Systolic Blood Pressure Intervention Trial
Phase: NA
Conditions: Hypertension
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

 
Systolic Blood Pressure Intervention Trial (SPRINT) 
 
 
 
 
 
 
 
 
 
Protocol Version 4.0 
 
 
November 1, 2012 

Table of Contents 
 
Executive Summary ..................................................................................................... 1  
 
Chapter 1 – Introduction and Background .................................................................... 3 
 
Chapter 2 – Overview of Trial Design ......................................................................... 12 
 
Chapter 3 – Participant Selection ............................................................................... 15 
 
Chapter 4 – Intervention ............................................................................................. 23 
 
Chapter 5 – Measurements and Follow-up ................................................................. 31 
 
Chapter 6 – SPRINT MIND ........................................................................................ 38 
 
Chapter 7 – Health-Related Quality of Life and Economic Analyses ........................... 45 
 
Chapter 8 – Safety Monitoring and Reporting ............................................................. 51 
 
Chapter 9 – Clinical Outcome Measures .................................................................... 55 
 
Chapter 10 – Statistical Considerations ...................................................................... 59 
 
Chapter 11 – Data Management ................................................................................ 67 
 
Chapter 12 – Quality Control ...................................................................................... 70 
 
Chapter 13 – Study Organization ............................................................................... 76 
 
References –  ............................................................................................................. 85 
 
Appendices: 
 
Appendix 1: 
Abbreviations Used 
Appendix 2: 
Computational Details and Sensitivity Analyses for the CVD outcomes 
Appendix 3: 
Computational Details and Sensitivity Analyses for the MIND outcomes 
Appendix 4: 
SPRINT Organizational Chart 
Appendix 5: 
Membership and Charges of the Committees and Subcommittees 
Appendix 6: 
Participating Sites 
 
 
 
 
 
 

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SPRINT Protocol 
Executive Summary  
 
 
The Systolic Blood Pressure Intervention Trial (SPRINT) is a 2-arm, multicenter, 
randomized clinical trial designed to test whether a treatment program aimed at reducing 
systolic blood pressure (SBP) to a lower goal than currently recommended will reduce 
cardiovascular disease (CVD) risk. About 9250 participants with SBP ≥ 130 mm Hg and 
at least one additional CVD risk factor will be recruited at approximately 90 clinics within 
5 clinical center networks (CCNs) over a 2-year period, and will be followed for 4-6 
years. Approximately 4300 participants will have chronic kidney disease (CKD), and 
3250 will be aged 75 or older.  The primary outcome is the first occurrence of a 
myocardial infarction (MI), acute coronary syndrome (ACS), stroke, heart failure (HF), or 
CVD death.  Secondary outcomes include all-cause mortality, decline in renal function or 
development of end stage renal disease (ESRD), dementia, decline in cognitive function, 
and small vessel cerebral ischemic disease.    
 
Design 
 
SPRINT will randomize about 9250 participants aged ≥ 50 years with SBP ≥130 mm Hg 
and at least one additional CVD risk factor. The trial will compare the effects of 
randomization to a treatment program of an intensive SBP goal with randomization to a 
treatment program of a standard goal.  Target SBP goals are <120 vs <140 mm Hg, 
respectively, to create a minimum mean difference of 10 mm Hg between the two 
randomized groups. The primary endpoint is incident CVD events identified over a 
follow-up period of up to six years. The primary hypothesis is that CVD event rates will 
be lower in the intensive arm.  Both the number of randomizations and the length of 
follow-up may differ from these targets depending on how observed values of 
parameters differ from estimates used to design the study.  Secondary hypotheses 
include whether the lower SBP goal reduces CVD event rates and progression of renal 
disease in people with CKD, whether the lower SBP goal reduces progression of CVD 
event rates in people aged 75 or older, the impact of treatment strategy on health-related 
quality of life (HRQL), and the relative cost-effectiveness of the two strategies. 
Investigation of relevant genetic pathways and other genetic analyses will also be 
conducted. The sample size of the trial will be enriched by including 4300 persons with 
CKD (estimated GFR  20-59 ml/min/1.73 m2) to permit assessment of treatment effect 
on CVD in this subgroup, as well as on measures of progression of kidney disease.  The 
trial will also include 3250 participants who are 75 years old or older. The SPRINT 
Memory and cognition IN Decreased hypertension (SPRINT MIND study) will test 
whether the lower SBP goal influences the rate of incident dementia and mild cognitive 
impairment, global and domain-specific cognitive function, and small vessel ischemic 
disease. The sample sizes for each of the three components of the MIND study are 
different. Incident dementia will be determined in all participants.  The rate of non-
dementia related cognitive decline in important domains of cognition will be measured in 
2800 persons representative of all  SPRINT participants and from these 2800 persons 
the magnetic resonance imaging (MRI) study will involve a sub-set of 640 participants. 
 
 
 
 

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Patient population 
 
Although epidemiologic evidence strongly suggests that lowering SBP will reduce CVD 
risk in nearly all adults, for practical and public health reasons the hypothesis is most 
efficiently studied in persons with an elevated risk of CVD.  Thus, the trial will recruit 
persons 50 years or older with SBP ≥130 mm Hg and at least one additional CVD risk 
factor.  Three groups will be excluded – patients with diabetes, patients with polycystic 
kidney disease (PKD), and patients who have had a stroke – because they are the target 
groups of completed or ongoing trials that are testing a lower BP goal.  SPRINT will 
focus on three high risk groups:  patients with clinical CVD other than stroke, patients 
with chronic kidney disease (estimated glomerular filtration rate [eGFR]  20-59 
mL/min/1.73 m2), and patients who have a Framingham Risk Score (FRS) of ≥15%.  A 
large subgroup will be participants who are 75 years old or older.  This trial is expected 
to enroll 50% women and 40% who are members of minority groups (African Americans, 
Hispanics, Native Americans, and Asians)  
 
Sample size and power 
 
Based on the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack 
Trial (ALLHAT) event rates adjusted downward approximately 50% for temporal changes 
in CVD risk factors and improved therapy, a sample size of 9250 provides approximately 
90% power to detect a 20% effect on the primary composite endpoint of CVD mortality 
and non-fatal MI, ACS, stroke, and heart failure.  The annual event rate used in this 
calculation was 2.2%.  Recruitment of a subgroup of 4300 participants with CKD 
provides 80% power to detect a 20% effect on the same CVD composite endpoint.  The  
probable dementia component of the MIND study will provide 80% power to detect a 
15% reduction in the incidence of dementia, 2800 SPRINT-MIND participants will 
provide ample power to detect a 20% reduction in the rate of decline in cognitive function 
between the two arms (more intensive vs. less intensive blood pressure control).  In 
addition, MRI testing to detect differences in small vessel ischemic disease and total 
brain volume will provide 80% and 90% power, respectively, between the two strategy 
groups in SPRINT.   
 
 
Other secondary outcomes 
 
Several additional secondary outcomes will be examined, such as markers of renal 
function in non-CKD participants, co-morbidities, quality of life, and cost-effectiveness.  
Adverse events (e.g., postural hypotension, including falls) and biochemical changes will 
be measured and analyzed by randomized arm. 
 
 
 
 

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Chapter 1 – Introduction and Background  
 
1.  Background 
 
1.1 Hypertension, public health and the need for a clinical trial testing a lower SBP 
target. 
 
Elevated blood pressure (BP) is an important public health concern.   It is highly 
prevalent, the prevalence may be increasing, and it is a risk factor for several adverse 
health outcomes, especially coronary heart disease, stroke, heart failure, chronic kidney 
disease, and decline in cognitive function.  Given the high prevalence and severity of 
adverse outcomes, even small improvements in the treatment of elevated BP would 
result in widespread benefit.  The benefit of lowering SBP to around 140 mm Hg is well-
accepted, but patients treated to this level of BP are still at increased risk of BP-related 
adverse outcomes.   Observational studies document a progressive increase in risk as 
BP rises above 115/75 mm Hg.  Such epidemiologic evidence suggests there may be 
substantial benefit to targeting treatment to a SBP <120 mm Hg instead of <140 mm Hg.  
In contrast, targeting to <120 mm Hg may be harmful or unnecessarily costly and 
burdensome with limited expectation of benefit.  Apart from the Action to Control 
Cardiovascular Risk in Diabetes (ACCORD) trial, which was restricted to participants 
with diabetes mellitus, no clinical trial has been conducted to test the hypothesis that 
more intensive reduction in SBP to <120 mm Hg is beneficial compared to the current 
recommendation of a goal SBP <140 mm Hg.  At present, the results from clinical trials 
that have addressed related hypotheses are ambiguous.  A definitive clinical trial testing 
whether lowering SBP below 120 mm Hg is better than lowering SBP below 140 mm Hg 
in non-diabetic hypertensive patients is needed, and this has been designated by an NIH 
Expert Panel as the most important hypothesis to test regarding the prevention of 
hypertension-related complications (2007).  
 
1.1.1 Prevalence of hypertension  
 
Approximately 1 billion people worldwide have hypertension (HTN) (Kearney and others, 
2005).  HTN is highly prevalent in the adult population of the US, especially among those 
aged >60 years.  Two-thirds of those over age 60 have HTN, and the prevalence has  
increased in recent decades (Chobanian and others, 2003;Cutler and others, 
2008;Hajjar and Kotchen, 2003;Ong and others, 2007;World Health Organization, 2002).  
By age 50 years, isolated systolic hypertension (ISH) is the most common form of HTN, 
and is associated with greatest risk of target organ damage and adverse health 
outcomes (Franklin, 1999;Franklin and others, 2001).   
 
1.1.2 Hypertension as a cardiovascular risk factor 
 
The importance of BP, especially SBP, as an independent risk factor for coronary 
events, stroke, chronic heart failure (CHF), and ESRD is well documented (Vasan and 
others, 2001;Collins and others, 1990;Macmahon and others, 1990;Sacco and others, 
2001;Jackson, 2000;Staessen and others, 1997;Hsu and others, 2005;Chobanian and 
others, 2003;Gillum, 1991;Prospective Studies Collaboration, 2002;Levy and others, 
1996).  There is also substantial epidemiologic and clinical trial evidence supporting a 
role for hypertension therapy in reducing risk for age-related dementia, including 
vascular dementia and Alzheimer's dementia (Forette and others, 1998;Luchsinger and 

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Mayeux, 2004;Reitz and others, 2007;Skoog and Gustafson, 2003;Skoog and others, 
2005;Skoog and Gustafson, 2006;Tzourio and others, 2003).  Clinical trial data have 
shown reductions in CVD outcomes, including incident stroke (35% to 40%), MI (15% to 
25%), and CHF (up to 50%) (Chobanian and others, 2003;Psaty and others, 1997;Neal, 
Macmahon, and Chapman, 2000).   However, optimal targets for BP lowering are not 
established. 
 
1.1.3   Support for current target 
 
In addition to the Seventh Report of the Joint National Committee on Prevention, 
Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) (Chobanian and 
others, 2003), most recent practice guidelines recommend a target SBP <140 mm Hg in 
persons with established uncomplicated hypertension (Campbell and others, 
2009;Mancia and others, 2007;Mancia and others, 2009;National Collaborating Centre 
for Chronic Conditions, 2006;National Heart Foundation of Australia (National Blood 
Pressure and Vascular Disease Advisory Committee), 2009;Whitworth, 2003).  The 
benefits of lowering high BP in reducing CV morbidity and mortality are well-established 
(Cutler, MacMahon, and Furberg, 1989;Psaty and others, 1997).  A meta-analysis 
evaluating the treatment efficacy of hypertension therapy in adults over age 60, from 
three major trials from different countries (Liu and others, 1998;SHEP, 1991;Staessen 
and others, 1997) found that lowering SBP significantly reduced all-cause and CVD 
mortality by 17% and 25% respectively, and all CVD end-points by 32% (Staessen and 
others, 1999;Staessen, Wang, and Thijs, 2001), though both treatment goals and the 
achieved SBP were >140 mm Hg. 
 
1.1.4   Risk of SBP above normal but below current target 
 
The World Health Organization estimates that about two-thirds of the cerebrovascular 
disease burden and one-half of the coronary heart disease (CHD) burden on a 
worldwide basis is attributable to SBP >115 mm Hg (World Health Organization, 2002).  
Further, SBP > 115 mm Hg has been estimated to account for 7.6 million premature 
deaths (13.5% of the global total), 92 million disability-adjusted life years (6.0% of the 
global total), 54% of stroke, and 47% of ischemic heart disease.  About half of this 
burden is in persons with a SBP<145 mm Hg  (Lawes, Vander, and Rodgers, 2008).  
The JNC-7 defined pre-hypertension based on the evidence that SBP values between 
120 and 139 mm Hg and diastolic blood pressure (DBP) values between 80 and 89 mm 
Hg are associated with increased cardiovascular (CV) risk.  Although the risk of a BP 
between 120/80 and 139/89 mm Hg is not as pronounced as that associated with a BP 
above 140/90 mm Hg (Chobanian and others, 2003), 36% of the adult US population 
had a BP within this range in the 2007-2008 National Health and Nutrition Examination 
Survey (Wang and Wang, 2004).   
 
Strong evidence from large population-based longitudinal observational studies indicates 
that, regardless of other cardiovascular risk factors, SBP levels of about 115 mm Hg in 
adults over the age of 40 years are associated with lower CVD event rates, including 
death and slower progression of subclinical CVD (Lewington and others, 2002;Sipahi 
and others, 2006) compared to higher SBPs.  In the Framingham Heart Study (FHS), the 
risk of CVD following 10 years of follow-up among persons with SBP 130-139 mm Hg 
and/or DBP 85-89 mm Hg and SBP 120-129 mm Hg and/or diastolic blood pressure 
(DBP) 80-84 mm Hg was significantly higher when compared to their counterparts with 
SBP <120 mm Hg and DBP <80 mm Hg (Vasan and others, 2001).  Experience in the 

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Atherosclerosis Risk in Communities (ARIC) and Women’s Health Initiative (WHI) 
studies also showed that individuals with SBP of 120-139 mm Hg and/or DBP of 80-89 
mm Hg had an increased risk of CV events, relative to persons with SBP <120 mm Hg 
(Hsia and others, 2007;Kshirsagar and others, 2006).  A large meta-analysis of data 
from 61 population-based longitudinal epidemiological studies showed a strong 
continuous graded relationship between SBP and CVD death risk for all age deciles 
between 40-89 years, independent of other CVD risk factors, beginning at SBP levels of 
about 115 mm Hg (Lewington and others, 2002).  For those aged 40-69 years, there was 
an approximate doubling in the rates of death from stroke, ischemic heart disease and 
other vascular causes with each increase of 20 mm Hg in usual (that is, long-term 
average) SBP.   
 
