and to Albion Laboratories (Clearfield, UT) for donating study pills. We also wish to thank Heather Tosteson, PhD, for her role in the preparation of this manuscrim.
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APPENDIX
1
Participating Institutions
and Principal Staff
Clinical Centers-The Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD: Paul K. Whelton, MD (Principal Investigator), Lawrence Appel,
MD, Jeanne
Charleston,
RN, Arlene
Taylor
Dalcin,
RD, Craig
Ewart,
PhD,
AEP Vol. I, No. 5 August IYYI: 455-471
Linda Fried, MD, Delores Steffen,
MPH,
Kaidy, Michael
and W. Gordon
Walker,
J. Klag, MD, Shiriki MD; University
469
Satterfield et al. PHASE I DESIGN
TOHP:
Kumanyika,
of Alabama
PhD,
Lyn
at Birmingham,
Investigator), Karen Copeland, Birmingham, AL: Albert Oh erman, MD (Principal RD, Heidi Hataway, MS, James Raczynski, PhL1, Neil Rappaport, PhD, Mildred Sehn, and Roland Borhani,
Weinsier, MD
MD; University
(Principal
of California
Investigator),
Edmund
at Davis, Bernauer,
Davis, PhD,
CA:
Nemat
Patricia
0.
Borhani,
Carlos de la Cruz, Andrew Ertl, I&g Heustis, Marshall Lee, MD, Wade Lovelace, Ellen O’Connor, Liz Peel, and Carolyn Sugars, RD; East Boston Neighborhood Health Center,
East Boston,
Corkery,
Morri:,, MPH, Jackson,
MA: James 0. Taylor,
Llenis
MPH,
Eleanor
Chantanop,
Goodwin,
G. Langford,
RN,
Stephen
MD, and Shirley
Miller,
burgh,
Milas,
for Health Charles
School of Medicine,
tor),
Julie
School,
Project
MPH,
Minnesota, meyer,
Ivan
Boston,
PhD,
Investigator),
Jay Sullivan,
NJ: Norman
Lee Dolan,
Sheila
of Pittsburgh,
Pitts-
Arlene
Brinkmann,
MA: Charles Cann,
Mayrent,
MD, Heather
W. Caggiula,
and
RN,
PhD,
MAT, PhD,
Tosteson, PhD,
Cook,
MN: John
Elizabeth
Reilly,
Central
RD, and and Har-
Data
Investiga-
Ellie Danielson, PhD, Janet Bernard
MIA,
Lang,
PhD,
Rosner,
Van Denburgh;
RD, Peter
PhD, Project
MD (Scientific Kaufmann,
PhD,
Laboratory-University
PhD (Project
Nutrient
Investigator),
Hospital
Jeffrey A. Cutler,
Farrand,
RD,
Roth,
MD (Principal
ScD,
PhD, and Martin
Belcher,
and Peggy Neibling;
Katherine
Hebert,
PhD;
PhD,
Raker,
MD (Principal
RN,
Patricia
Marilyn
R. Greenlick, Margaret
MA; St. Louis University
H. Hennekens,
Nancy
Eva Obarzanek,
Minneapolis,
Merwyn
and Women’s
Lung, and Blood Institute:
Erica Brittain,
Mills,
PhD,
McKenzie,
Center-Brigham
David Gordon,
Heart, PhD,
Marlene
PhD, and Betsy Wagner,
Cristina
Sherry
Satterfield, Officer),
Memphis, RD, Laretha
Judy Randle,
MA; University
MA, John Givi,
RD, Connie
ScD,
Office-National Ed Lakatos,
of Tennessee,
M. Batey,
MS,
MS, John Kiley,
Amy Brewer,
PhD,
St. Louis, MO: Jerome D. Cohen,
Buring,
MacFadyen,
Suzanne
David
PhD,
RD; Coordinating
Kim Eberlein, Jean
Ernst, Stevens,
Mattfeldt-Beman,
vard Medical
MD, J oe Murphy,
Mary Cameron,
E. Yamamoto, DrPH; Kaiser Permanente Center Investigator), OR: Th omas M. Vogt, MD (Principal
Jack Hollis,
MA, Victor
Lana Shepek,
University
Glare
of Mississippi,
Jennings,
Investigator),
MD (Principal
Portland, Denise
Hertert,
Mildred
King Wright;
RD, and Vera I. Lasser,
Research,
Steve Smith,
Martha
MS, and Monica
Coultrera,
Stephanie
Beth Walker
MPH,
Investigator),
PhD, Stephanie
Investigator),
PA: Lewis H. Kuller,
N. Carole
Investigator),
Keough,
RD; New Jersey Medical School, Newark,
Vossberg,
Pat Kennedy,
Ellen
MD (Principal
MD (Principal
L. Lasser, MD (Principal Hamill,
Mary
Corrigan,
and Nancy
B. Applegate,
MD (Principal
MD,
RN, and Frank Sacks, MD; University
RN, Sheila
MD, Judy Mahalak, William
Evans,
Pistorino,
MS: Herbert
Dianne TN:
A.
Director), Center-Tufts
Andrea
of Dom-
University,
Boston, MA: Margo Woods, ScD (Project Director), B.J. Kremen Goldman, RD, and Elaine Blethen, RD; Lipid L a b ora t ory-Channing Laboratory, Brigham and Women’s Hospital, Boston, MA: Frank Sacks, MD (Director of Lipid Laboratory); Data and
Safety Monitoring
Committee-Jeremiah
Agras, MD, Marianna Fordyce-Baum, Kotchen, MD, Laurence McCullough,
APPENDIX
Stamler,
MD (Chairperson),
PhD, C. Morton PhD, and Ronald
W. Stewart
Hawkins, ScD, Theodore Prineas, MB, BS, PhD.
2
Sample Size-Estimate The variance
of the mean
of Variance BP (x) at either
V[x, = o- ’ = u;
baseline + cr;/N
or termination + a,ZINK
can be written
as:
470
SarterhelLl et ill. TOHP: PHASE 1 DESIGN
where: vIli = between-person &I = between-visit rr;
= within-visit
variance variance variance
N = numher
of visits
K = number
of measurements
Resides these components, variation,
correlation
p = the observed
where
of follow-up
supplement need
3
-
tracking Thus,
the variance
in BP is also affected
of tune.
(x2) can be written
The variance
by temporal of the change
‘I:
“2) = 2CI? (1 -- p) correlation
for the life-style
interventions.
to estimate
=
over periods
(x!) to termination V(x,
months
per vi,lt
the Lrariance of :he ch,lnge
or the tracking
from baseline
= 3
of the BP means
interventions
to estimate
components
over an average
and 6 months
the variance
of follow-up
of the change
and the tracking
of 18 for the
in means,
we
correlation.