1.1.5   Evidence for possible benefit of lower target on CV outcomes 
 
Clinical trial evidence of benefit from achieving SBP levels that approach the current  
recommended goal of <140 mm Hg with pharmacologic treatment is strong, but a trial  
specifically designed to test lowering the SBP treatment goal below the 140 mm Hg 
level, the ACCORD trial, found no clear evidence of benefit.   The ACCORD trial tested 
the research question of whether a therapeutic strategy aimed at reducing SBP to <120 
mm Hg was more effective in reducing CVD events than a strategy aimed at SBP <140 
mm Hg in participants who had diabetes and were at increased risk for CVD events.  
ACCORD found a non-significant reduction in CV events in the intensively treated group, 
though a lower than expected event rate contributed to an inability to exclude a clinically 
meaningful effect (The ACCORD Study Group, 2010). The lack of overall benefit was 
generally consistent across a variety of subgroups.   This is in contrast to prior 
experience of improved outcomes with more compared to less intensive BP reduction in 
the diabetic participants in the United Kingdom Prospective Diabetes Study (UKPDS) 
and in the diabetic subgroups in the Hypertension Optimal Treatment trial (HOT), 
Systolic Hypertension in the Elderly Program (SHEP) and Systolic Hypertension in 
Europe trial (Syst-Eur).   Importantly, none of these trials tested the same level of 
intensity of BP reduction or the low BP goal employed in ACCORD.  Consistent with 
previous trials, ACCORD did find a large reduction in the incidence of stroke in the 
intensively treated group, and though the incidence of serious adverse effects was 
significantly greater in the intensive treatment group, adverse events occurred with 
relatively low frequency overall. 
 
Results from overall or subgroup analyses of other CV outcome trials are mixed, with 
some providing support for the benefit of a lower BP goal but others not providing such 
evidence.  In addition, supportive data from other trials have generally been based on 
analyses of achieved BP rather than pre-defined treatment goals.  For example, the 
Hypertension Detection and Follow-up Program (HDFP) showed reductions in mortality 
(17%) and CVD mortality (19%) in participants randomized to Stepped Care treatment of 
hypertension compared with Referred Care.  Participants in the Stepped Care arm 
averaged 159 mm Hg at baseline and achieved SBP levels of 130 mm Hg at 4 years and 
140 mm Hg at 5 years of follow-up (Abernethy and others, 1986;HDFP, 1979b;HDFP, 
1979a;HDFP, 1982).  In the Heart Outcomes Prevention Evaluation (HOPE) study, the 
use of ramipril in high-risk patients lowered SBP by 3-4 mm Hg from a baseline mean of 
139 mm Hg compared to placebo and reduced the composite CVD endpoint that 
included CVD death (26%), MI (20%), stroke (32%), revascularization (15%), and CHF 
(23%) (Yusuf and others, 2000).  In the European Trial on Reduction of Cardiac Events 
with Perindopril in Stable Coronary Artery Disease (EUROPA), use of perindopril (vs. 

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placebo) resulted in a 5/2 mm Hg reduction in BP (from a mean baseline value of 137/82 
mm Hg) and a 20% reduction in CVD events (Fox, 2003).  The perindopril protection 
against recurrent stroke study (PROGRESS) showed a significant reduction in stroke 
and major vascular events associated with a 9/4 mm Hg reduction in BP  from a baseline 
mean of 147/86 mm Hg (PROGRESS Collaborative Group, 2001).  More importantly, in 
a prespecified subgroup analysis, those receiving 2 drugs (perindopril plus indapamide) 
had greater reductions in BP (12/5 mm Hg) and risk (43%) compared with placebo 
versus those on perindopril alone compared with placebo (5/3 mm Hg and 5%), 
supporting the hypothesis that lower BP is better.  There were similar reductions in the 
risk of stroke in hypertensive and non-hypertensive subgroups (all p<0.01).  Finally, in 
the Comparisson of Amlodipine vs. Enalapril to limit Occurences of Thrombosis trial 
(CAMELOT), a placebo-controlled trial of patients with heart disease and DBP <100 mm 
Hg (mean 129/78 mm Hg), amlodipine decreased BP by 4.8/2.5 mm Hg and CVD events 
by 31% (hazard ratio [HR], 0.69; 95% CI, 0.54-0.88); whereas enalapril lowered BP by 
4.9/2.4 mm Hg but did not decrease events (HR, 0.85; 95%CI 0.67-1.07) (Nissen and 
others, 2004). 
  
Other trials have not supported the hypothesis of benefit from a lower SBP target.  In the 
HOT study, there were no differences in CVD events between groups randomized to 
target DBPs of ≤90 mm Hg vs ≤85 mm Hg vs ≤80 mm Hg in the entire cohort of 18,790 
hypertensive participants; the average on-treatment SBP levels were 140 mm Hg and 
144 mm Hg, respectively, in the ≤80 and ≤90 mm Hg target groups (Hansson and 
others, 1998).  Only a post hoc analysis of the diabetic subgroup (n=1,501) showed that 
major CVD events were reduced by 51% (p=0.005) in those randomized to the lower BP 
goal.  The average on-treatment SBP levels were 140 mm Hg and 144 mm Hg in the 
≤80 and ≤90 mm Hg target groups, respectively (Hansson and others, 1998).  Likewise, 
there was no special benefit in those with an achieved SBP of 130 mm Hg vs. 134 mm 
Hg in the Prevention of Events with Angiotensin Converting Enzyme (PEACE) trial, 
which compared  trandolapril treatment to placebo in persons with stable coronary artery 
disease (Braunwald and others, 2004).  In the aggregate, these trials had only modest 
net reductions in SBP (4-6 mm Hg), though ACCORD and other trials have shown that a 
much larger reduction (14 mm Hg difference in SBP between the two arms) can be 
achieved. 
 
The ACCORD BP results provide a strong rationale for testing the potential benefits of 
intensive BP lowering.  (i) The confidence interval around ACCORD’s non-significant 
effect does not exclude benefit in the range of 20% to 25% reduction in the rate of CV 
events. Effects of that magnitude would be of considerable importance to public health.  
(ii) Serious adverse effects were significantly more frequent in the intensive treatment 
group, but occurred with low frequency overall.  (iii) People without diabetes, who are 
probably less prone to microvascular disease but were excluded from ACCORD, may 
benefit from more intensive BP lowering.  (iv) ACCORD excluded people with serum 
creatinine levels >1.5 mg/dL, which are prevalent in the US population and associated 
with high CV risk. (v) the glycemia arm of the ACCORD trial was stopped early because 
of an excess in total mortality and the possibility of interaction between these two 
interventions is still under investigation.  The safety and benefit of intensive BP reduction 
in patients > age 75 remain to be tested.  Thus, it is imperative that the potential benefits 
and harms of intense SBP-lowering be examined definitively in this and other high-risk 
populations, e.g. those with chronic kidney disease (CKD) or underlying CVD.   
   

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1.1.6 Possible harm from treatment of SBP to <120 mm Hg 
 
There are a number of reasons for requiring recommendations to lower SBP treatment 
goals be based on definitive trial evidence.  Treating to lower BP levels with medications 
could be harmful.  For example, one proposed mechanism that has some support in post 
hoc analyses of clinical trials (Cruickshank and others, 1987;Cruickshank, 2000;Somes, 
Shorr, and Pahor, 1999), known as the “J-curve” hypothesis, states that lowering DBP 
too much may decrease coronary artery perfusion and increase the risk of CVD events 
in patients with coronary artery disease (CAD).  In post-hoc observational analyses of 
clinical trial experience, the level of DBP below which risk increased has varied by trial, 
sometimes being as high as <85 mm Hg (Cruickshank and others, 1987).  In 
corresponding analyses of SHEP participants, the higher risk was reported with DBP 
<55-60 mm Hg during treatment (Somes and others, 1999). 
 
Further, if treatment has little or no benefit, adding drugs is a waste of patients’ and 
payers’ resources and time.  For example, in a cost-effectiveness analysis of the HOT 
trial, which overall did not show a significant benefit for lower DBP goals, the cost-
effectiveness ratios, expressed as cost per year of life gained, were most favorable for 
the DBP ≤90 mm Hg target group ($4262) and for added aspirin treatment ($12,710) 
(HOT, 1998).  In the moderately intensive treatment (DBP ≤85 mm Hg) group, the cost-
effectiveness ratio escalated to $86,360; with intensive treatment (DBP ≤80 mm Hg), 
costs further increased to $658,370 per year of life gained. Only treatment to a DBP 
target of 90 mm Hg and co-administering aspirin were considered highly cost effective; 
intensive BP lowering down to 80 mm Hg was clearly very costly. 
 
A third reason for not recommending lower SBP goals without definitive clinical trial 
evidence relates to the increased number of drugs required to achieve these goals.  For 
example, in the African American Study of Kidney disease and hypertension (AASK) 
trial, the intensive BP goal (achieved SBP = 128 mm Hg) group required an average of 
3.04 drug classes compared with 2.39 in the conventional BP goal group (Wright, Jr. and 
others, 2002a) and in the ACCORD  BP trial experience >3 drug classes were required 
for the intensive SBP goal group to achieve a SBP average of 119 mm Hg, compared 
with  2  classes in the standard SBP goal group with a mean SBP achieved of 134 mm 
Hg (The ACCORD Study Group, 2010).  In addition to being more costly and having 
greater potential for drug-related adverse events, even 1-2 more medications per day 
may contribute to reduced adherence to other evidence-based drug treatment (e.g., 
statins or aspirin). Patients may choose to not take medications without more evidence 
for safety and benefit. In addition to being more costly, burdensome, and potentially 
risky,  a 20-mm Hg lower SBP goal (and/or a 10 mm Hg lower DBP goal) would likely 
mean  that up to 70-80 million Americans now considered "prehypertensive" may require 
drug therapy  for a condition that has not been proven to be benefited by treatment 
(Greenlund, Croft, and Mensah, 2004). 
 
Finally, all medications carry an intrinsic risk of side effects which may adversely affect 
clinical outcomes and quality of life, and lead to drug interactions, especially in older 
persons who may need to take a variety of medications.   
 
1.1.7 Conclusion 
 
If the SPRINT results are positive and support a SBP goal <120 mm Hg, and this is fully 
applied in practice a large number of major CVD could be prevented each year, in the 

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U.S. alone.  If the results are negative and SPRINT is sufficiently powered and well-
conducted, then recommendations for SBP goal in the treatment of most hypertensive 
patients, including those with stage 3 CKD and pre-existing CVD, would 1) allow for a 
redoubled focus on achieving a SBP goal of <140 mm Hg, and 2) abrogate the need for 
the additional effort and cost of achieving a lower SBP goal than currently recommended 
for most patients with elevated BP.  If none of the major outcomes show harm from 
lowering to <120, and if any of the outcomes are positive, SPRINT may make a 
substantial contribution to public health.   
 
1.2  SPRINT’s target patient population 
 
Although epidemiologic evidence strongly suggests that lowering SBP will reduce CVD 
risk in nearly all adults, for practical and public health reasons the hypothesis is most 
efficiently studied in high-risk individuals.  A high risk population stands to benefit most in 
the sense that a greater number of events may be prevented per treated individual.  
Furthermore, results in a diverse high risk population will likely generalize to lower risk 
populations, at least in terms of relative risk reduction.  Thus, the SPRINT trial will recruit 
patients 50 years or older with SBP >130 mm Hg who either have or are at high risk for 
CVD.  SPRINT will focus on three high risk groups:  individuals with clinical CVD other 
than stroke, individuals with CKD (estimated glomerular filtration rate [eGFR]  20-59 
ml/min/1.73 m2), and individuals without clinical CVD who have high estimated CVD risk  
based on factors such as smoking, low levels of HDL, high levels of LDL or age.   Three 
other groups will be excluded: patients with diabetes, patients with polycystic kidney 
disease (PKD), and patients who have had a stroke.   Patients with diabetes have been 
studied in the ACCORD trial; patients with prior stroke and PKD are part of other 
ongoing trials. 
 
1.2.1 Chronic Kidney Disease (CKD) 
 
An important and under-studied high-risk group for CVD is the population with CKD 
(Coca and others, 2006).  In the U.S., the number of persons with Stage 3 CKD (eGFR 
between 30 and 60 ml/min/1.73 m2) has recently been estimated to be 7.7% of the adult 
population, or 15.5 million (Coresh and others, 2007).  Patients with prevalent CVD have 
a high prevalence of CKD, with reported ranges of 30-60% (Keeley and others, 
2003;Levey and others, 1998;Shlipak and others, 2002).   
 
Individuals with CKD are at high risk for CVD events (Shlipak and others, 2009;Go and 
others, 2004;Rahman and others, 2006;Weiner and others, 2004;Foster and others, 
2007;McCullough and others, 2007;Rashidi and others, 2008;Fried and others, 2009).  A 
meta-analysis of reported data from prospective studies in Western populations 
demonstrated that people with an eGFR of <60 ml/min/1.73m2 have a relative risk of 1.4 
for CVD, compared to those with an eGFR of >60 ml/min/1.73m2 (Di Angelantonio and 
others, 2007).  The relative risk increases as eGFR declines (Go and others, 2004).  
Pooled data from the ARIC and CHS cohorts demonstrated that participants with CKD 
were also at increased risk for stroke (Weiner and others, 2007), and CKD was a risk 
factor for CVD and all-cause mortality independent of traditional CVD risk factors 
(Weiner and others, 2004).  In ALLHAT, despite exclusion criteria designed to exclude 
participants with significant GFR impairment, about 18% of participants had an eGFR 
30-60 ml/min/1.73m2.  In that CKD subgroup, CHD was 38% higher and combined CVD 
35% higher than in those with an eGFR >90 ml/min/1.73m2 (Rahman and others, 2006).  