1. have
The estimated total variances for BP in black znd white males and females been published (42). These \vere ccw.hmed by t&ing weighted averages using
the race and gender distribution (43).
These
average
of the Hypertension
components
I)c:ectior.
ar,d Follow-Up
Program
for DAP were: u;
= 109.11 26.76
o-1 = fll
zz
r,
= 233.13
cr;
=
43.39
rrf =
13.16
1.41
For SBP they were:
Therefore, (averaged
variance of the mean AI’ at baseline or termmation Vtxjr the estimated over three visits with three readings !)er visit) was 118.85 for DBP and
249.06 for SBP. 2. A study of tracking of .58 for DBPs taken point.
corre!ation
4 years apart.
Data from an indcstrial
of BP in Wales
(44) suggested
popc!ation
(45) suggested
a l-year
for an average of 12 measurements taken at four visits with visit. The tracking correlation observed is heavi!y Influenced and measurements.
a correlation
This was based on a sing!e measurement
The relationship P fr”e = pohs x (u;
of observed + cr,;lN
at each
correlation
of .85
three measurements per by the number of visits
(,o,,,,) to true (o,,,,,) correlation
is:
+ crf/NK)la;
with the variance components defined as previously. These data suggest true 4-year and 1 -year correlations of .85 and .91, respectively. Interpolating to 6 and 18 months, the true correlations in TOHP for DBP were estimated to be .92 and .90, respectively. Given three visits with three measurements each, we expected of approximately .84 (6 months) and .83 (18 months). These
to observe correlations figures led to estimated
471
Satterfield et al. TOHP: PHASE I DESIGN
AEI’ Vo1 I, I\;u. 5 Atr~u\r fW1: 455-471
variances
for the change
anti 40.41
(standard
in LIRP means
error,
For SBP, the observed ant1 .81 and .85 for l-year, correlations three
in TOHP
measurements
(6 months)
and
and true tracking respectively.
were estimated each,
in means
of 99.62
104.61
(standard
error,
(standard
10.23)
(standard
error,
correlations
Interpolating to observe
These
figures
error,
f&r 18 months
6.17)
for 6 months
of observation. were .67 and .83 for 4-years to 6 and
to he ,853 and .847.
we expected
.79 (18 monthx).
change
of 38.03
for 18 months
6.36)
9.98)
18 months,
Given
correlations
three
the true visits with
of approximately
led to estimated
variances
for 6 months
of observation
of observation.
.80 for the and
Prevention
Phase I Design Suzanne Satterfield, MD, Jeffrey A. Cutler, MD, Herbert G. Langford, MD, William B. Applegate, MD, Nemat 0. Borhani, MD, Erica Brittain, PhD, Jerome D. Cohen, MD, Lewis H. Kuller, MD, Norman L. Lasser, MD, Albert Oberman, MD, Bernard Rosner, PhD, James 0. Taylor, MD, Thomas M. Vogt, MD, W. Gordon Walker, MD, and Paul K. Whelton, MD, for the Trials of Hypertension Prevention Collaborative Research Group Phase I of the Trials of Hypertension Prevention (TOHP) wus a Nutionul Heurt, Lung, and Blood Institute-sponsored, 3-yeur, natlonul, multicenter, randomized, controlled trial designed to test the feasibility and efjicay of three life-style (weight loss, sodium restriction, and stress management) and four nutntlon supplement (calcium, mugnesium, fish oil, and potassium) interventions aimed at lowering diastoltc blood pressure in those whose blood pressure wus initially in the high normal range (80 to 89 mm Hgj. A total of 2 182 eo 1un teers were recruited and allocated to the various treatment urms, such that each hypothesis was tested with a power of 85%) or higher to detect a diastolic blood pressure treutment effect of 2 mm Hg. The four nutrition supplement interventions were delivered in a double-blinded f us h’ron und the three life-style interventions, single (observed) -blinded. Phase I tL)as designed to provide u rigorous test of short-term lowering of blood pressure for each of the seven treatments chosen and proslides the basis for planning of a subsequent long-term trial of hypertension prevention. Ann Eptdemiol I99 I ; I :455471. KEY WORDS:
Hypertension.
prevention.
nonpharmuco&c
interzbenrion.
INTRODUCTION Phase I of the Trials of Hypertension ter, randomized of several (DBP)
nonpharmacologic
in the high
cooperative
Prevention
trial of 3-years’ duration normal
agreements
interventions range
testing
(TOHP)
aimed at lowering
(80 to 89 mm Hg).
with the National
was a US national,
the feasibility
Heart,
The
multicen-
and short-term
efficacy
diastolic
pressure
blood
trial was funded
Lung, and Blood Institute
through (NHLBI)
From the Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (S.S., J.O.T.); D’IVISIO~ of Epldemwlogy and Clinical Applications, National Heart, Lung, and Blood Institute. Bethesda, MD (J.A.C., E.B.); Department of Medune. University of Mississippi, Jackson, MS (H.G.L.); Department of Preventive Medicine, UnlversltyofTennessee, Memphis, TN (W.B.A.); Department of Community Medicme, University of Cahfomia, Davis, CA (N.O.B.); St. LOUIS University School of Medicine, St. Louis, MO (J.D.C.); Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Plrtsburgh, PA (L.H.K.); New Jersey Medical School, Newark, NJ (N.L.L.); Division of General and Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL (A.O.); Department of Preventive Medicine, Harvard Medical School, Boston, MA (B.K.); East Boston Neighborhood Health Center, East Boston, MA (J.O.T.); Kaiser Permanente Center for Health Research, Portland, OR (T.M.V.); and The Johns Hopk Ins University School of Hyg:lene and Public Health, Baltimore, MD (W.C.W., P.K. W. ). This article IS dedicated by the Trials of Hypertension Prevention (TOHP) investigators to the memory of Herbert Langford, MD, who died on January 26, 199 I and served as Chairman of Phase I. Address reprint requests to: Suzanne Satterfield, MD, TOHP Coordinating Center, Brigham and Women’s Hospital, 55 Pond Avenue, Brookhe, MA 02146. Received Aprd 30, 1990; rewsed February 12, 199 1. c 1991 Elsev~er Science Publishmg Co., Inc.
1047.279719l/$fi7.50
456
Satterfield et al.