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The effect of BP control on the development of CVD in the CKD population is far less 
clear (Berl and others, 2005). 
A strategy of treating to a lower BP goal may reduce the progression of kidney disease. 
The risk of CKD increases progressively beginning with pre-HTN levels of BP through 
the various stages of HTN (Haroun and others, 2003).  Several observational studies 
have suggested that achievement of lower BP is associated with lower risk of adverse 
kidney outcomes (Bakris and others, 2000;Klag and others, 1996;Schaeffner and others, 
2008).  However, two  randomized clinical trials, AASK and the Modification of Diet in 
Renal Disease Study (MDRD) that examined lower-than-usual BP goals failed to show 
an overall significant beneficial long-term effect of lower BP on decline in kidney function 
(Klahr and others, 1994;Wright, Jr. and others, 2002b)  Both studies enrolled participants 
with non-diabetic CKD and randomized them to a mean arterial pressure (MAP) goal of 
<92 mm Hg (corresponding to <125/75 mm Hg) or a MAP goal of <107 mm Hg 
(corresponding to <140/90 mm Hg).  The AASK trial compared two BP goals based on 
MAP (102-107 vs. <92 mm Hg) in 1094 African Americans with hypertensive kidney 
disease; the achieved difference of 128/78 vs. 141/85 did not reduce the progression of 
CKD (Wright, Jr. and others, 2002b).  However, subgroup analyses of long-term (up to 
10 years) post trial follow-up suggested the possibility of  benefit in participants with 
baseline urinary protein excretion equivalent to >300 mg/day who were randomized to 
the lower goal (Appel and others, 2008).  Among 585 non-diabetic participants with 
Stage 3/4 CKD in MDRD, 24% had PKD and only 53 were African American (Klahr and 
others, 1994).  Mean baseline proteinuria was 2.2 g/d, and a beneficial effect of the 
lower BP goal on GFR was observed in the subgroup with urinary protein > 1 g/d 
(Peterson and others, 1995;Sarnak and others, 2005).  In addition to the inherent 
problems associated with subgroup analysis, major caveats of these results from the 
MDRD Study were that the number of patients in the heavy proteinuric subgroups was 
small and the results were confounded by the use of angiotensin converting enzyme 
(ACE) inhibitors.  Together, these studies fail to show convincing renoprotective effects 
for the lower BP goal; however their results have led to clinical recommendations that 
patients with high levels of proteinuria should have blood pressure goals below 140/90 
mm Hg. They were not adequately powered to consider CVD outcomes.  Nonetheless, 
they successfully demonstrated the feasibility of achieving significant separation in BP in 
large cohorts with advanced CKD.  Given the rapid increase in the prevalence of CKD, 
the effects of aggressively lowering BP on the risks of CVD and CKD progression need 
to be clarified in a sample that appropriately mirrors the U.S. population with CKD 
(Sarnak and others, 2003).   
 
1.2.2 SENIOR participants and SPRINT-MIND 
 
Including a large subgroup of participants aged 75+ will provide data on whether 
intensive BP treatment will reduce CVD and renal events in the elderly.  Both the 
Treatment of Hypertension in Patients over 80 Years of Age (HYVET) (Beckett and 
others, 2008) and the SHEP (SHEP, 1991) trials found that a SBP delta of 15 and 11 
mm Hg, respectively, between treated and placebo groups resulted in >30% reduction in 
stroke, HF, and overall CVD events in the treated groups.  Unlike HYVET and SHEP, 
which had SBP levels of about 150 and 143 mm Hg at the end of the trials, SPRINT will 
have a substantially lower SBP target of <120 mm Hg in the intensive treatment group, a 
goal which has never been tested in the elderly.  No previous large scale trial has 
examined the impact of treating SBP in the elderly to <120 mm Hg versus <140 mm Hg.   
 

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Importantly, the elderly pose an additional question as to the safety of intensive SBP 
lowering in a population with known wider pulse pressures and a risk of excessively low 
DBP with intensive SBP treatment.  In addition to concerns about hypotension, syncope, 
and falls, there may be a point of maximal benefit beyond which lowering BP could be 
detrimental in the elderly.  This is a specific concern related to very low DBP, which 
could compromise coronary blood flow.  The SPRINT-Senior cohort will allow us to more 
precisely assess the safety of the lower SBP goal.   
 
The SPRINT Senior cohort also provides a critically important the main body of 
participants for SPRINT-MIND.  Dementia is a leading cause of placement into nursing 
homes and assisted living facilities (guero-Torres and others, 2001;Guralnik and others, 
1997;Magsi and Malloy, 2005;National Institute on Aging, 2000). Dementia affects 24 
million individuals globally and 4.5 million persons in the US, a number that is expected 
to double by 2040 (Ferri and others, 2005;Plassman and others, 2007). Both dementia 
and a precursor, mild cognitive impairment (MCI), are highly prevalent among adults 
over age 70, with estimates running between 15-20% and 40-50% respectively in 
persons over age 80. In addition, there is evidence that MCI is also highly prevalent in 
persons above age 60 with CKD. Notably, approximately 15% of persons with MCI 
progress to dementia each year (Petersen, 2000), accruing substantial negative societal 
impact, and threatening the quality of life of its victims, their families and other 
caregivers.  Proven strategies for prevention and delay of cognitive decline and 
dementia are lacking, and there is a clear need for clinical trials testing promising 
preventive interventions.  Even a moderately effective strategy could have tremendous 
benefits, with a 5-year delay in onset of dementia estimated to decrease the number of 
cases of incident dementia by about 50% after several decades (Brookmeyer and 
others, 2002).  
 
Cognitive impairment can have multiple etiologies and vascular risk factors are 
implicated in a large proportion of dementias including neurodegenerative dementias like 
Alzheimer’s type (Qiu, Winblad, and Fratiglioni, 2005c). With this strong link to CVD risk 
plus several observational studies suggesting that the ideal SBP to lower CVD risk may 
be below 120 mm Hg (Chobanian and others, 2003) it is possible that targeting intensive 
blood pressure control intensive blood pressure control may have substantial 
implications for preserving brain function.    
 
Substantial epidemiologic evidence identifies hypertension as a risk factor for dementia. 
Longitudinal observational studies have yielded mixed results, depending on the age at 
which blood pressure  is measured, the impact and duration of treatment, duration of 
hypertension, and level of BP control (Birns and others, 2006;Qiu, Winblad, and 
Fratiglioni, 2005).  Midlife hypertension appears to increase the risk of all-cause 
dementia in large prospective cohort studies (Freitag and others, 2006;Kivipelto and 
others, 2001b). However, lower SBP in older adults has been associated with 
subsequent development of dementia (Nilsson and others, 2007). Clinical trials of 
antihypertensive treatment have also provided conflicting experience regarding the 
impact of treatment of hypertension on the risk of cognitive impairment and dementia in 
older people (Guo and others, 1999;Hajjar and others, 2005; Veld and others, 2001). 
Four large randomized, placebo-controlled studies have investigated the effects of 
antihypertensive agents on the incidence of dementia. The Syst-Eur (Staessen and 
others, 1997) and the Perindopril Protection Against Recurrent Stroke Study 
(PROGRESS) studies (Tzourio and others, 2003) found that more aggressive 
antihypertensive treatment reduced the rate of small vessel ischemic disease (also the 

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primary outcome of SPRINT MIND MRI), a risk factor for dementia (Dufouil and others, 
2009), as well as reducing dementia incidence by 50% compared to placebo. In contrast, 
the Study on Cognition and Prognosis in the Elderly (SCOPE) and SHEP trials (SHEP, 
1991) found no significant difference in incidence of dementia between the active 
treatment and placebo groups, although differential missing data for the placebo vs. 
treatment groups may explain the SHEP findings (Di Bari and others, 2001). More 
recently, the HYVET-COG, a BP lowering trial in people age ≥80, was powered to detect 
a 33% reduction in adjudicated incident dementia (Peters 2008). The trial was stopped 
prior to its planned date of completion due to significant reductions in stroke and all-
cause mortality in the intervention group.  It yielded a 14% non-significant reduction in 
incident dementia.  One reason for the non-significant result was a loss of power due to 
the unexpectedly early conclusion of follow-up, resulting in a relatively short, two-year 
period of follow-up. One possible explanation for the ambiguous relationships described 
between hypertension, hypertension treatment and preservation of cognitive function is 
that the cognitive measures included in most of these trials have not been sensitive 
enough to detect early, but clinically important, cognitive changes in a cohort with intact 
general cognitive function at baseline. Studies using more sensitive neuropsychological 
tests, such as the testing proposed for SPRINT-MIND, have shown the strongest 
relationships (Elias and others, 1993;Kivipelto and others, 2001a;Kivipelto and others, 
2001c;Knopman and others, 2001).   
 
Hypertension is the primary risk factor for small vessel ischemic disease and cortical 
white matter abnormalities (Basile and others, 2006;Kuller and others, 2010;Liao and 
others, 1996;Longstreth, Jr. and others, 1996). Chronic kidney disease is also 
associated with white matter abnormalities (Ikram and others, 2008), thus the SPRINT 
population is at high risk for significant white matter changes. Longitudinal studies 
document that hypertension-associated white matter abnormalities are an independent 
risk factor for cognitive decline and dementia (Verdelho and others, 2007;Vermeer and 
others, 2003), lower extremity functional abnormalities (Rosano and others, 2005), and 
clinical stroke (Debette and others, 2010).  However, there is limited evidence that better 
control of BP slows the progression of white matter lesions in the brain (Dufouil and 
others, 2005).  Recently reported results from the Women’s Health Initiative Memory 
Study (WHIMS) indicate that white matter volume (detected by MRI) is associated with 
baseline BP, even after adjustment for treatment, other CVD risk factors, and age (Coker 
L.H. and others, 2008).  Although the beneficial effects of treating hypertension on CVD, 
such as stroke have been shown (Collins and others, 1990), it is not known whether 
intensive lowering of SBP as proposed in SPRINT will provide reduction in the risk for 
developing white matter disease and brain volume loss. 
 
SUMMARY 
 
Higher than optimal BP is the leading cause of disability adjusted life-years lost on a 
global basis, and more intensive control of SBP than is currently recommended may 
contribute to reductions in stroke, heart failure, coronary heart disease, chronic kidney 
disease, and dementia.  This potential benefit must be weighed against potential risks, 
including complications resulting from low coronary, cerebral, and renal perfusion 
pressure and the medications themselves.  Definitive evidence from a well designed and 
conducted trial should form the foundation for pertinent recommendations and 
healthcare policies. 
 
 

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Chapter 2 – Overview of Trial Design 
 
The SPRINT randomized controlled clinical trial will examine the effect of a high BP 
treatment strategy aimed at reducing SBP to a lower goal than is currently 
recommended.   The primary objective is to determine whether randomization to this 
intensive strategy is more effective than a standard strategy in reducing the incidence of 
serious cardiovascular disease events.  Other important study objectives are to assess 
the impact of more intensive SBP reduction on renal function, incidence of probable 
dementia, quality of life, cost-effectiveness, cognitive function and small vessel ischemic 
disease.   
 
The study cohort will include approximately 9250 people aged ≥ 50 years with SBP ≥130 
mm Hg. SPRINT will focus on three high risk groups:  patients with clinical CVD other 
than stroke, patients with chronic kidney disease (estimated glomerular filtration rate 
(eGFR) 20  -59 mL/min/1.73 m2), and patients who have a Framingham Risk Score 
(FRS) of ≥15%.    Participants will be recruited over a 2-year period at approximately 80 
to 100 clinics in 5 clinical center networks (CCNs) and will be followed for up to 6 years.  
Both the number of randomizations and the length of follow-up may differ from these 
targets depending on how observed values of parameters differ from estimates used to 
design the study.  Approximately 4300 SPRINT participants will have CKD, and 3250 will 
be age 75 or older.  Chapter 3 presents the eligibility criteria for the trial. 
 
Participants will be stratified by clinic and randomly assigned to either the intensive or 
standard SBP lowering strategy.  Chapter 4 and 5 provides a general description of the 
intervention.   
 
The primary outcome will be a composite end-point consisting of the first occurrence of a 
myocardial infarction (MI, by electrocardiogram (ECG) or hospitalization), stroke, heart 
failure, non-MI acute coronary syndrome, or CVD death.  Study outcomes are described 
in Chapters 6, 7 and 9. 
 
The sample size for SPRINT is estimated to provide 90% power to detect a 20% relative 
decrease in the rate of the composite primary outcome in participants randomized to the 
more intensive SBP lowering strategy. Sample size estimation is described further in 
Chapter 10. 
 
The major objectives of the SPRINT trial are as follows: 
 
2.1 
Primary Hypothesis 
 
In people aged ≥ 50 years with SBP ≥130 mm Hg and either a history of CVD, eGFR 
between  20 and 59, or a Framingham Risk Score (FRS) indicating 10-year CVD risk of 
≥15%, does a therapeutic strategy that targets a SBP of < 120 mm Hg reduce the rate of 
CVD events compared to a strategy that targets a SBP of < 140 mm Hg?   This 
hypothesis will be tested using a composite outcome including 
• 
cardiovascular death,  
• 
myocardial infarction,  
• 
stroke,  
• 
heart failure, and 
• 
non-MI acute coronary syndrome 

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ascertained over a follow-up period of up to 6 years.  Interim monitoring for overall trial 
efficacy will be based on the accrued rate of this primary outcome. The anticipated event 
rate for this outcome is 2.2%/year.   
 
2.2 
Subgroup Hypotheses  
 
SPRINT will examine intervention effects in a number of subgroups; these are presented 
in greater detail in Chapter 10.   Two subgroups are of particular interest due their 
connection to possible biological mechanisms affecting the primary outcome:  
 
1. participants with and without CKD (eGFR <60 ml/min/1.73m2) at baseline,  
2. participants < or ≥ 75 years at baseline. 
 
Consistency of the effects for the intervention on the primary outcome will also be 
examined in subgroups defined by gender, race/ethnicity (black vs. non-black), presence 
of clinical CVD at baseline (i.e., primary and secondary prevention participants) and 
tertiles of baseline systolic BP. 
 
Subgroup analyses for secondary outcomes are described in Chapter 10.   
 
2.3 
Secondary Hypotheses  
 
SPRINT prespecifies two types of secondary hypotheses.  The first type will address 
secondary outcomes in analyses designed to support and confirm the primary analysis.  
These will include components of the primary composite outcome, total mortality, and a 
composite of the primary composite with total mortality (CVD-free survival).  The other 
type addresses two areas of non-cardiovascular clinical effects: renal and cognitive 
outcomes.   
 
2.3.1 Objectives for renal outcomes and the CKD subgroup 
 
1.  For the CKD subgroup, we will determine whether the intensive intervention arm 
experiences a lower rate of a composite of renal outcomes composed of: 
• 
ESRD or 
• 
A 50% decline from baseline eGFR  
 
2.  For the non-CKD subgroup, we will determine whether the intensive intervention arm 
experiences a lower rate of progression to CKD, defined as 
• 
ESRD or 
• 
30% decrease from baseline eGFR and an end value of <60 ml/min/1.73M2  
 
2.3.2 SPRINT MIND Hypotheses 
 
1. All-cause Dementia.  The incidence of all-cause dementia will be lower in SPRINT 
participants assigned to the intensive SBP treatment arm compared to their 
counterparts assigned to the standard SBP treatment arm. 
 
2. Cognitive Decline.  The combined rate of decline in all domains of cognition will be 
slower in the intensive SBP treatment arm compared to the standard SBP treatment 

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arm. This hypothesis will be tested in a randomly selected subset of 2800 
participants enrolled in SPRINT.  
 
3. MRI Brain Changes.  The volume small vessel ischemic disease (SVID) will be lower 
in SPRINT participants assigned to the intensive SBP treatment arm compared to 
their counterparts assigned to the standard SBP treatment arm. A sub-hypothesis is 
that total brain volume will also be greater (thus less atrophy) in the intensively 
treated group. The MRI sub-study will be conducted in 640 participants chosen from 
the 2800 selected to receive regular extensive cognitive assessment. 
 