AEP Vol. I,No.5 August 1991: 455-471
TOHPPHASEI DESIGN
as the first phase
for a larger
trial of hypertension
prevention.
Ten
clinical
centers
across the United States and a coordinating center, which included central laboratories and a nutrient data center, were selected by peer review. A lo-month planning phase
was initiated
randomization completed
in Septemher
wab completed
on January
1986. R ecruitment by October 4, 1988.
12, 1990, and the average
began on August 3, 1987, and End point data collection was
period of follow-up
was approximately
18 months.
BACKGROUND Approximately
20% of the adult population
(BP) (l),
pressure myocardial been
a major risk factor
infarction
and congestive
demonstrated
in descriptive
cohort,
in many
specific
determinants
environmental factors,
countries
including
diet,
recognized
that altered
1988 reports
of the Joint of High
interventions
especially
for whom Recent
treatment
reports
Evidence
that
trials
(HCP)
small
and the Dietary
trials randomized
of whether
previously
tervention
or follow-up
determine
if hypertensives
macologic
treatment
sample
can
Detection,
and
care limit
the
1984 and
Evaluation
and
the use of nonpharmacologic with very mild hypertension, risks than
Study
tested
lower
benefits
(11,
12).
interventions
might
in individuals
at risk
BP derives
size of middle-aged
of these include
diastolic Program
(14,
15). Both
to a nonpharmacologic
objective
without
with
from
Control
(DISH)
hypertensives The
primarily
subjects
the Hypertension
in Hypertension
intervention.
HCP
Both
of hypertension
could be maintained
alone.
and
life-style
(13-16).
well-controlled
without
genetic that
of hypertension
nonpharmacologic
therapy
Intervention
and While
it is also increasingly
(8-10).
on the
the development
The most important
both
and costs of medical
of individuals
nonpharmacologic
of relatively
hypertension.
toxicity,
may pose greater
of this disorder
(2-4).
has accrued
H owever,
have recommended
medication
in preventing
development
understood,
have
case-control
and sex groups
drug therapy
in the treatment
with
relationships
both
in the treatment
(5-7).
Committee
Pressure
blood
including
role.
of life, potential
raised the question
also be of value for future clinical
Blood
disease,
These
evidence
therapy
antihypertensive National
has elevated
heart
studies,
yet fully
well established
quality
of lifelong
(2-4).
age, race,
Substantial
may play a major
the usefulness Treatment
most
of pharmacologic
has been
failure
BP are not
play a role.
The effectiveness its complications
heart
States
and coronary
as well as analytic
and across
of high
factors
in the United
for stroke
of both
medication
the effectiveness
trials
inwas to
but with nonphar-
of a combined
reduction
calories, sodium, and alcohol intake in previously well-controlled hypertensives After 4 years, 39% of the active, compared to only 5% of the control group, normotensive
without
and sodium
restriction
rates,
weight
normal
with
weight
antihypertensive separately
loss in overweight
(15). Recently,
medication.
DISH,
in mild hypertensives, subjects
and
which
reported sodium
the Trial of Antihypertensive
tested
weight
the highest
reduction
of
(14). were loss
success
in subjects
of
Interventions
and Man-
agement in overweight mild hypertensives reported the greatest reduction weight loss was combined with antihypertensive medication (16). In the last 10 years, a few trials tested the benefit of nonpharmacologic
in BP when interven-
tions in populations with BP in the normal range. One of the most recent of these, a 5-year trial of 201 overweight subjects with BP in the high normal range used a multifactorial intervention that combined weight loss, alcohol reduction, sodium
Satterfield et al. TOHP: PHASE I DESIGN
AEP Vol. I, h’u. 5 August 1991: 455-471
reductron,
and exercise
loss. The other
(17). BP reduction
relatively
macologic
treatment
Prevention
Trial
population
and achieved
goals of sodium
was related
particularly
large trial (841 participants)
in a population (HPT)
(18).
with BP in the normal
Thus trial was successful
its goal in weight
reduction
or potassium
BP was seen in the weight
testing
loss (net weight
efficacy style
prevention
of various
trials.
net decline
in
(1.8 mm Hg DBP, and 2.4 mm Hg systolic
BP
sodium
chosen
reduction,
The
supplement
in reducing
Although
some
in reducing
in a large cohort.
Randomized
but there
The four nutritional calcium
(32-34),
randomized these The
decision
intervention intervention
The
weight
trials
suggested
no trials selected
(3%37),
a nutrition
in previous
included
and
supplementation
rather
out in hyperten(24-28).
potassium While
showed
(29-3
some would
dietary
l),
previous lower BP,
inconsistent
than
studies
of moderate
individuals
of these supplements
short-term,
loss,
this conclusively
were carried
and fish oil (38-41).
and
life-style
weight
the efficacy
in nonhypertensive
that administration
to be small
life-
loss was the intervention
trial established
for evaluation
three
were
the
three
results. counseling
strategy was based on the knowledge that adherence to dietary counseling is often disappointing (18) and on our desire to provide an optimal test
of the hypothesis. ability
tested.
trial,
of TOHP
trials of stress management
magnesium
to choose
Of these,
BP (22, 23), no previous
supplements
tended
were
first phase
controlled
have been
trials suggested
studies
any of the previous
BP had been most firmly established
small,
sodrum reduction sive subjects,
in the
than
for use in a larger
interventions
for evaluation
largest
aim of the trial was to determine
regimens
and stress management.
whose effectiveness (19-21).
Since the primary
nonpharmacologic
and four nutrition
interventions
a normotensive
loss, 7.7 lbs), but not its
(SBP) after 3 years of follow-up). The first phase of TOHP was larger (2182 participants) hypertension
of weight
of nonphar-
range was the Hypertension in recruiting
supplementation.
loss groups
to degree
the efficacy
457
to achieve
However, similar
our choice
changes
of supplement
by dietary
dosage
was predicated
on an
counseling.
OBJECTIVES The overall
objective
nutritional
and behavioral
among
individuals
The
specific
of the first phase of the TOHP interventions
with high normal aims originally
was to determine
were feasible
and effective
levels of DBP (defined
2.
To evaluate
BP
were:
the level of adherence
with the interventions
centers
to recruit
over a 27- to 36-
period.
3. the trend
To determine
the efficacy of these nonpharmacologic
in DBP change
over time
4. To assess the feasibility prevention. 5. training
selected
in lowering
as 80 to 89 mm Hg).
1. To assess the ability of each of the ten participating clinical and randomize at least 200 participants over a period of 9 months. month
whether
in a favorable
of proceeding
interventions
in altering
direction.
with a full-scale
trial of hypertension
To develop and evaluate the organizational components, logistical support, materials, and study forms for the implementation of a long-term, full-scale,
nonpharmacologic
trial.
In actuality, recruitment lasted for 13 months rather than 9, follow-up was phased out rather than continued to a common termination date, 5 months were reserved for
458
Satterfield et al. TOHP: PHASE I DESIGN
AEP Vol. I, No. 5 August 1991: 4.55-471
Randomization (2.182)
Lifes;**
)
Supple yams
stage 1
I
I
I
Weight Loss
I
I
I
I
Calcium
Magnesium
Sodium
Stress
Control
(327)
(242)
(589)
(237)
(308)
I Control
(2271
(234)
(19) stage 2 I
I
Fish Oil
Potassium
I
(178)
Control (1751
(175)
1 Randomization scheme for phase I of the Trials of Hypertension Prevention. The total numher randomized, 2182, includes 18 participants randomized directly into stage 2 of the supplements intervention. (See text for complete discussion of randomization.)
FIGURE
transition
to phase
II. As a resclt,
the follow-up
period
was 18 months
rather
than
27
to 36 months.
DESIGN
This trial tested (Figure
a broad range of interventions
1). The allocation
style and supplement of its promise allocations
hypothesis,
to the life-style allocations
to provide
with a particular
to the supplement
and
intervention
test of each life-
restriction
investigations.
were 300 participants
management,
size of 2182 subjects
a reliable
focus on sodium
results from earlier
interventions
loss, 225 in stress
in a fixed sample
was designed
but lack of conclusive
315 in weight projected
scheme
in sodium
560 in the control
because
The projected restriction, group.
were 234 to each active
The
supple-
ment
and 232 to the placebo group. The allocation schemes with the actual numbers randomized in phase I of TOHP are shown in Tables I and 2. All of the clinics tested a subset of the interventions.
Three
clinics
clinics
restriction subjects),
tested only life-style
participated (327
in both subjects),
and four tested
interventions,
arms of the trial. six tested
the
two tested Six clinics
value
of a weight
the value of a stress management
(see Table I). Each clinic provided one common interventions. This control group was allocated
only supplements, tested
and five
the value of sodium
loss intervention
intervention
(308
(242 subjects)
control group for both of its life-style a larger number of participants (589
subjects) than the active treatment groups because the weight reduction group could only be compared to the high weight subset of control participants (256 subjects) and not the entire group of controls.
459
Satterheld et al.
AEP Vol. I, No. 5 August 1991: 455-471
TOHP:
TABLE 1 randomized
Allocatic:n of TOHP participants, into
life-style
Weight reduction
66
60 63
69
45
49 47 63
42
Seven
of the ten clinics
and two tested
participants
participated
supplements
were allocated
m the nutritional
diglycine/d,
5013 placebo
or magnesium
potassium
as Chelazomes), placebo);
of participants
the eligibility
stage
1, medical
tested
both life-style
fatty
history
regarding
and supplement
assigned
placebo)
and
the failure
trial,
control
to receive
magnesium
placebo
(either
group calcium
(360 mg OS-Cal
175 were randomized
to
178 to receive
175 to receive
placebo
2). The somewhat
of some
stage
(either smaller
1 participants
in stage 2, such as compliance
disorders,
interventions
arm of the
as Promega),
(see Table
for inclusion bleeding
stage,
acidsid,
as K-DurZO),
necessary
or a common
and 234 to receive
in stage 2 reflects
criteria
supplements
500), 227 to receive
in the second
mg of omega-3
or olive oil as Promega
meet
Life-style control
stages of the supplements
were randomly
as O&al
(60 mEq of potassium/d,
K-Dur placebo number
(3000
In both
to one of the two supplements
calcium/d,
of magnesium
fish oil
of suhlecta
Stress management
exclusively.
(see Figure 1). In the first stage, 137 subjects
( 1000 mg of elemental
receive
numbers
66 32 3118
33 3.27
trial,
(actual
interventions)
Sodium reduction
Clinic
by clinic
PHASE I DESIGN
and BP. The
maintained
five clinics
separate
control
to in that
groups
for each arm of the trial. Both the life-style ment
TABLE 2 supplement
procedure,
Allocation
of TOHP
and the supplement
eligibility
participants,
and exclusion
arms of the trial shared criteria,
by clonic (actuC~l numbers
and parallel
of subjects
a common
recruit-
data collection
sched-
randomired
mtcl
interventions)
Stage 1 Calcium
Magnesium
27
?i?
il 23 I7 21 _
48 22 I4 22
92 11 ?3i
11 ZZi
Stage 2 Placebo
Potassium
Fish oil
Placebo
460
TABLE
AEP Vol. 1. No. 5 August 1991: 455-471
Satterfield et al. TOHP: PHASE 1 DESIGN
3
Sample
size and power” DBP Size of comparison
Intervention
A for 80% power
Active
Control
327 308 242 237 227 lit?
417 256 323 ‘34 234 175
Iii
iii
ules.
However,
substantially
(mm
the
Hg)
consisted
required
life-style
to implement
The supplement tirst stage, numbers pants
period
of intense
through
run-in
tish oil, potassium,
SAMPLE
SIZE
AND
changes
period
and then
the
interventiona
Life-style
with
individual
intervention,
mainte-
and placeho-controlled.
to be as similar
participants
or placebo.
were
design.
were randomized
At the end of 6 months,
of approximately
the same participants
10 weeks,
This
as possible.
which
were rerandomlzed
In the in equal partici-
doubled
as a
to receive
or placebo.
POWER
The sample control
period,
calcium,
a washout
period,
were designed
run-In
magnesium,
.Y! .‘)I .KI .K
followed t7y a less intensive period of follow-up.
were double-hlinded
which
after a 6- to 8-week to receive
went
second
interventions
of two stages,
98
.93 .‘I3
arm of the trial had an open
of an initial
Power for A=3mmHg
Hs)
2.12 2.42 2.44 !.iL? ?.iY 2.Y7 2.w
.Y4 .86 .K6
and group counseling, lasting from 2 to 3 months nance period for the remainder of the 18smonth arm consisted
(mm
.YY .Y6 .Y6 .Y4
methodologies The
A for 80% power
Power for A= 2mmHg
1.32 I.51 1.52 I.@ 1.61 I.84 1.85
different.
interventions
SBP
sizes and corresponding
comparisons
are presented
m mean BP represent
calculated
using the following
power estimates fc>r each of the intervention and fc>r determining 3. Th e p ower calculations
in Table
two-sided
tests with ;I significance
level of .05 and were
formula:
where: ] = the area to the left of [ ] on the standard
@[
normal
curve
CY = 0.05 Z,_,r:J
=
1.96
d = th e expected son groups
difference
in BP change
between
the intervention
CJ = standard error of change in BP; 6.17 for supplements for change in DBP, and 9.98 for supplements and change
in SBP
11, = the number
m the active
intervention
group
and compari-
and 6.36 for life
Satterfield et al.