 
 

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Chapter 3 – Participant Selection  
 
3.1 Eligibility Criteria            
 
The objective of setting inclusion/exclusion criteria is to identify a trial population that will 
ensure adequate event rates for statistical power, provide maximum generalizability, and 
maximize safety.  Inclusion/exclusion criteria were made as simple as possible to ensure 
standard implementation across all SPRINT study sites.  Specifically, the SPRINT 
eligibility criteria were developed to facilitate the identification and inclusion of a trial 
population at high risk for the major trial endpoints, including CVD, CKD, cognitive 
decline, and dementia.  Hence, the trial population is comprised of individuals in three 
major classes: those with existing CVD, existing CKD, or an elevated estimated risk for 
CVD disease based on age and other risk factors.   
 
Implementation of these inclusion and exclusion criteria and related recruitment 
strategies will be accomplished to meet several goals with respect to composition of the 
study population.  The overall goal for recruitment is 9,250 participants, although the 
final number of randomizations may be between 8,500 and 10,000.  For the target of 
9,250 participants, we will strive to include approximately 4300 (46%) with chronic 
kidney disease (eGFR 20 -59 ml/min/1.73m2), expected to be divided approximately 
evenly below and above 45 ml/min/1.73m2, and approximately 3250 (35%) who are at 
least 75 years old.  In addition, we will strive to include 50% women, 40% minorities, and 
40% with clinical or subclinical cardiovascular disease.  Among these goals there is an 
implicit hierarchy based on study hypotheses and design considerations: first, attain the 
overall sample size, to preserve power for the main hypothesis of SPRINT; second, 
reach the required sample sizes for formal sub-group hypotheses among participants 
with CKD and among seniors; and third, ensure a sufficiently diverse study population so 
that results are broadly applicable to the affected U.S. population.  We will monitor these 
goals on an ongoing basis and the Recruitment, Retention, and Adherence 
Subcommittee and the Steering Committee will evaluate recruitment strategies and 
implement corrective actions.   
    
 
a) Inclusion Criteria 
 
1. At least 50 years old 
 
2. Systolic blood pressure  
SBP: 130 – 180 mm Hg on 0 or 1 medication 
SBP: 130 – 170 mm Hg on up to 2 medications 
SBP: 130 – 160 mm Hg on up to 3 medications 
SBP: 130 – 150 mm Hg on up to 4 medications 
 
3. There are no diastolic blood pressure (DBP) inclusion criteria, since risk is more 
related to SBP than DBP in the age and risk population anticipated for SPRINT.  If a 
screenee is otherwise eligible for SPRINT but presents with a treated BP and/or 
number of medications that fall outside the SPRINT inclusion criteria, BP-lowering 
medications may be adjusted prior to the randomization visit to determine whether, 
with such adjustments, the screenee will meet eligibility criteria for SPRINT. A 
screenee who presents on no BP medications should have documentation of SBP 

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≥130 mm Hg on 2 visits within 3 months prior to the randomization visit in order to be 
eligible for the trial. 
 
4. Risk (one or more of the following): 
a) Presence of clinical* or subclinical** cardiovascular disease other than stroke 
b) CKD, defined as eGFR   20 – 59 ml/min/1.73m2 based on the 4-variable 
Modification of Diet in Renal Disease (MDRD) equation and latest lab value, 
within the past 6 months. (If the serum creatinine is unstable within the last 6 
months, enrollment into SPRINT could be delayed until the serum creatinine 
has been stabilized and the eGFR is still within the allowed range.) 
c) Framingham Risk Score for 10-year CVD risk ≥ 15% based on laboratory 
work done within the past 12 months for lipids  
d) Age ≥ 75 years. 
 
5. Clinical CVD (other than stroke) 
a) Previous myocardial infarction (MI), percutaneous coronary intervention 
(PCI), coronary artery bypass grafting (CABG), carotid endarterectomy 
(CE), carotid stenting  
b) Peripheral artery disease (PAD) with revascularization 
c) Acute coronary syndrome with or without resting ECG change, ECG 
changes on a graded exercise test (GXT), or positive cardiac imaging 
study  
d) At least a 50% diameter stenosis of a coronary, carotid, or lower extremity 
artery 
e) Abdominal aortic aneurysm (AAA) ≥5 cm with or without repair 
 
6. Subclinical CVD 
a) Coronary artery calcium score ≥ 400 Agatston units within the past 2 
years. 
b) Ankle brachial index (ABI) ≤0.90 within the past 2 years. 
c) Left ventricular hypertrophy (LVH) by ECG (based on computer reading), 
echocardiogram report, or other cardiac imaging procedure report within 
the past 2 years. 
 
b) Exclusion Criteria 
 
1. An indication for a specific BP lowering medication (e.g., beta-blocker following 
acute myocardial infarction) that the person is not taking and the person has not 
been documented to be intolerant of the medication class. (If a screenee has a non-
hypertension indication for a BP-lowering medication (e.g., beta-blocker post-MI, 
renin angiotensin system (RAS) blocker for CVD prevention, or alpha blocker for 
benign prostatic hypertrophy (BPH)), the screenee should be on the appropriate 
dose of such medication before assessing whether he/she meets the SPRINT 
inclusion criteria.  If the investigator believes that a potential participant has such an 
indication but is not receiving appropriate treatment, he/she should encourage the 
potential participant’s primary care provider to consider placing the patient on the 
appropriate therapy prior to proceeding with the screening process.) 
2. Known secondary cause of hypertension that causes concern regarding safety of 
the protocol. 
3. One minute standing SBP < 110 mm Hg.  Not applicable if unable to stand due to 
wheelchair use. 

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4. Proteinuria in the following ranges (based on a measurement within the past 6 
months) 
(a) 24 hour urinary protein excretion ≥1 g/day, or  
(b) If measurement (a) is not available, then 24 hour urinary albumin excretion ≥ 
600 mg/day, or  
(c) If measurements (a) or (b) are not available, then spot urine protein/creatinine 
ratio ≥ 1 g/g creatinine, or 
(d) If measurements (a), (b), or (c) are not available, then spot urine 
albumin/creatinine ratio ≥ 600 mg/g creatinine, or  
(e) If measurements (a), (b), (c), or (d) are not available, then urine dipstick ≥ 2+ 
protein 
5. Arm circumference too large or small to allow accurate blood pressure 
measurement with available devices 
6. Diabetes mellitus.  Participants taking medications for diabetes at any time in the 
last 12 months are excluded.   Participants are also excluded if there is 
documentation of: FPG at or above 126 mg/dL, A1C ≥6.5 percent, a two-hour value 
in an OGTT (2-h PG) at or above 200 mg/dL or a random plasma glucose 
concentration ≥200 mg/dL.  The diagnosis of diabetes must be confirmed on a 
subsequent day by repeat measurement, repeating the same test for confirmation. 
However, if two different tests (eg, FPG and A1C) are available and are concordant 
for the diagnosis of diabetes, additional testing is not needed. If two different tests 
are discordant, the test that is diagnostic of diabetes should be repeated to confirm 
the diagnosis.  
7. History of stroke (not CE or stenting) 
8. Diagnosis of polycystic kidney disease 
9. Glomerulonephritis treated with or likely to be treated with immunosuppressive 
therapy 
10. eGFR <   20 ml/min /1.73m2 or end-stage renal disease (ESRD)  
11. Cardiovascular event or procedure (as defined above as clinical CVD for study 
entry) or hospitalization for unstable angina within last 3 months 
12. Symptomatic heart failure within the past 6 months or left ventricular ejection 
fraction (by any method) < 35% 
13.    A medical condition likely to limit survival to less than 3 years, or a cancer 
diagnosed and treated within the past two years that, in the judgment of clinical 
study staff, would compromise a participant’s ability to comply with the protocol and 
complete the trial.  Exceptions to the exclusion for diagnosed cancer would include, 
for example, non-melanoma skin cancer, early-stage prostate cancer, localized 
breast cancer. 
14. Any factors judged by the clinic team to be likely to limit adherence to interventions.  
For example, 
(a) Active alcohol or substance abuse within the last 12 months  
(b) Plans to move outside the clinic catchment area in the next 2 years without 
the ability to transfer to another SPRINT site, or plans to be out of the study 
area for more than 3 months in the year following enrollment. 
(c) Significant history of poor compliance with medications or attendance at clinic 
visits  
(d) Significant concerns about participation in the study from spouse, significant 
other, or family members 
(e) Lack of support from primary health care provider 

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(f) Residence too far from the study clinic site such that transportation is a 
barrier including persons who require transportation assistance provided by 
the SPRINT clinic funds for screening or randomization visits  
(g) Residence in a nursing home. Persons residing in an assisted living or 
retirement community are eligible if they meet the other criteria. 
(h) Clinical diagnosis of dementia, treatment with medications for dementia, or in 
the judgment of the clinician cognitively unable to follow the protocol 
(i) Other medical, psychiatric, or behavioral factors that in the judgment of the 
Principal Investigator may interfere with study participation or the ability to 
follow the intervention protocol 
15. Failure to obtain informed consent from participant  
16. Currently participating in another clinical trial (intervention study). Note: Patient must 
wait until the completion of his/her activities or the completion of the other trial 
before being screened for SPRINT. 
17. Living in the same household as an already randomized SPRINT participant 
18. Any organ transplant 
19. Unintentional weight loss > 10% in last 6 months 
20. Pregnancy, currently trying to become pregnant, or of child-bearing potential and 
not using birth control 
 
 
 
c) Additional Criteria 
I. SENIOR  
 
Whereas there are no eligibility criteria specific to the SENIOR subgroup other than age, 
the general eligibility criteria were influenced by consideration of factors of importance to 
the inclusion of older participants in SPRINT, including cognitive status, orthostasis, 
transportation, and site of residence (e.g., nursing home).  The goal is to assemble a 
representative population of older patients for whom intensive BP lowering is reasonable 
to consider from a medical perspective.  This goal is motivated by the perspective that 
there may be some older persons with advanced frailty and/or multiple comorbid 
conditions whose health is so poor that it would not be reasonable to attempt to treat 
SBP as intensively as needed to control SBP to less than 120 mm Hg. 
 
II. Participants with CKD 
 
For the purposes of SPRINT, qualifying CKD is defined by eGFR, determined during the 
6 months prior to randomization, between  20 and 59 ml/min/1.73m2, inclusive, based on 
the 4-variable MDRD equation.  Patients with significant proteinuria, defined as a 24-
hour urine protein excretion exceeding 1 gram, or rough equivalents thereof (see 
Exclusion Criterion 4 above), will be excluded from SPRINT based on evidence from 
previous trials suggesting that intensive BP lowering therapy may be beneficial with 
respect to slowing the progression of CKD.  The vast majority of participants with CKD 
so defined will likely be at high risk for CVD.  An estimated 82.3% of those who qualify 
with eGFR between 45 and 59 ml/min/1.73m2 will have a Framingham Risk Score for 
CVD exceeding 15% over 10 years, and an estimated 71.2% have a Framingham Risk 
Score for CVD exceeding 20% over 10 years; hence, these participants will contribute 
substantially to the overall event rate and provide the basis for informative subgroup 
analyses. 
 
III. MIND 

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Dementia Screening - All individuals will receive dementia screening at baseline and 
every 2 years following baseline.  Individuals who have been previously diagnosed with 
dementia by their physicians are excluded from SPRINT and SPRINT MIND. 
 
Comprehensive Cognitive Assessment substudy – A subset of 2800 participants 
enrolled in SPRINT will also be assigned to undergo more extensive cognitive 
assessment to evaluate the impact of the intervention on decline in overall and domain-
specific cognitive function that does not meet criteria for dementia. With limited 
exceptions, all clinics will enroll participants into this 2800 subset, and this subgroup is 
expected to be representative of all randomized participants, including the important 
CKD and SENIOR participants.  
 
IV. MIND MRI 
 
Individuals who enroll in the Comprehensive Cognitive Assessment substudy at a clinic 
within sufficient proximity to a SPRINT MIND MRI center, generally defined as within a 2 
to 3 hour driving radius, are eligible to enroll in the MIND MRI Study.  The MIND MRI 
Study will have a recruitment goal of approximately 640 participants. Standard safety-
related exclusions pertaining to the ability to have a magnetic resonance imaging 
procedure performed will be applied. 
 
Recruitment and risk implications of inclusion and exclusion criteria 
 
As shown in Table 3.1, according to analyses of the National Health and Nutrition 
Examination Survey (NHANES) data for 1999-2004, approximately 6% of the US 
population meets the basic eligibility criteria related to age and SBP, and are free of 
diabetes and previous stroke.  Among that group, approximately 70% meet the risk 
criteria described above.  The vast majority of these individuals have an estimated 10-
year risk of CVD exceeding 20% and the population average 10-year risk for CVD is 
approximately 28%.  (Note that the use of the FRS in this manner likely underestimates 
the risk of those individuals with existing CHD and stage 3 CKD.)  This analysis provides 
evidence that the recruitment pool will be large enough to enable us to recruit 
successfully and to generalize our ultimate results to a reasonably large proportion of the 
US population. 
 
Table 3.1.  Distribution of 10-year risk of CVD in NHANES participants who met basic 
SPRINT eligibility criteria 
Criteria 
% of US 
Population 
meeting basic 
eligibility criteria 
(age, SBP, no 
DM or stroke) 
% of those 
meeting basic 
eligibility 
requirements 
who meet risk 
criteria 
10-year CVD Risk Distribution 
(%) 
Mean 
10-yr 
CVD 
risk 
(%) 
5-
10% 
10-
15% 
15-
20% 
20+% 
CHD or Stage 3 
CKD or FR>15% 
6.7 
70.3 
1.3 
3.2 
24.3 
71.1 
28.6 
 
In additional analyses of the NHANES potentially eligible pool, 16.3% had stage 3 CKD  
(3.6% had eGFR < 45ml/min/1.73m2), 15.6% had a history of CVD, 34.6% were 75 
years old or older, 8.1% were African Americans, and 49.8% were women.  Stage 3a 
CKD, defined as eGFR 45-59 ml/min/1.73m2, but a urine albumin-to-creatinine (ACR) ≤ 

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10 mg/g, comprised 6.1% of the eligible pool..  These analyses, shown in Table 3.2, 
provide evidence to support our recruitment targets for participants with CKD, in the 
SENIOR population, minorities and women. 
 