AEP Vol. 1, No. 5 August 1991: 455-471
461
TOHP: PHASE I DESIGN
no = the number
in the corresponding
control
group
The variances of the change in mean BP from baseline to termination were estimated based on data from the Hypertension Detection and Follow-up Program (HDFP) (42, 43) and on tracking correlations for a population in Wales (44) and another industrial population (45) (details are provided in Appendix 2). Since both baseline and termination BPS were averages of nine measurements, taken at three visits with three readings per visit, the variability of the BP measure was minimized, thus favorably affecting the power of the trial to detect true differences. Original power estimates, based on projected sample sizes, provided for at least 94% power to detect a 2-mm Hg change in DBP and at least 91% power to detect a 3 -mm Hg change in SBP. In addition, the projected sample sizes allowed for detection of changes of 1.6 mm Hg in DBP and 2.5 mm Hg in SBP with 80% power. As shown in Table 3, with the actual numbers randomized, all tests had at least 86% power to detect a 2-mm Hg change in DBP and at least 80% power to detect a 3-mm Hg change in SBP.
SCREENING AND RANDOMIZATION
Screening The aim was to screen men and women aged 30 to 54 years who had no evidence of medically diagnosed hypertension, gross obesity, or other exclusion criteria (Table 4). The most important eligibility criterion was BP. At each visit, three BP measurements were recorded. The cumulative average of the readings for DBP had to fall within the following predetermined ranges for participants to proceed to the next screening visit (SV): SV 1: DBP 75 to 97 mm Hg (average of three readings). SV 2: DBP 77 to 94 mm Hg (average of six readings). SV 3: DBP 80 to 89 mm Hg (average of nine readings). Thus, for a participant to be declared eligible at the end of the third screening visit, the average of all nine DBP measurements obtained at screening visits 1, 2, and 3 had to be within the range of 80 to 89 mm Hp. During screening visits, participants were weighed and body mass index (BMI), defined as kg/m2, was used to determine eligibility. Those participants who had a BMI greater than 36.14 (approximately 160% of ideal body weight) were excluded. Those eligible for inclusion were further classified into high- (BMI of 26.08 to 36.14 for men and 24.26 to 36.14 for women) and low-weight strata (BMI < 26.08 for men; ~24.26 for women) for randomization. Compliance was an eligibility criterion, assessed in the following ways: (1) ability to complete and return a satisfactory 24-hour urine collection and food frequency questionnaire (all subjects), and (2) ability to take 66% or more of prescribed nutrition supplement pills during a 6-week placebo run-in phase (supplements only). Final decisions on eligibility were made at the status review visit (SRV).
Randomization The preliminary steps of the randomization procedure varied according to the types of intervention offered at a given clinic. Those clinics conducting only life-style interventions proceeded immediately to randomization, while those conducting only
462
AEP Vol. 1, No. 5 August 1991: 455-471
Satterfield et al.
TOHP:
PHASE I DESIGN
TABLE 4
Exclusion
criteria
1. Evidence of current hypertension, as defined by nine baseline DBP readings averaging 90 mm Hg or greater, or current use (within the previous 2 months) of antihypertensive medications. 2. Diastolic BP < 80 mm Hg, based on the average of nine readings. 3. Gross obesity, BMI 2 .0514 lb/in’ (36.14 kg/m*). 4. History of any cardiovascular disease, including myocardial infarction, angina, intermittent claudication, congestive heart failure, and stroke. 5. History of diabetes mellitus, defined by self-report or ever use of insulin or oral hypoglycemic agents. 6. History of chronic renal failure and/or kidney stones. 7. Recent history of psychiatric disorders, defined by hospitalization within the previous 5 years for such a condition or current use of antipsychotic or antidepressant medications. skin cancer) in past 5 years. 8. History of malignancy (other than nonmelanoma 9. Serious physical handicaps, including severe arthritis, blindness, or other handicap, that would contraindicate participation in any of the TOHP interventions. 10. Current alcohol intake of more than 21 drink&k. disease, such as peptic ulcer, diverticulitis, ulcerative colitis, 11. History of chronic gastrointestinal inflammatory bowel disease, or other conditions judged by study clinician to be a contraindication to admission to TOHP. 12. Any other serious or life-threatening illness that requires regular medical treatment. 13. Current use (within the past 2 months) of medications that could interfere or interact with study interventions, including diuretics, beta-blockers, and anticoagulants. 14. Serum cholesterol level 2 260 mg/dL, as determined by local laboratory. 15. Serum creatinine level 2 1.7 mg/dL for men or 1.5 mg/dL for women. 16. Casual serum glucose 2 200 mg/dL. 17. Unexplained hyperkalemia. 18. Hypercalcemia, as determined by local laboratory. 19. Unwillingness to discontinue use of preparations of any of the micronutrient supplements being tested in TOHP. 20. Unwillingness to discontinue a dietary regimen incompatible with TOHP interventions, such as a medically supervised diet or a formal weight loss program. 21. For women, current pregnancy or intent to become pregnant during the study period. 22. Current participation in other ongoing clinical trials or prior participation in an active intervention group in the Hypertension Prevention Trial. 23. Participation of another household member in TOHP; TOHP employees; persons living with TOHP employees. 24. Plans to move out of the study area (generally defined as ~50 miles from the study site), such that it would be difficult to come to the study site. 25. Unwillingness to accept randomization into any study group. 26. Inability to cooperate as assessed by clinic staff. 27. Inability or unwillingness to give informed consent.
supplement
interventions
delayed randomization
until after the completion
of the
run-in period to test compliance with pill taking. Clinics conducting both types of interventions utilized a preliminary allocation to one of these two tracks, after which randomization proceeded as at the single-track clinics. Participants in the low-weight stratum were excluded from participation in the weight loss and exercise program or serving as its control but were randomized to all other treatment and control groups. Those
in the high-weight
and controls.
stratum were randomized to all TOHP
The coordinating
center
verified the eligibility
treatment
groups
of the participant
for
randomization on the basis of the data collected at the three screening visits and notified the respective clinical center prior to the date of the SRV. During the SRV, once the participant was also determined eligible on the basis of compliance, the clinic notified the coordinating center by telephone and obtained a randomization assignment. Clinics were also provided with sealed envelopes containing randomization
463
Satterfield et al. TOHP: PHASE I DESIGN
AEP Vol. 1, No. 5 August 1991: 455-471
TABLE 5
TOHP phase I data collection
schedule for life-style interventions
Screening visit
1.