Table 3.2.  Characteristics of SPRINT eligible sample based on NHANES data.   
Eligibility requirements include age>50, SBP>130, eGFR>  20, ACR<600 mg/g and no 
history of stroke or diabetes.  
Characteristic 
Proportion (%) 
% Prior CVD 
15.6 
% CKD 
16.3 
    % Stage 3b CKD 
       3.6 
    % Stage 3a + ACR > 10 mg/g 
       6.6 
    % Stage 3a + ACR ≤ 10 mg/g 
       6.1 
% Senior (age>75) 
34.6 
% Female 
49.8 
% Black 
8.1 
% Hispanic 
7.4 
% SBP 130-139 on no BP lowering medications 
15.2 
% with FRS < 15% per 10 yrs 
4.5 
 
3.2 Recruitment:  Informed Consent, Screening, Baseline 
 
Recruitment 
The SPRINT recruitment goals are described above.  Specific community resources will be 
used to target women and minority/under-served populations to ensure adequate 
representation of these groups in SPRINT.  Recruitment strategies that have worked well in 
other trials related to hypertension and CKD will be used. Centralized training for CCN and 
Clinical Site staffs regarding recruitment issues will be provided before recruitment begins.   
 
The goal of participant recruitment is to create a trial population that will ensure 
adequate event rates for statistical power while maximizing participant safety and 
generalizability to the population for which the intervention is intended.  A multifaceted 
approach to screening and enrollment is essential to achieve the recruitment goal. For 
this multicenter trial, recruitment strategies targeting both existing populations within the 
clinical practice of the research sites as well as individuals from outside these practice 
settings will be used to identify potentially eligible participants.   
 
The Recruitment, Retention and Adherence Subcommittee will play a significant role in 
monitoring the progress of study-wide recruitment and provide a forum for advising the 
CCNs and clinical sites on problem identification, goal setting, strategy deployment and 
evaluation in their efforts to achieve site and study-wide recruitment goals. This may 
include guidance for enhancing the recruitment of ethnic groups, women and the elderly. 
The Subcommittee will also contribute to the development of the recruitment tools 
including culture-, gender- and age-specific materials to promote enrollment among 
these important subgroups.     
 
3.2.1 Regulatory and Ethical Considerations, including the Informed Consent 
Process 

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The study will be conducted in accordance with Good Clinical Practice (GCP), all 
applicable subject privacy requirements, and the guiding principles of Helsinki, including 
but not limited to: 
 
1. Local Institute Review Board (IRB)/Central IRB review and approval of 
study protocol and any subsequent amendments. 
2. Subject informed consent for main trial, SPRINT MIND, genetic testing, 
and post trial contact, and any ancillary studies.  The study consent will 
contain the six essential elements from GCP guidelines that include:  
• 
Research statement, reasonably foreseeable risks or discomforts, 
reasonably expected benefits to subjects or others, appropriate 
alternatives, extent of confidentiality, compensation or treatment 
for injury. 
• 
Additional elements where appropriate such as unforeseeable 
risks to subjects, embryos, or fetuses, investigator-initiated 
termination of participation, additional costs, significant new 
findings, authorization for release of protected health Information 
for research purposes. 
     3. Investigator reporting requirements. 
 
Written informed consent and Health Insurance Portability and Accountability Act 
(HIPAA) authorization must be obtained from each person prior to enrollment into 
SPRINT.  In collaboration with the CCNs, the SPRINT Coordinating Center will provide 
full details and template documents for the above procedures in the Manual of 
Procedures and provide training to the investigators and clinical staff on regulatory and 
ethical considerations.  All study personnel will be responsible for completing and 
remaining current with all applicable human subjects’ protection, good clinical practice 
and data security and privacy training requirements 
 
3.2.2 Existing Populations in the Clinical Site Practices 
Methods for identifying potentially eligible participants within the clinical practice of the 
research settings may include:  a targeted review of medical records or databases for 
those meeting the trial's inclusion criteria, referrals from providers/employees within the 
practice and/or from practice participants themselves. Additional approaches may also 
include written materials such as direct mailing and/or advertisement on such items as 
appointment reminders.      
 
3.3. Screening Visits/ Baseline Visits 
 
Screening Activity Considerations 
Each SPRINT clinical center should consult their local IRB regarding approval 
requirements to access internal medical record searches for potential SPRINT patients.  
Depending upon the institution, prior approvals for data transfer agreements may be 
needed to obtain de-identified patient information.  Pursuant to such agreements 
investigators may be required to sign a privacy agreement to protect the patient’s 
protected health information (PHI) as well as comply with other policies and procedures 
as defined by the institution’s designated privacy, security and compliance services.  
 
SPRINT clinical centers will work with the respective CCNs to complete Health 
Insurance Portability and Accountability Act (HIPAA) Privacy rule documents, 
preparatory to research waivers and training prior to patient medical record searches. 

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Once local regulatory requirements have been approved, investigator plans to identify 
potential study patients may be implemented.  Large scale data base searches, stratified 
by key specified inclusion criteria may also yield a global assessment of the potentially 
eligible study population.  Other study parameters (e.g. age, race, gender CKD status, 
etc.) can be added to further specify the eligible population. 
 
Prior to conducting prescreening and screening activities, it may also be necessary to 
request additional approvals beyond the IRB (e.g. physician approval or consultation for 
a screening referral to the SPRINT clinic).  Participant informed consent must also be 
obtained prior to performing any procedures related to the trial.   
 
Screening Visits/Baseline Visit  
The following are key elements of the screening and baseline visits and are outlined in 
the study assessments and procedures below:  
 
Screening Visit(s) 
1. Verify participant's interest in study. 
2. Obtain in person study consent and HIPAA authorization for main trial, and if 
applicable, SPRINT MIND, genetic testing and any ancillary studies 
3. Continue collection of screening information, including such items as contact 
information, additional eligibility information including BP measurement, concomitant 
medications, and medical history. 
 
Baseline visit (Randomization Visit) 
1. Confirmation that all inclusion/exclusion criteria satisfied  
2. Verification of participant consent and HIPAA authorization. 
3. Verification of participant contact information 
4. Obtain a Release of Information, as permitted by local policy, to collect event and 
serious adverse event (SAE) documentation 
5. Completion of the study randomization procedure and baseline data collection, 
including obtaining BP, ECG, and blood and urine samples for analysis and storage at 
the central lab 
 
Data obtained from the screening, and randomization visits must be supported in the 
patient’s source documentation.  Visit data will be entered into the SPRINT database 
within a specified time frame determined by the SPRINT Coordinating Center. 

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Chapter 4 – Intervention 
 
Blood Pressure Goals 
 
 Participants eligible for the trial will be randomized to one of two goals: SBP <120 mm 
Hg for the more intensive goal (Intensive Group) and SBP <140 mm Hg for the less 
intensive goal (Standard Group). Figures 4.1 and 4.2 describe the treatment algorithms 
for the two treatment groups. Although there are no diastolic blood pressure (DBP) 
inclusion criteria, participants in both groups with DBP ≥90 mm Hg will be treated to a 
DBP goal of <90 mm Hg if needed after meeting the SBP goal, because of the many 
trials documenting the CVD benefits in treating to a DBP goal <90 mm Hg.   
 
Antihypertensive Classes (Agents)  
 
Use of once-daily preparations of antihypertensive agents will be encouraged unless 
alternative dosing frequency (e.g., BID) is indicated/necessary. One or more medications 
from the following classes of agents will be provided by the study and intended for use in 
managing participants in both randomization groups to achieve study goals: 
 
• 
Angiotension converting enzyme (ACE)-inhibitors 
• 
Angiotension receptor blockers (ARBs) 
• 
Direct vasodilators 
• 
Thiazide-type diuretics 
• 
Loop diuretics 
• 
Potassium-sparing diuretics 
• 
Beta-blockers 
• 
Sustained-release calcium channel blockers (CCBs) 
• 
Alpha1-receptor blockers 
• 
Sympatholytics 
 
Combination products will be available, depending on cost, utility, or donations from 
pharmaceutical companies 
 
Selection of Antihypertensive Medications 
 
The SPRINT trial is testing a treatment strategy question regarding different SBP goals 
and not testing specific medications.  The SPRINT BP treatment protocol is flexible in 
terms of the choice and doses of antihypertensive medications, but there should be 
preferences among the drug classes, based on CVD outcome trials results and current 
guidelines.  NHLBI is updating various guidelines.  The update of hypertension 
recommendations, JNC-8, should be available early in the recruitment phase of SPRINT. 
These updates, along with any new scientific developments, will be considered during 
and following SPRINT protocol development and throughout the trial. 
 
The investigator may select among the available SPRINT antihypertensive medications 
for initiation of therapy.  Other drugs not supplied by the trial may also be used as the 
investigator determines appropriate.  However, all antihypertensive regimens should 
include one or more drug classes with strong CVD outcome data from large randomized 
controlled hypertension trials, i.e., a thiazide-type diuretic, calcium channel blocker, ACE 
inhibitor or ARB.  Current evidence, the most recent JNC guidelines and over 40 years 

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of clinical trial experience in hypertension support the inclusion of a thiazide-type diuretic 
as one of the agents for patients without compelling reasons for another medication, or 
contraindication or intolerance to a thiazide-type diuretic.  (ALLHAT, 2002;Beckett and 
others, 2008;Chobanian and others, 2003;Psaty and others, 1997;SHEP, 1991) Other 
classes associated with substantial reductions in CVD outcomes in hypertension trials, 
e.g. ACE inhibitors, ARBs, and calcium channel blockers, combine effectively with 
thiazides for lowering BP (Julius and others, 2004).  ACE inhibitors and ARBs also 
combine well with CCBs; if three drugs are needed, a thiazide-type diuretic, a RAS 
blocker (ACE inhibitor or ARB, but usually not both), and CCB make a very effective and 
usually well-tolerated regimen (Calhoun and others, 2009).  The preference for the order 
in which these agents are selected is left to the investigator as long as the SBP goals 
are achieved.  A loop diuretic may be needed in addition to or in place of a thiazide-type 
diuretic for participants with advanced CKD. 
 
Beta-adrenergic blockers, which were recommended in JNC-7 among the 4 preferred 
classes after diuretics, are now considered to be less effective in preventing CVD events 
as primary treatment of hypertension compared with thiazide-type diuretics, CCBs, and 
RAS blockers (Lindholm, Carlberg, and Samuelsson, 2005)  However, there are patients 
for whom beta-blockers should be part of the initial therapy, namely those with coronary 
artery disease, including chronic stable angina or previous MI (Rosendorff and others, 
2007).  
 
Finally, although renoprotective benefits have been demonstrated in CKD patients with 
proteinuria, ACE inhibitors (and likely other RAS blockers) are less effective than other 
classes in lowering BP and in preventing CVD events in African American and elderly 
hypertensive patients unless combined with a diuretic or CCB (Julius and others, 
2004;Mancia and others, 2007;National Collaborating Centre for Chronic Conditions, 
2006;Wright and others, 2005;Wright and others, 2008).   
 
Since more than three drugs will be necessary in many participants to reach the 
intensive SBP goal, other classes will also be available in SPRINT.  These include the 
potassium-sparing diuretics, spironolactone and/or amiloride, which are very effective as 
add-on agents for BP-lowering in “resistant hypertension” (Calhoun and others, 2008).  
However, they should be used with careful monitoring in participants with CKD or any 
tendency to hyperkalemia.  Alpha-blockers have been used effectively as add-on 
therapy in the AASK, ACCORD and Anglo-Scandinavian Cardiac Outcomes (ASCOT) 
trials.  However, alpha-blockers should be used only in combination with one or more 
other agents proven to reduce CVD events in hypertensive patients (ALLHAT, 2003).  
Sympatholytics, direct vasodilators, and/or loop diuretics may also be added for BP 
control in combination with agents proven to reduce CVD events. 
 
Among thiazide-type diuretics, the most consistent and robust CVD outcome data have 
been seen with chlorthalidone (ALLHAT, 2002;SHEP, 1991).  Chlorthalidone 12.5-25 
mg/d has been shown to be more effective in lowering BP over 24 hours than 
hydrochlorothiazide 25-50 mg/d (Ernst and others, 2006).  Among CCBs, amlodipine has 
been used in far more hypertension CVD outcome trials than any other agent and has 
more robust CVD outcome data.  Amlodipine should be considered first when a CCB is 
to be used.  In the presence of significant proteinuria, amlodipine should probably be 
used in conjunction with a RAS blocker.  If a non-dihydropyridine CCB (e.g., diltiazem) is 
to be used, it should not be combined with a beta-blocker. 
 

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The ACCORD experience (The ACCORD Study Group, 2010) has shown that a 
treatment strategy that includes a variety of classes, can produce a 14 mm Hg delta in 
SBP between the two randomized groups. The average number of antihypertensive 
drugs used to produce this difference was 3.4 and 2.1 in the Intensive and Standard 
Groups, respectively.   It is anticipated that the study participants in the CKD subgroup of 
SPRINT will require a greater number of antihypertensive drugs to reach the lower BP 
goal (Cushman and others, 2008) 
 
 
Visit Frequency 
 
For both randomized groups, routine visit frequency will be monthly for the first three 
months after randomization, then every three months for the duration of the trial.   
“Monthly visits will continue in the Intensive Group until SBP <120 mm Hg (or no more 
titration planned) and in the Standard group whenever SBP > 160 mm Hg.”   Additional 
visits will be scheduled as needed for management of adverse effects or for monitoring 
significant medication changes or other clinical issues. 
 
Intensive BP Goal Group (Figure 4.1) 
 
The SBP goal for the Intensive Group, <120 mm Hg, should be achievable in the 
majority of participants within 8-12 months of follow-up based on the ACCORD 
experience (The ACCORD Study Group, 2010).  For most participants in the Intensive 
Group, a two- or three-drug regimen of a diuretic and either an ACE inhibitor or ARB 
and/or a CCB should be initiated at randomization.  If a diuretic is contraindicated or not 
tolerated, an ACE inhibitor or ARB plus a CCB should be initiated.  A beta-blocker 
should be included in the initial regimen, usually in combination with a diuretic, if there is 
a compelling indication for a beta-blocker.  Drug doses should be increased and/or 
additional antihypertensive medications should be added at each visit in the Intensive 
Group, usually at monthly intervals, until the participant's goal of <120 mm Hg has been 
reached or the investigator decides no further antihypertensive medications may be 
added. 
 
SPRINT provides a unique opportunity to determine both the efficacy and safety of 
intensive BP control in elderly populations.  However, based on limited data, there is a 
concern that this population may be less tolerant of aggressive BP lowering.  Therefore, 
in participants ≥75 years of age randomized to the intensive BP goal who are on 0-1 
antihypertensive medications and have baseline SBP <140 mm Hg, antihypertensive 
therapy may be initiated with a single agent at the discretion of the investigator with a 
return visit scheduled in one month.  If the participant is asymptomatic at the first post-
randomization visit and SBP ≥130 mm Hg, a second agent will be added and titration 
continued as indicated in above.   
 
Milepost Visits 
 
”Clinical inertia” in hypertension management, where clinicians fail to intensify therapy 
despite patients not being at goal BP, has been observed in both clinical practice 
(Berlowitz and others, 1998) and  clinical trial settings (Cushman and others, 2002). For 
this reason, “Milepost Visits” were used in the intensive BP group in the ACCORD trial to 
assist in reaching goal SBP (Cushman and others, 2007).  For SPRINT participants in 
the Intensive Group, Milepost Visits will be every 6 months throughout follow-up, 

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beginning at the 6-month visit.  If the SBP is not <120 mm Hg at a Milepost Visit, then an 
antihypertensive drug from a class different from what is being taken should be added, 
unless there are compelling reasons to wait.  A “Milepost Exemption Form” will be 
completed whenever a new drug is not added at a Milepost Visit in which the 
participant’s BP is not <120 mm Hg to document the reason for not adding a drug and to 
outline a plan for making progress toward goal in that participant.  Milepost Visit 
procedures do not apply to the Standard Group.  Once the Intensive Group participant 
has been prescribed 5 drugs at maximally tolerated doses, if the BP remains above goal 
at subsequent Milepost Visits, it will be permitted to substitute a different class into the 
regimen instead of adding another drug or increasing the dose of a drug.  However, 
additional (more than 5) drugs may be needed to achieve goal SBP in some participants.  
Medication adherence will be assessed routinely in SPRINT and should be evaluated 
especially carefully for participants not at goal on 4 or more medications.  Strategies to 
enhance adherence are described in brief in Chapter 5 and in detail in the Manual of 
Procedures and Adherence Binder. 
 
Standard BP Goal Group (Figure 4.2) 
 
The SBP goal for the Standard Group, <140 mm Hg, should be achievable in the 
majority of participants within 3-6 months, based on the ACCORD experience (The 
ACCORD Study Group, 2010).  The standard BP protocol is designed to achieve a SBP 
of 135-139 mm Hg in as many participants as possible.  Participants in this group may or 
may not be on treatment with one or more antihypertensive medications.  If 
antihypertensive medication(s) is indicated per protocol, consideration should be given 
to including a thiazide-type diuretic as initial therapy or as part of the regimen, unless 
there is a compelling indication for another drug class or intolerance to a thiazide. 
 
At the randomization visit, Standard Group participants on previous antihypertensive 
drug therapy should be converted to SPRINT medications or no medications, depending 
on what the investigator believes is most likely to achieve a SBP level between 135-139 
mm Hg.  Because we expect a decrease in average SBP within the Standard Group 
following randomization due to improved adherence, lifestyle counseling, and intra-
individual variation, sometimes described as “regression to the mean”, treatment should 
not be intensified at the randomization visit for Standard Group participants unless SBP 
≥160 mm Hg or there is a compelling reason to add medication, e.g., management of 
fluid balance in participants with CKD.  Following the randomization visit, medication 
dose titration or addition of another drug is indicated if SBP is ≥160 mm Hg at a single 
visit or is ≥140 mm Hg at two successive visits. 
 
Because it is not known if lowering SBP to the more intensive SPRINT goal of <120 mm 
Hg, compared with the standard goal of <140 mm Hg, is beneficial, neutral, or harmful in 
patients such as those entered into the SPRINT trial, careful step-down (a reduction of 
the dose or number of antihypertensive drugs) is allowed for participants in the Standard 
Group.  Down-titration was not permitted in the HOT Trial if DBP was well below the goal 
for a participant (Hansson and others, 1998) – this likely contributed to the small 
differences in achieved BP between the three randomized groups and limited the study's 
ability to detect differences in outcomes.  Therefore, down-titration was included in the 
ACCORD and AASK standard BP protocols and was successful in generating the 
planned differences in BP between treatment arms.  Down titration should be carried out 
if the SBP is <130 mm Hg at a single visit or <135 mm Hg at two consecutive visits 
(Figure 4.2). 

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Diastolic Blood Pressure Treatment 
 
Once the SBP goal has been achieved in any participant, the antihypertensive regimen 
should be intensified if DBP remains ≥100 mm Hg at a single visit or ≥90 mm Hg at two 
successive visits to achieve DBP <90 mm Hg.  The visit intervals and decisions for 
titration (other than the BP levels) will be similar to those used for the SBP goal.  Since 
beta-blockers reduce DBP more than SBP relative to other antihypertensive 
medications, a beta-blocker could be considered for such participants (Cushman and 
others, 2001). 
 
Use of Home BP Devices 
 
Home BP devices will not be provided to all participants by the trial.  Since virtually all 
BP outcome trials have used office BP determinations and home readings are subject to 
more bias and error, in SPRINT titration of medications to goal should be based on office 
readings rather than home BP determinations.   
 
Assessment of Orthostatic Hypotension (OH), Measurement of Standing Blood 
Pressure 
 
Standing BP will be measured at screening, baseline, 1 month, 6 months, 12 months, 
and annually thereafter using the same BP device that is used to measure seated BP.  
After seated determinations, participants will be asked to stand.  Beginning when their 
feet touch the floor, BP will be taken one minute later in the same arm used for the 
seated measurements, using the BP device.  Participants will be asked after the 
standing determination if they had any symptoms of orthostatic hypotension during the 
standing BP measurement.  The Coordinating Center will calculate BP change using the 
standing measurements minus the mean of the seated measurements.  
 
Participants with standing SBP <110 mm Hg will not be eligible for randomization (may 
be rescreened if corrected).  However, the detection of asymptomatic orthostatic 
hypotension, i.e., orthostatic hypotension unaccompanied by orthostatic symptoms of 
dizziness, presyncope or syncope, will not influence the antihypertensive drug treatment 
algorithm.  Symptomatic orthostatic hypotension will be managed as described in 
"Management of Symptomatic Orthostatic Hypotension" (see Manual of Procedures). 
 
 
4.1 Lifestyle Recommendations and Background Therapy 
 
The purpose of including lifestyle recommendations and background therapy in SPRINT 
is twofold.  First, it fosters high quality general medical care in all SPRINT participants in 
accordance with current practice guidelines.  Second, it is intended that background 
therapies will be utilized equally across both study arms in order to minimize the 
differences in the effects of non-study strategies on the SBP or CV outcomes between 
arms.  The background therapy recommendations will be provided to the participants 
and their physicians.  Background therapy is considered part of usual recommended 
care for patients at risk of CVD and, as such, is not covered by research study costs.  
The delivery of these background therapies will be left up to the participants' own 
clinicians. 
 

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The Lifestyle and Background Therapy Working Group will coordinate the provision of 
the most current and relevant participant educational materials to be made available for 
study-wide use. These will include the topics of medical nutrition therapy, weight 
management, physical activity, smoking cessation, and anti-thrombotic therapy, and will 
complement educational materials related to the BP interventions that are part of the 
trial. Unlike most educational materials for BP, the SPRINT materials will not include 
specific goals for BP as these will depend on the participants' randomized treatment 
assignment.  Specific recommendations will include: a) weight loss in those who are 
overweight or obese; b) adoption of a diet rich in fruits, vegetables and low-fat dairy 
products (the DASH diet) with appropriate modifications for participants with CKD; c) 
reduction in sodium intake to recommended levels; d) reduction of alcohol consumption 
to recommended levels; and e) participation in regular aerobic exercise.  SPRINT 
participants will be encouraged to stop smoking (if a current smoker) and to follow 
current guidelines for testing for and treatment of dyslipidemia and the use of 
antithrombotic therapy. 
 
 

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Figure 4.1 Treatment Algorithm for Intensive Group (Goal SBP < 120 mm Hg) 
 
 
 
 
 

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Figure 4.2 Treatment Algorithm for Standard Group (Goal SBP < 140 mm Hg) 
 

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 Chapter 5 – Measurements and Follow-up  
 
5.1.1 Schedule of Follow-Up Visits    
   
Post-randomization follow-up visit schedules for data collection do not differ by treatment 
group assignment.  However, the visit schedule for treatment, that is achieving the BP 
goals, may differ by group while blood pressure goals are being met because of PRN 
visits not shown on Table 5.1.  Additional information on treatment schedules is 
contained in Chapter 4 describing the SPRINT BP intervention. For data collection in 
both randomized groups, all participants will have post-randomization visits at Months 1, 
2, 3, 6, and every 3 months thereafter.  For the purpose of event ascertainment, all 
participants in both treatment groups will be queried regarding the occurrence of a 
possible event on the same schedule, specifically every 3 months. 
 
5.1.2 Procedures by Visit 
 
Scheduled examination components are shown by visit in Table 5.1.  Assessments 
performed at the various visits include blood and urine collection, physical measures, 
and questionnaires.  Assessments will be performed on the same schedule for both 
randomization groups.  Baseline characteristics to define the patient population include 
sociodemographics, anthropometrics, BP, pulse, current and past medical history, 
concomitant medications, laboratory, dementia screening, cognitive function (subset), MRI 
(subset) and quality of life measurements.  A physical examination is included for safety but is 
not standardized, and left to the discretion of the investigator.  
 
5.2. Blood and urine collection and laboratory assays  
 
Specific laboratory assessments (e.g. serum creatinine, fasting serum glucose, etc) are 
important for determining eligibility status.  During follow-up, laboratory results will be 
used to monitor and adjust therapy in efforts to maintain blood pressure goals, assess 
safety (e.g. serum potassium concentrations), and to assess for study-related outcomes 
(e.g. deterioration of estimated glomerular filtration rate or increased protein excretion). 
 
Serum, plasma, and urine samples will be stored for future measurements of other less 
traditional CV risk factors.  White blood cells will be collected at baseline for DNA 
extraction for future genetic studies. It may prove possible to identify subgroups, 
defined by specific genes or genetic markers, which respond differentially to the various 
blood pressure treatment strategies. 
 
5.3. Physical Examination Measures   
 
5.3.1 Seated Blood Pressure and Pulse 
Seated blood pressure and pulse are measured at each clinic visit after a rest period 
using an automated device or manual devises if necessary.  The preferred method is the 
automated device as it offers reduced potential for observer biases and decreased 
demand on staff in terms of training and effort in data collection. 
 
 
 
 

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Table 5.1.  Measures and Frequency  
 
 
 
Screening 
/RZ 
 
1 mo 
 
2 mo 
 
3 mo 
 
6 mo 
 
9 mo 
 
1 yr 
 
Q 3 
mo 
 
Q 6 
mo 
 
2 yr 
 
3 yr 
 
4 yr 
5 yr or 
Close 
out 
Fasting blood collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Chemistry profile 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
     Fasting glucose 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
     Lipid profile 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
     Serum and plasma storage   
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
     Genomic material 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Albumin, creatinine 
X 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
     Urine storage 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
Physical measures 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Seated blood pressure, pulse, 
     & medication adjustment                
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
     Standing blood pressure 
X 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
     Weight 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
     Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
     ECG 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
     Physical examination 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
     4 meter walk (> 75 ONLY) 
X   
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
Questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
     Sociodemographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
     Smoking/alcohol use 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
     Concomitant medications 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
     Adherence & Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
     Outcomes Ascertainment 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Health related quality of life 
 
 
 
 
 
 
 
 
 
 
 
 
 
         EQ-5D 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
         Veterans Rand 12 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
         PHQ-9 Depression 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
         Patient satisfaction 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
Health related quality of life 
(subsets) 
 
 
 
 
 
 
 
 
 
 
 
 
 
          Falls Efficacy (FESI-I) 
X 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
          Sexual Function  (FSFI/IEFF) 
X 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 

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MIND Questionnaires/Tests 
 
Screening 
or RZ 
 
2 yr 
 
4 yr 
Close-out* 
    Dementia Screening  
 
 
 
 
          MoCA 
X 
X 
X 
(X) 
          Digits Symbol Coding Test  
X 
X 
X 
(X) 
          Logical Memory Test  
          Story  A 
X 
X 
X 
(X) 
    Cognitive Battery (subset) 
 
 
 
 
        Hopkins Verbal Learning Test 
X 
X 
X 
 
       Trail Making Tests A and B 
X 
X 
X 
 
        Digit Span 
X 
X 
X 
 
        Boston Naming Test 
X 
X 
X 
 
       Modified Rey-Osterrieth Figure 
X 
X 
X 
 
       Verbal Fluency Animals 
X 
X 
X 
 
 
*Dementia screen will be obtained at study close-out if there has been more than a year since the prior screen. 
 
 
5.3.2 Standing (Orthostatic) Blood Pressure    
 
Standing BP will be measured at screening, baseline, 1 month, 6 months, 12 months, 
and annually thereafter using the same BP device that is used to measure seated BP.  
After seated determinations, participants will be asked to stand.  Beginning when their 
feet touch the floor, BP will be taken one minute later in the same arm used for the 
seated measurements, using the BP device.  Participants will be asked after the 
standing determination if they had any symptoms of orthostatic hypotension during the 
standing BP measurement.  The Coordinating Center will calculate BP change using the 
standing measurements minus the mean of the seated measurements.  
 
 
5.3.3 Anthropometric Measurements (Weight and Height) 
 
Body fat is a significant predictor for subclinical and clinically manifested cardiovascular 
disease.  In addition, exercise and dietary modification with the goal of reducing total 
body fat may facilitate blood pressure control.  Anthropometric measures gathered for 
SPRINT include height and weight for the calculation of body mass index.   
 
5.3.4  Electrocardiography 
 
A 12-lead ECG is obtained at baseline and at the 2 and 4 year follow-up visits and close-
out visits to ascertain the occurrence of silent (unrecognized) MI, primarily, as well as 
atrial fibrillation and left ventricular hypertrophy. The baseline ECG is used to identify 
previous (including silent) MIs, and to identify evidence of left ventricular hypertrophy.   

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5.3.5 Physical Examination  
 
The physical examination includes components of a systems-based examination 
deemed necessary for safety by the SPRINT site investigator.  Elements of the 
examination to be completed may vary depending upon the health status and any 
symptoms reported by the participant, the time and type of visit (initial, interval, annual, 
final). The physical examination will not be standardized or data entered, but will be 
available in the source documents for each participant. 
 
5.3.6 Four meter walk 
 
Participants who are 75 years old or older at baseline will be asked to complete a timed 
4 meter walk to assess physical function.  This will be done at baseline and annually.  
 
 
5.4. Questionnaires 
 
5.4.1 Medical History 
 
A detailed history of cardiovascular disease is collected at screening.   The presence of 
CVD and CKD prior to entry into the study serves as an eligibility and stratification factor.  
Data regarding the duration of chronic kidney disease and the presence of complications 
are important for descriptive purposes, subgroup analyses, and prognostic analyses.  
 
5.4.2 Sociodemographics 
 
Information is collected during screening/baseline regarding age, race and ethnicity, 
gender, level of education, marital status, persons living with participants and United 
States (zip) postal code. These data will be used to identify eligible participants and to 
characterize the final study population.  
 