Months of follow-up 3
6
12
L
I
L
L
L
L
L
2
3
BP Weight Demographic Physical activity Health experience Prescription drug
L
General well-being
L
Occupational
Rand
18 L
L
L
L
L L
L
L L
L
L
L
S
S
data S
Hassles scale Cardiovascular
reactivity
Anthropometric Food frequency
L
24-hr recall
L
Blood
L
24-hr urine
L
S
S
S
W
W
W L
L
-
L
L
L
L
L = all life-style participants; S = stress and sample of other life-style participants at stress clinics; W = weight and sample of other high-weight participants; Blood = glucose, cholesterol, creatinine, potassium, and calcium (lo. tally for eligibility); 24-hr urine-sodium, potassium. and creatinine.
assignments possible.
considered
for use when Once
telephone
the assignment
contact
with
was communicated
the coordinating
to the participant,
center
was not
he or she was
officially randomized.
FOLLOW-UP The follow-up visit schedule was, of necessity, relatively complex due to the varied interventions and the differential length of follow-up for life-style and supplement interventions. The data collection schedule for life-style interventions is summarized in Table 5 and the corresponding schedule for nutrition supplement participants, in Table 6. The most important follow-up measure was BP. All follow-up BP values were calculated as an average of nine observations, three readings taken at each of three visits 7 to 30 days apart. For life-style participants, nine BP measurements were taken at baseline, 12, and 18 months, and for supplement participants, nine readings were taken at baseline and 6 months for each stage of the supplement intervention. Interim BP measurements, consisting of three readings taken on one visit, were taken at 3 and 6 months for life-style participants and at 3 months for supplement participants. These interim measures were used primarily for safety monitoring. The final 18-month visits for the life-style arm of the trial were completed by January 12, 1990; the mean follow-up was 75 weeks. Other trial-wide follow-up measurements included pulse rate, body weight measurements, medical histories, physical activity questionnaires, the Psychological General Well-Being Scale, demographic and participant contact information, and urine samples (see Tables 5 and 6). Additionally, for supplements, information on side
464
Satterfield et al. TOHP: PHASE I DESIGN
TABLE
6
TOHP
AEP Vol. 1, No. 5 August 1991: 455-471
phase 1 data collection Stage
schedule for supplements
interventions
1
Stage New baseline
Screening visit 1 BP
s
Weight Demographic Physical actlvlty Health expenence PrescriptIon drug
S S
General
2
6 mo
3 mo
Rand
s
s
S
s
2
1
Rand
s s s
s
3
6
mo
mo
S S
S
S
S S
S S
S
S
data
S S
24-hr
S
recall
Blood
S S S S
S urine
Side effects
3
S
S
Food frequency
24-hr
Washout 10 wk
S
well-being
Occupational
3
2
S assess.
S S
S
Pill count
S
effects
was obtained,
Table
6).
ASCERTAINMENT
and pill count
data were collected
SF
S
S
S S
as a compliance
measure
(see
OF END POINTS
Primary
End Points
The primary
end point
of this trial was change
of the fifth Korotkoff
sound),
end point
in SBP (defined
was change
Initially,
uniform
recertification random
SF
from baseline
training
was performed
as the appearance
and certification at 6-month
zero sphygmomanometer.
To minimize
When
possible,
tion visits as compared
Intermediate
separate
facilities
to intervention
as the disappearance
visits.
The other
of the first Korotkoff
of BP observers
intervals.
ment allocation. Persons certified to measure aspects of the trial, nor were they allowed assignment.
in DBP (defined
to final follow-up
were required,
BP recordings
bias, observers
major sound).
were made
were blinded
and with
BP were not involved with intervention access to data that would reveal group or entrances
were used for data colllec-
visits.
End Points
Intermediate end points tions. Twenty-four-hour
were selected to evaluate implementation of specific intervenurine samples were used to monitor sodium reduction, as well
as magnesium, calcium, and potassium supplementation. For the sodium intervention group, five 24-hour urine samples were obtained-two before randomization and three after randomization. from all other
a
to treat-
life-style
Twenty-four-hour participants
urine
samples
to assess confounding.
for sodium
were also collected
In addition,
food frequency
TOHP: PHASE I DESIGN
questionnaire
and 24-hour
all life-style placebo
dietary
participants.
controls,
four 24-hour
hour urine samples tion.
For the
composition The loss.
group
determined
Psychological specific
included
General
Lazarus’ Hassles
group,
for the
Well-Being Scale.
These
acid
three
24-
phospholipid for 50% of the
a trial-wide
group
was weight
measurements,
which
loss intervention, group
measure,
reactivity
were
80% of the
in other intervention
management
Cardiovascular
were
groups.
scores
on the
and the intervention
to mental
stressors
was also
from all participants in the stress manageand 20 %I of those in other interventions
controls,
also offered
fatty
reduction
and girth individuals
stress
data were obtained
which
plasma
and was determined
to the weight
Scale,
80% of their life-style
in the four centers
before randomization and two after randomiza-
for the weight
skinfold
randomized
points
from
as well as their
controls.
end point
and 20% of high-weight
end
used as a measure. ment
fish oil and their
controls,
Intermediate
end point
were obtained
and their controls,
before randomization
fish oil supplement,
for all participants
high-weight
participants
receiving
end points
intake
participants
were obtained-two
intermediate
Secondary
calcium
urine samples
as the intermediate
receiving primary
of sodium
and
For potassium
were obtained-one
served
participants
recall estimates
For magnesium
and two after randomization.
QUALITY
465
Satterfield et al.
AEP Vol. 1, No. 5 August 1991: 455-471
strebs management.
CONTROL Extensive
efforts were made to control
tee of the trial,
the Data Collection
to review quality control to requiring sessions,
reports
centers.
In addition,
Assurance
and performance
digit
preference,
collection
produced
met regularly
centers.
staff in training
data
rates were regularly
subcommit-
Committee,
of the clinical
of all data collection
monitoring
and follow-up
of study data. A standing
and Quality
procedures
the participation
compliance,
the quality
error
rates,
and distributed
two site visits were made to each clinic
In addition
and certification protocol
to the clinical
to assess compliance
with
the protocol.