 
5.4.3 Smoking/alcohol use 
 
Consumption of alcohol and tobacco have important implications on cardiovascular risk, 
and adherence to medication regimens.  Participants will be assessed at baseline for 
lifetime tobacco exposure, alcohol intake and binge drinking.  At annual assessments, 
current smoking will be assessed. 
 
5.4.4 Concomitant Medications 
 
Information regarding the participants’ concomitant non-study medication therapy is 
collected and documented at baseline and then reviewed and revised at annual follow-
up visits. Appropriate sources for obtaining this information include participant (or 
significant other) report, current pharmacy action profiles, and verification of medications 
documented in the medical record. Although data are collected on all current therapies, 
emphasis is placed on concurrent antihypertensive, cardiovascular, chronic kidney 
disease and dementia medications as well as background risk reduction therapy such as 
aspirin and lipid-lowering drugs.    
 

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5.4.5  Monitoring Adherence     
 
Adherence to antihypertensive medications will be assessed as follows:   
 
First, an adherence scale will be administered to all participants at the baseline, 12 month and 
48 month visits in order to identify low adherence.   
 
Secondly, at every medication management visit, participants will be administered a single 
item to screen for low adherence.  If the participant’s response to this item indicates a possible 
problem with adherence, or if the participant is not at the appropriate blood pressure target, 
study personnel will address the specific issues and barriers for each study participant that 
may be preventing optimal adherence.  In such instances, administration of the Adherence 
Scale (to identify reasons for nonadherence) is recommended, as is use of the materials and 
procedures described in the adherence binder.  Details regarding the adherence monitoring 
procedure, scoring algorithm for the Adherence Scale and the procedures to follow when low 
adherence is identified, are provided in the MOP.   
 
5.4.6 Adverse events 
 
Adverse event ascertainment and reporting is described in chapter 8. 
 
5.4.7 Study-related outcomes 
 
Both randomized groups will be assessed for study related outcomes in the same way 
and on the same schedule.  After randomization, participants will be assessed every 3  
months for cardiovascular and renal outcomes.  Medical records will be collected for 
adjudication of study outcomes as described in Chapter 9.  Clinical center staff will use 
available resources and contact information to assess vital status annually on 
participants not attending study visits. 
 
 
5.4.8 Health-Related Quality of Life 
 
All participants will be assessed for the effect of interventions on health-related quality of 
life (see Chapter 7). HRQL data will be collected at Baseline, 12 months and annually 
thereafter.  Depression using the PHQ-9 scale will be assessed at baseline and annually 
thereafter.  A modified TSQM General Satisfaction subscale will be administered at 
baseline and at 1 and 4 years.  A subset of participants will undergo additional data 
collection related to fall self-efficacy and sexual functioning at baseline, 6 months and 
annually thereafter.  
 
5.4.9 MIND Battery: Dementia Screening 
 
All participants will undergo a dementia screening at baseline and every 2 years 
thereafter.  The tests will include the Montreal Cognitive Assessment (MoCA), Digit 
Symbol Coding test, and Logical Memory test.  A subset of 2800 participants will 
undergo an additional comprehensive battery of neurocognitive tests conducted at 
baseline, Month 24, and Month 48. In addition to the neurocognitive tests, a subsample 
of 640 MIND participants will have a Baseline and Month 48 MRI examination.   
 
 
 

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5.5. Medications and Adherence 
 
Adherence 
 
As part of a central pretrial training session, all investigators and clinical coordinators will 
receive instruction on adherence issues.  Additionally, study staff will periodically have 
refresher and retraining instruction in the overall adherence program throughout the trial.  
Also critical to maintaining good adherence is the routine discussion of participants who 
show problems with adherence and brain-storming about problem-solving strategies 
during clinic team meetings and Study Coordinator meetings and conference calls.  Of 
particular importance is the involvement of all members of the clinic team, including clinic 
leadership, in adherence-related monitoring and problem-solving.   
 
Drug Dispensing, Ordering, Storage, and Disposal     
Drug Dispensing 
 
The complexity created by the large number of medications and multiple treatment 
strategies employed by SPRINT requires substantial attention to the process of 
medication dispensing. All study medications dispensed to the participants will be 
labeled and identified with the study name, participant’s name, medication name, 
strength and quantity, directions for use, and authorized prescriber’s name. An 
emergency study-related phone number for study drug information will also appear on 
the label. All participants are to be verbally counseled on medication administration. 
Written instructions will also be provided.  
 
Participants receive medication supplies at regularly scheduled visits in sufficient 
quantity to last until the next scheduled visit. Medication dispensing may occur in the 
intervening periods between visits in case of emergency, loss, or schedule changes. A 
tracking mechanism is maintained for all dispensing actions. It is recommended that 
authorized dispensing personnel be limited in number to assure proper adherence with 
established accountability and dispensing procedures.  
 
Drug Supply Ordering 
Each Clinical Site, upon completion of procedures for study initiation, will receive a 
standard initial shipment (determined by the Coordinating Center and prepared by the 
Drug Distribution Center (DDC)) of study drug supplies for the trial. It is expected that 
this initial shipment will suffice for a specified number of visits for a given number of 
randomized participants. Subsequent ordering of inventory will be managed by the site, 
primarily through the web-based inventory system. Sites are responsible for 
appropriately managing their inventory and are able to customize their medication 
quantities to suit the prescribing practices of their site. 
 
The DDC in consultation with each Clinical Site sets inventory levels for each item. 
When an item reaches the reorder point, additional stock is automatically shipped from 
the DDC.  
 
Drug Receipt and Storage 
Drug shipments are sent to the Clinical Site in care of a designated staff member. The 
shipment is inspected for damage and its contents reconciled with the accompanying 

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SPRINT Shipping Notice. The inventory is logged using the established tracking 
mechanism. Packing slips are filed in a secure location. Any damage or discrepancies in 
the shipment are to be reported promptly to the DDC for corrective action. Each Clinical 
Site is responsible for storing the study drug supplies in a locked, secure area with 
limited access. Manufacturer recommendations and local policies for drug storage are 
followed.  
 
Drug Disposal 
 
Clinical Sites are authorized to destroy SPRINT stock locally, complying with any local 
policies and procedures. Destruction will be documented on the SPRINT Local 
Destruction Form, with a copy sent to the DDC. All study drugs are labeled with an 
expiration date. Prior to expiration, the DDC will automatically ship replacement stock 
based on the current electronic inventory profile. Once replacement stock is received the 
clinical site will destroy expired stock and document destruction as described above. 

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Chapter 6 – SPRINT MIND  
 
6.1 SPRINT-MIND Overview 
 
SPRINT-MIND is an integral part of the overall SPRINT study and all SPRINT 
participants will participate in one or more components of SPRINT-MIND. There are 
three objectives of SPRINT-MIND. The primary objective is to determine whether a 
strategy of intensive blood pressure lowering to target systolic blood pressure (SBP) 
<120 mm Hg versus a standard treatment target of 140 mm Hg will produce a greater 
reduction in the incidence of all-cause dementia.  The second objective is to determine 
whether global cognitive function measured in key specific domains of cognition will 
decline less in persons randomized to a SBP goal of <120 mm Hg versus a standard 
treatment goal of 140 mm Hg in a representative sub-sample of approximately 2800 
SPRINT participants. The third objective is to assess whether MRI-derived changes in 
brain structure differ by treatment assignment in a subset (approximately 640) of the 
2800 participants. 
 
6.2 Study Hypotheses and Aims  
 
6.2.1 All-cause Dementia 
 
Primary hypothesis: Over an average of 60 months, the incidence of all-cause dementia 
will be lower in SPRINT participants assigned to the intensive SBP treatment arm 
compared to their counterparts assigned to the standard SBP treatment arm.  This 
hypothesis will be tested in all SPRINT participants. 
 
6.2.2 Cognitive Decline  
 
Secondary hypothesis: Over an average of 48 months, the rate of global decline in 
cognition measured across key domains of cognition will be lower in the intensive SBP 
treatment arm compared to the standard SBP treatment arm. This hypothesis will be 
tested in a representative subset of approximately 2800 participants enrolled in SPRINT.  
 
6.2.3 MRI Brain Changes 
 
The Primary brain MRI hypothesis is that over an average of 48 months, the volume 
small vessel ischemic disease (SVID) will be lower in SPRINT participants assigned to 
the intensive SBP treatment arm compared to their counterparts assigned to the 
standard SBP treatment arm. An additional hypothesis is that total brain volume will also 
be greater (thus less atrophy) in the intensively treated group. The MRI sub-study will be 
conducted in approximately 640 participants chosen from the 2800 subset of participants 
selected in 6.2.2. 
 
 
6.3   Study Design 
 
6.3.1 Study Population 
 
We will ascertain incident all-cause dementia in all participants enrolled in SPRINT.  In 
addition, approximately 2800 participants will be selected to receive additional cognitive 
assessments at baseline, 24 months, and 48 months in order to examine changes in 

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global and domain-specific cognition. Participants participating in the MRI substudy will, 
at baseline, generally be required to reside within 1.5 hours travel distance to a 
designated study MRI Scanner. The components of the two cognitive batteries selected 
to assess dementia incidence and decline in cognition are listed in Table 5.1 of Chapter 
5. 
 
6.4 Procedures for Identifying Incident All-Cause Dementia in SPRINT (see Figure 
6.1).  
 
6.4.1 Overview 
 
A 3-step process will be used to ascertain incident cases of all-cause dementia.  First, to 
identify possible cases of dementia a brief Cognition Screening Battery will be 
administered to all participants. Participants who score below the pre-designated 
screening cut-point for possible cognitive impairment during follow-up will be 
administered a more comprehensive and detailed neurocognitive test battery (the 
Extended Cognitive Assessment Battery) plus the Functional Assessment Questionnaire 
which assesses impairments in daily living skills as a result of cognitive impairments.  
Last, all  the above available tests and questionnaire data will be submitted to a 
centralized, web-based system for adjudication by a panel of dementia experts who will 
assign final study classifications of probable dementia (PD), mild cognitive impairment 
(MCI) or no impairment (NI).  
 
6.4.2 Cognition Screening Battery  
 
A brief screening battery consisting of 3 well-validated neurocognitive tests will be 
administered to all participants at study randomization and repeated at years 2, 4 and at 
closeout (unless the participant has undergone the screening battery in the past year 
prior to closeout). This battery requires 15 minutes or less to administer.  
 
Tests included in the SPRINT-MIND Cognition Screening Battery were selected because 
they are sensitive to detecting dementia, easy to administer and brief. They are:  
 
1. The Montreal Cognitive Assessment (MoCA) The MoCA (Nasreddine et al.,  
2005) is part of the NIH Toolbox and is a reliable and valid brief screening 
instrument for characterizing global cognitive functioning. It has been used 
previously to screen for dementia and MCI with sensitivity of >85%. The MoCA 
has several sub-scales that can be used to characterize more specific cognitive 
functions. 
 
2. Digit Symbol Coding test (DSC) The DSC ((Wechsler, 1996b; Wechsler D., 1981)  
is a sub-test of the Wechsler Adult Intelligence Scale-IV.  It measures 
psychomotor speed and working memory.  The DSC and its predecessor the 
Digit Symbol Substitution test have been extensively used and normed.  
 
3. Logical Memory test (LM):  The LM test is a sub-test of the Wechsler Memory 
Scale-IV(Wechsler, 1996a; Wechsler, 1996a).  It measures episodic verbal 
memory and has extensive normative data. Episodic verbal memory is an 
especially sensitive predictor of early Alzheimer’s dementia and amnestic MCI. 
 

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The sensitivity and specificity of the Cognition Screening Battery to detect 
participants with poorer cognitive function will be evaluated on an ongoing basis during 
the trial by using available baseline cognition data from SPRINT. We estimate 20-25% of 
participants will trip the battery  (see SPRINT MOP for specific battery cut-points) and 
receive a brief assessment of the impact of their cognitive function on daily life (the 10 
item Functional Assessment Questionnaire).  At the years 2 and 4 follow-up, participants 
who trip the screening battery will also be administered the SPRINT Extended 
Cognitive Assessment Battery for adjudication of incident dementia.  In order to achieve 
the 20-25% target, various cut-points for the Cognition Screening Battery will be 
compared and adjustments will be made to maximize study efficiency and economy 
during the trial. 
 
6.4.3 SPRINT Extended Cognitive Assessment Battery  
The Extended Cognitive Assessment Battery will provide a more comprehensive and 
detailed assessment of specific major cognitive functions (memory, language, 
visuospatial skills, executive function) that are necessary for classification of dementia 
and for detecting domain-specific changes. During follow-up years 2 and 4, participants 
scoring in the impaired range on the Cognition Screening Battery will be administered 
the Extended Cognitive Assessment Battery at their next scheduled visit (typically a 
blood pressure assessment and medication distribution visit).  This entire battery 
requires less than 40 minutes including scoring and data entry and less than 30 minutes 
in persons without significant memory impairment.  
 
The neurocognitive tests comprising the Extended Cognitive Assessment Battery are:    
 
1)  The Hopkins Verbal Learning Test (HVLT) (Brandt and Benedict, 2001): A 
measure of episodic verbal learning and memory, this test is a 12-item list 
learning and memory task with immediate recall, delayed recall and recognition 
components. 
 
2)  The Trail Making Test: Parts A and B (Reitan R.M., 1958): The Trail Making Test 
(TMT) is a two-part test measuring speed of processing and executive function.  
The times to complete Part A and Part B are the primary measures of interest. 
 
3)  Digit Span test (Wechsler D., 1981):  The Digit Span test (DST), a subtest of the 
Wechsler Adult Intelligence Scale-IV, requires the participant to recite gradually 
increasing series of digits forward and backward. The DST measures 
concentration and working memory.  
  
4)  The Boston Naming Test (Kaplan E et al., 1983) The Boston Naming Test (BNT) 
is used to assess language function. The participant is asked to name familiar 
objects from simple drawings.   The number of correctly identified objects is the 
variable of interest.   We will use a validated short form that includes 15 items.  
 
5)  The Modified Rey-Osterrieth Complex Figure (mRey-O). (Saxon, 2003)  The 
mRey-O measures of visuospatial and visuomotor function and non-verbal 
memory by having participants copy and reproduce from memory a multi-
component figure. For ease of use and scoring reliability, the mRey-O figure will 

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be faxed to the CC and scored centrally. 
 
6)  Category Fluency-Animals.  The animal fluency task requires the participant to 
spontaneously name as many animals as possible in 60 seconds. It provides an 
assessment of semantic fluency. 
  