STUDY
ORGANIZATION The
ten clinics
involved
more, Maryland;
nia, Davis, California; chusetts;
University
Memphis, Portland, Center
of
Oregon;
Jackson,
New Jersey Medical Pennsylvania;
Health
School,
Hospital,
Balti-
ofCalifor-
East Boston,
University
Massa-
of Tennessee,
New Jersey; University
Center
St. Louis,
Women’s
University,
University
Center,
Newark,
Kaiser Permanente
and
Hopkins
Alabama;
Mississippi;
and St. Louis University, at Brigham
at Johns
Birmingham,
East Boston Neighborhood
Pittsburgh,
was located
were located
Alabama.
of Mississippi,
Tennessee;
Pittsburgh,
in TOHP
Uni+ersity
for Health
Missouri. Harvard
The
of
Research,
Coordinating
Medical
School,
Boston, Massachusetts, as was the special laboratory responsible for analyses for stage 2 of the supplement arm. The Nutrition Data Center was located at Tufts University, Boston,
and the central
Minnesota,
Minneapolis,
An Executive
laboratory
for clinical
studies
was located
at the Unilrersiry
of
Minnesota.
Comnnttee
\vas formed,
and consisted
of the chairpersons
of four
subcommittees (Design and Analysis, Data Collection and Quality Assurance, Interventions, and Publications and Presentations), the NHLBI Project Officer, the Coordinating Center Director, and the Study Chairman. The Executive Committee’s function
466
Sacterfield et al.
AEP Vol. 1, No. 5 August 1991: 455-471
TOHP: PHASE I DESIGN
was to resolve any operational problems arising between Steering Committee meetings. The Study Chairman, elected by the Steering Committee, served as Chairman of both the Steering Committee and the Executive Committee. The trial was directed by a Steering Committee composed of one representative from each of the clinics as well as from the Coordinating Center and NHLBI. Each unit had one vote, usually cast by the principal investigator. Six subcommittees reported regularly to the Steering Committee: Design and Analysis, Eligibility and Recruitment, Interventions, Data Collection and Quality Assurance, Publications and Presentations, and Clinic Coordinators. The Data and Safety Monitoring Committee (DSMC) was an external advisory group, appointed by the NHLBI, with the advice of the Steering Committee. The committee reviewed the initial study protocol and monitored study data for treatment effects, either beneficial or harmful, which might warrant alteration or early termination of one or more interventions. The DSMC was also responsible for making specific recommendations to the Steering Committee and NHLBI regarding continuation of the trial, with or without changing the protocol, and for advising on whether to proceed with phase II of TOHP.
SUMMARY Phase I of TOHP was a 3-year, national, multicenter, randomized, controlled trial designed to test the feasibility and short-term efficacy of three life-style and four nutrition supplement single-factor interventions aimed at lowering BP in those with an initial pressure in the high normal range. Following a uniform recruitment, screening, and randomization process, participants were treated and followed for an average of either 18 (life-style interventions) or 6 (nutrition supplement interventions) months. The primary end point was DBP, but careful measurements of SBP and interventionspecific intermediate end points were also obtained. Extensive precautions were taken to ensure the collection of high quality data and the careful monitoring of progress during the trial. Phase I provides a rigorous evaluation of short-term BP lowering for each of the seven treatments tested and provides the basis for planning of a subsequent longer-term trial of hypertension prevention. Phase I of the Trials of Hypertension Prevention was supported by cooperative agreements HL37849, HL37852, HL37853, HL37854, HL37872, HL37884, HL37899, HL37904, HL37906, HL37907 and HL37924 from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The investigators are grateful to Marion Laboratories (Kansas City, MO), Schering-Plough (Miami, FL), and WarnerzLambert (Morris Plains, NJ) for donating pills and calendar packs and to Albion Laboratories (Clearfield, UT) for donating study pills. We also wish to thank Heather Tosteson, PhD, for her role in the preparation of this manuscrim.
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APPENDIX
1
Participating Institutions
and Principal Staff
Clinical Centers-The Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD: Paul K. Whelton, MD (Principal Investigator), Lawrence Appel,
MD, Jeanne
Charleston,
RN, Arlene
Taylor
Dalcin,
RD, Craig
Ewart,
PhD,
AEP Vol. I, No. 5 August IYYI: 455-471
Linda Fried, MD, Delores Steffen,
MPH,
Kaidy, Michael
and W. Gordon
Walker,
J. Klag, MD, Shiriki MD; University
469
Satterfield et al. PHASE I DESIGN
TOHP:
Kumanyika,
of Alabama
PhD,
Lyn
at Birmingham,
Investigator), Karen Copeland, Birmingham, AL: Albert Oh erman, MD (Principal RD, Heidi Hataway, MS, James Raczynski, PhL1, Neil Rappaport, PhD, Mildred Sehn, and Roland Borhani,
Weinsier, MD
MD; University
(Principal
of California
Investigator),
Edmund
at Davis, Bernauer,
Davis, PhD,
CA:
Nemat
Patricia
0.
Borhani,
Carlos de la Cruz, Andrew Ertl, I&g Heustis, Marshall Lee, MD, Wade Lovelace, Ellen O’Connor, Liz Peel, and Carolyn Sugars, RD; East Boston Neighborhood Health Center,
East Boston,
Corkery,
Morri:,, MPH, Jackson,
MA: James 0. Taylor,
Llenis
MPH,
Eleanor
Chantanop,
Goodwin,
G. Langford,
RN,
Stephen
MD, and Shirley
Miller,
burgh,
Milas,
for Health Charles
School of Medicine,
tor),
Julie
School,
Project
MPH,
Minnesota, meyer,
Ivan
Boston,
PhD,
Investigator),
Jay Sullivan,
NJ: Norman
Lee Dolan,
Sheila
of Pittsburgh,
Pitts-
Arlene
Brinkmann,
MA: Charles Cann,
Mayrent,
MD, Heather
W. Caggiula,
and
RN,
PhD,
MAT, PhD,
Tosteson, PhD,
Cook,
MN: John
Elizabeth
Reilly,
Central
RD, and and Har-
Data
Investiga-
Ellie Danielson, PhD, Janet Bernard
MIA,
Lang,
PhD,
Rosner,
Van Denburgh;
RD, Peter
PhD, Project
MD (Scientific Kaufmann,
PhD,
Laboratory-University
PhD (Project
Nutrient
Investigator),
Hospital
Jeffrey A. Cutler,
Farrand,
RD,
Roth,
MD (Principal
ScD,
PhD, and Martin
Belcher,
and Peggy Neibling;
Katherine
Hebert,
PhD;
PhD,
Raker,
MD (Principal
RN,
Patricia
Marilyn
R. Greenlick, Margaret
MA; St. Louis University
H. Hennekens,
Nancy
Eva Obarzanek,
Minneapolis,
Merwyn
and Women’s
Lung, and Blood Institute:
Erica Brittain,
Mills,
PhD,
McKenzie,
Center-Brigham
David Gordon,
Heart, PhD,
Marlene
PhD, and Betsy Wagner,
Cristina
Sherry
Satterfield, Officer),
Memphis, RD, Laretha
Judy Randle,
MA; University
MA, John Givi,
RD, Connie
ScD,
Office-National Ed Lakatos,
of Tennessee,
M. Batey,
MS,
MS, John Kiley,
Amy Brewer,
PhD,
St. Louis, MO: Jerome D. Cohen,
Buring,
MacFadyen,
Suzanne
David
PhD,
RD; Coordinating
Kim Eberlein, Jean
Ernst, Stevens,
Mattfeldt-Beman,
vard Medical
MD, J oe Murphy,
Mary Cameron,
E. Yamamoto, DrPH; Kaiser Permanente Center Investigator), OR: Th omas M. Vogt, MD (Principal
Jack Hollis,
MA, Victor
Lana Shepek,
University
Glare
of Mississippi,
Jennings,
Investigator),
MD (Principal
Portland, Denise
Hertert,
Mildred
King Wright;
RD, and Vera I. Lasser,
Research,
Steve Smith,
Martha
MS, and Monica
Coultrera,
Stephanie
Beth Walker
MPH,
Investigator),
PhD, Stephanie
Investigator),
PA: Lewis H. Kuller,
N. Carole
Investigator),
Keough,
RD; New Jersey Medical School, Newark,
Vossberg,
Pat Kennedy,
Ellen
MD (Principal
MD (Principal
L. Lasser, MD (Principal Hamill,
Mary
Corrigan,
and Nancy
B. Applegate,
MD (Principal
MD,
RN, and Frank Sacks, MD; University
RN, Sheila
MD, Judy Mahalak, William
Evans,
Pistorino,
MS: Herbert
Dianne TN:
A.
Director), Center-Tufts
Andrea
of Dom-
University,
Boston, MA: Margo Woods, ScD (Project Director), B.J. Kremen Goldman, RD, and Elaine Blethen, RD; Lipid L a b ora t ory-Channing Laboratory, Brigham and Women’s Hospital, Boston, MA: Frank Sacks, MD (Director of Lipid Laboratory); Data and
Safety Monitoring
Committee-Jeremiah
Agras, MD, Marianna Fordyce-Baum, Kotchen, MD, Laurence McCullough,
APPENDIX
Stamler,
MD (Chairperson),
PhD, C. Morton PhD, and Ronald
W. Stewart
Hawkins, ScD, Theodore Prineas, MB, BS, PhD.
2
Sample Size-Estimate The variance
of the mean
of Variance BP (x) at either
V[x, = o- ’ = u;
baseline + cr;/N
or termination + a,ZINK
can be written
as:
470
SarterhelLl et ill. TOHP: PHASE 1 DESIGN
where: vIli = between-person &I = between-visit rr;
= within-visit
variance variance variance
N = numher
of visits
K = number
of measurements
Resides these components, variation,
correlation
p = the observed
where
of follow-up
supplement need
3
-
tracking Thus,
the variance
in BP is also affected
of tune.
(x2) can be written
The variance
by temporal of the change
‘I:
“2) = 2CI? (1 -- p) correlation
for the life-style
interventions.
to estimate
=
over periods
(x!) to termination V(x,
months
per vi,lt
the Lrariance of :he ch,lnge
or the tracking
from baseline
= 3
of the BP means
interventions
to estimate
components
over an average
and 6 months
the variance
of follow-up
of the change
and the tracking
of 18 for the
in means,
we
correlation.
1. have
The estimated total variances for BP in black znd white males and females been published (42). These \vere ccw.hmed by t&ing weighted averages using
the race and gender distribution (43).
These
average
of the Hypertension
components
I)c:ectior.
ar,d Follow-Up
Program
for DAP were: u;
= 109.11 26.76
o-1 = fll
zz
r,
= 233.13
cr;
=
43.39
rrf =
13.16
1.41
For SBP they were:
Therefore, (averaged
variance of the mean AI’ at baseline or termmation Vtxjr the estimated over three visits with three readings !)er visit) was 118.85 for DBP and
249.06 for SBP. 2. A study of tracking of .58 for DBPs taken point.
corre!ation
4 years apart.
Data from an indcstrial
of BP in Wales
(44) suggested
popc!ation
(45) suggested
a l-year
for an average of 12 measurements taken at four visits with visit. The tracking correlation observed is heavi!y Influenced and measurements.
a correlation
This was based on a sing!e measurement
The relationship P fr”e = pohs x (u;
of observed + cr,;lN
at each
correlation
of .85
three measurements per by the number of visits
(,o,,,,) to true (o,,,,,) correlation
is:
+ crf/NK)la;
with the variance components defined as previously. These data suggest true 4-year and 1 -year correlations of .85 and .91, respectively. Interpolating to 6 and 18 months, the true correlations in TOHP for DBP were estimated to be .92 and .90, respectively. Given three visits with three measurements each, we expected of approximately .84 (6 months) and .83 (18 months). These
to observe correlations figures led to estimated
471
Satterfield et al. TOHP: PHASE I DESIGN
AEI’ Vo1 I, I\;u. 5 Atr~u\r fW1: 455-471
variances
for the change
anti 40.41
(standard
in LIRP means
error,
For SBP, the observed ant1 .81 and .85 for l-year, correlations three
in TOHP
measurements
(6 months)
and
and true tracking respectively.
were estimated each,
in means
of 99.62
104.61
(standard
error,
(standard
10.23)
(standard
error,
correlations
Interpolating to observe
These
figures
error,
f&r 18 months
6.17)
for 6 months
of observation. were .67 and .83 for 4-years to 6 and
to he ,853 and .847.
we expected
.79 (18 monthx).
change
of 38.03
for 18 months
6.36)
9.98)
18 months,
Given
correlations
three
the true visits with
of approximately
led to estimated
variances
for 6 months
of observation
of observation.
.80 for the and