6.4.4 Additional measures 
 
Functional Assessment Questionnaire (FAQ). Since impairment of daily functioning is 
required for a classification of dementia, we also will administer, either locally (by 
certified SPRINT clinic staff) or centrally (by certified SPRINT staff from the coordinating 
center), the FAQ, a 10-item, validated questionnaire assessing functional status (Pfeffer 
and others, 1982), to a person previously designated by the participant who is familiar 
with his/her current abilities.  Administration of the FAQ will be limited to participants 
whose Cognition Screening Battery indicates possible impairment. Items assess 
functions like managing money and remembering names of familiar persons.   
 
6.4.5 Alternative cognitive assessment. 
 
If participants cannot come to the clinic for their follow-up exams or if they reside in 
nursing homes, study personnel will complete either a home or nursing home visit.  
Technicians conducting the home visit must be MIND certified.  The Screening Battery 
will be administered and if the participant scores below the cut-point, the Extended 
Battery will also be administered. 
 
Telephone assessment of general cognitive function is now standard practice in many 
large trials assessing for dementia outcomes. For SPRINT participants unable to receive 
a face-to-face cognitive assessment by certified SPRINT staff at their local clinic, a 
telephone assessment of cognition status to assess for incident dementia will be 
performed either locally or centrally by SPRINT certified staff.  The components of the 
phone interview are:  
 
Modified Telephone Interview for Cognitive Status (TICS-M), a validated 
instrument requiring <10 minutes (Welsh,  1993)  
Oral Category Fluency-Animals 
Oral Trail Making Test (Ricker et al., 1996) 
 FAQ to a contact 
 
 
For participants unable to be interviewed in-person or by phone, a previously identified 
contact will be administered: 
 
The Dementia Questionnaire (DQ). The DQ (Ellis , 1998;Kawaset al, 1994) is a 
semi-structured interview designed for a knowledgeable proxy to provide 
information regarding the participant’s cognitive and behavioral functioning and 
other health information needed to make a diagnosis of dementia and MCI and to 
identify causes of cognitive impairment.  Again, it will only be administered in the 
absence of an in-person or phone assessment and may be performed either by 
local or central staff who are SPRINT certified. 
 
 . 

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6.5 Adjudication of Dementia, MCI or No Impairment  
 
A primary goal of SPRINT MIND will be to determine the incidence of all-cause dementia 
in SPRINT and its relation to the treatment assignment.  Final classification (Dementia, 
MCI or No Impairment) will be made by a panel of experts consisting of neurologists, 
geriatricians, psychiatrists and neuropsychologists with recognized expertise in dementia 
blinded to study assignment and blood pressure data. Data used in the adjudication will 
include all available cognitive test data (SPRINT Cognition Screening Battery, SPRINT 
Extended Cognitive Battery), functional status assessments (FAQ or DQ) and additional 
data including demographic information and medical historyEach suspected case 
identified by our scoring criteria (see 6.4) will be randomly assigned to two members of 
the Adjudication Committee for review. Adjudicators will independently review all the 
available data via a web-based system before recording their classification-Dementia, 
MCI or No Impairment.  Each adjudicator will be masked to the other’s classification and 
to the participant’s treatment assignment. If the two adjudicators' classifications agree, 
then the classification will become final. Disagreements will be resolved at periodic face-
to-face meetings or by phone conferences between adjudicators and additional 
members of the Adjudication Committee until consensus is achieved. These procedures 
have been successfully used by our team in other large clinical trials including the 
Gingko Evaluation of Memory Study (GEMS) (DeKosky et al, 2008) and the Women’s 
Health Initiative Memory Study (WHIMS) (Shumaker et al, 2004). 
 
Participants classified as having dementia will no longer be assessed for cognitive 
function.  Those not classified as having dementia will continue to receive regularly 
scheduled cognitive assessments with the screening and extended cognitive batteries 
when indicated. 
 
6.5.1 Diagnostic Criteria for Dementia 
 
Criteria used for identifying dementia will be those described in the Diagnostic and 
Statistical Manual of the American Psychiatric Association-Fourth Edition (DSM-IV).  
These are: 
• Significant decline in memory and at least one additional cognitive domain; and 
• Significant functional impairment due to cognitive problems; and 
• Cognitive deficits are not due to obvious reversible causes such as acute 
illness, metabolic disturbances, infections, mood disorders or substance-
induced conditions; and cognitive deficits do not occur exclusively during the 
course of delirium. 
No attempt to classify dementia subtype will be made. 
 
6.5.2   Diagnostic Criteria for MCI  
 
While not a primary or secondary outcome, MCI syndrome is important because of its 
relevance to dementia.  MCI represents a transitional state between no cognitive 
impairment and dementia and specific subtypes of MCI are highly predictive of 
subsequent dementia. Thus, identifying MCI will provide valuable information about pre-
dementia cognitive impairment related to the SPRINT intervention.  Criteria to be used 
for identifying mild cognitive impairment syndrome are those described by Winblad et al., 
which are:    

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Non-Amnestic 
Single domain 
Isolated impairment in 
non-memory domain
Multi-domain 
Impairment in >1 
non-memory domain
 
Amnestic 
Single domain 
Isolated memory 
impairment
Multi-domain 
Memory impairment 
+ other impaired
• 
Observation by participant or proxy of cognitive decline; and 
• 
Deficit in performance in one or more cognitive domains; and 
• 
Absence of significant functional impairment attributable to cognition; and 
• 
No diagnosed dementia 
 
MCI will be further sub-classified into 4 categories using criteria adapted from Winblad, 
et Al. (Winblad et al, 2004) as follows: 
 
 
 
 
 
 
 
 
 
 
 
Specific cognitive tests in the Cognition Screening Battery and the Extensive Cognitive 
Assessment Battery will be used to subtype adjudicated cases of MCI.  
 
6.6  Baseline classification of cognitive status:  
 
Rare cases of dementia, where the participant or their personal physician are unaware 
of the diagnosis, may be identified during baseline cognitive testing.  In participants 
scoring below the cut-point on the Screening Battery, we will administer the FAQ to a 
contact in order to determine the presence of impaired daily function related to cognition  
(see 6.4.2).  
 
6.7  Definition of Cognitive Change Over Time Outcome (Extended Cognitive 
Assessment Battery Sub Sample). 
 
Each test score from the Cognition Screening Battery and the Extended Cognitive 
Assessment Battery will be used to measure decline in cognitive function.  The primary 
outcomes will be composite scores for two domains: 1) Memory, consisting of the 
Hopkins Verbal Learning Test, Logical Memory and the Modified Rey Osterrieth Figure, 
and 2) Processing Speed, consisting of Trails Making Tests and Digit Symbol Coding 
Test.  Prior to analysis of this outcome, we will review the science related to summary 
scores for cognitive function and may make modifications which will be specified prior to 
initiation of the analysis.   
 
6.8  Quality Control and Training 
 
At each clinical site, at least one person will be identified to serve as the trained and 
certified cognitive technician. Technicians will be trained during a central, intensive 
training session held in conjunction with the overall SPRINT training.  Training will 
include review of the MIND protocol and procedures for administration of the test 
batteries, demonstrations of each component of the SPRINT MIND test batteries, and 
opportunities to practice with feedback from trainers.  When a level of competence is 
attained, technicians will receive certification and approval to administer the test 
batteries to SPRINT participants.  During the course of the study as additional staff is 

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needed, certified technicians will train new technicians and submit materials to the MIND 
Coordinating Center for review.  Technicians will be recertified throughout the course of 
the trial by: 1) review of video or audio taped administrations; 2) observing web-based 
administrations and responding to specific questions.  Technicians will be encouraged to 
communicate questions or problems to the SPRINT MIND Coordinating Center. 
  
 
 
Figure 6.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
*At baseline, participants scoring below cutoffs specified during trial will also receive the 
FAQ. 
SPRINT MIND 
N= 9250 
N = 2800 (Representative Sample) 
Screening and Extended Assessment 
Battery, Baseline, Yrs  2 & 4  
 
N = 9250 
Screening Battery* 
Baseline, Yrs 2, 4 & Closeout 
 
NORMAL 
RANGE 
Screen 
Fail: 
Yrs 2 & 4 
Receive Extended 
Assessment 
Battery and Web- 
based Adjudication 
Dementia Positive 
 
NO FURTHER SCREENING 
 
No Dementia 
 
N= 640 MRI 
Yrs 0, 4 

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Chapter 7 – Health-Related Quality of Life and Economic 
Analyses  
 
7.1. 
Introduction 
In addition to the cardiovascular, renal and cognitive outcomes, SPRINT is well poised to 
examine differences in health-related quality of life (HRQL) as a result of its blood 
pressure interventions. Differences in HRQL may affect adherence, and thus the 
effectiveness of the two interventions. It is also reasonable to anticipate that in some 
cases, the intensive arm may result in diminished HRQL relative to the standard arm due 
to a number of factors: 
• 
side effects of specific medications or increased numbers and/or doses of 
medications required to achieve the <120 mm Hg goal, 
• 
increased occurrence of hypotensive symptoms, which may not only result in 
higher rates of falls and fractures, but also an increased fear of falling which 
may limit the participant’s perceived ability to engage in activities of daily 
living, and/or 
• 
reduced perfusion pressures and medication side effects which may 
contribute to erectile dysfunction in men, and possible sexual dysfunctions in 
women.  
 
On the other hand, the intensive arm may result in improved general HRQL versus the 
standard arm due to reduced number of medical events and more favorable physical 
and cognitive function. The effects of the two interventions upon HRQL are further 
nuanced by the possibility that some participants in either treatment arm may adjust to 
decrements in health status by changing their internal perception of favorable HRQL, 
known as “response shift”.  
 
There may also be potential health cost tradeoffs of the intensive versus standard 
treatment. While the intensive arm is anticipated to result in higher short-term costs due 
to more frequent office visits and greater medication use, this arm may also result in 
lower long-term costs from event-related hospitalizations and other medical costs if the 
treatment approach is efficacious in reducing these medical events. Assuming the 
primary outcomes are as hypothesized, examining the HRQL and cost-effectiveness of 
the intensive and standard treatment arms will be important determinants of the potential 
adoption of the intensive BP control in clinical practice, and will be informative in 
identifying subgroups of patients for whom intensive or standard BP control is most 
appropriate.  
 
7.2.  
Hypotheses 
 
7.2.1 HRQL Hypotheses 
 
The hypotheses generated for the HRQL measures are: 
 
• 
Overall HRQL  (Entire sample, Veterans RAND-12)  Intensive control of blood 
pressure compared to standard control will result in worse HRQL at the 1-year 
assessment, but better HRQL at the 5-year assessment.  The effect will be 
greater in those with lower baseline HRQL and greater number of comorbid 
conditions at baseline.   
 

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• 
Falls Self-efficacy (Subsample, Falls Self Efficacy Scale)  Intensive control of 
blood pressure compared to standard control will result in less favorable fall-
related self-efficacy at the 1-year assessment. The effect will be the greater in 
older participants, those with lower baseline HRQL, and those with a greater 
number of baseline comorbid conditions.  By Year 5, intensive control of blood 
pressure will result in more favorable fall-related self-efficacy compared to 
standard control. 
 
• 
Sexual function (Subsample, Modified Female Sexual Function Assessment 
/International Index of Erectile Function)  Intensive control of blood pressure 
compared to standard control will decrease sexual function among men and 
women participants at one year.  By year 5, the intensive treatment participants 
will report more favorable sexual function compared to participants in the 
standard treatment. 
 
7.2.2 Cost-Effectiveness Hypotheses 
 
The primary hypotheses generated for the economic and cost-effectiveness analyses 
are: 
 
• 
Intensive control of blood pressure compared to standard control will result in 
higher healthcare costs and utilization in the first year due to the greater 
number of office visits, medications, and lab tests likely required to achieve 
the intensive control targets. 
 
• 
Intensive control of blood pressure compared to standard control will result in 
lower healthcare costs and utilization over the study period due to decreased 
events and related health costs among intensive control participants. 
 
• 
The incremental cost-effectiveness ratio will be <$100,000/Quality Adjusted 
Life Years (QALY) gained when compared to the standard intervention.  
 
 
7.3.  
Health-Related Quality of Life Measures 
 
7.3.1 Rationale for Selection 
 
The SPRINT HRQL instruments were selected based upon the following criteria:  
(1) inclusion of the major dimensions shown in the literature to be affected by 
hypertension and its treatment; (2) brevity; (3) responsiveness to treatment-related 
changes, and (4) appropriateness for the age range, racial/ethnic diversity, and 
anticipated medical conditions of the participants in SPRINT. 
 
 
 
To reduce participant burden, some HRQL instruments will be administered to the entire 
SPRINT sample, while others will be administered only in a subsample of participants.   
All HRQL instruments will be self-administered unless participants require assistance 
due to sensory, motor, or cognitive deficits in which case the instruments will be 
administered by clinic staff or family/friends accompanying the participant to the clinic 
visit.  For Spanish-speaking participants, Spanish versions of all HRQL instruments will 
be administered to participants at all assessment points who indicate at baseline that 

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they do not have sufficient written English fluency to complete the instruments in 
English.   
 
7.3.2  Health-Related Quality of Life (HRQL) Measures 
 
Veterans RAND 12-item (VR-12) questionnaire. The VR-12 is a shorter version of the 
VR-36 (which is derived from the SF-36).  Changes of the VR-12 relative to the SF-12 
have lowered the floor and ceiling, improved the distributional properties, increased 
reliability, and improved discriminant validity of the physical and mental health summary 
scores.   Validated conversion formulas allow for direct comparisons to prior studies 
using the SF-36 or SF-12.   The VR-12 will be administered to all SPRINT participants at 
baseline and at annual visits thereafter. 
 
Fall Self-Efficacy Scale International (FES-I) The FES-I, shortened version, consists 
of seven items which the respondent answers on a 1-4 scale, indicating level of concern 
for falling. The activities are getting dressed or undressed, taking a bath or shower, 
getting in or out of a chair, going up or down stairs, reaching for something above your 
head or on the ground, walking up or down a slope, and getting out to a social event. An 
evaluation of the Short FES-I found good internal and 4-week test-retest reliability. The 
correlation between the Short FES-I and the FES-I was 0.97. The Short FES-I will be 
administered among a subsample of SPRINT participants.     
 
 
 
International Index of Erectile Function (IIEF) The IIEF-5 is the 5-item short form of 
the original 15-item IIEF, and was developed specifically for use in clinical settings to 
supplement physical examination and patient history. IIEF-5 scores can be classified into 
the following categories; severe erectile dysfunction (ED), moderate ED, mild to 
moderate ED, mild or no ED.  Scores less than 21 have 98% sensitivity and 88% 
specificity for the presence of ED. The IIEF-5 will be administered in a male subsample 
of SPRINT participants. 
 
 
 
Female Sexual Function Assessment (FSFI) The FSFI is a 19-item survey that 
assesses female sexual function over the past four weeks in 6 domains (desire, arousal, 
lubrication, orgasm, satisfaction, and pain).  Utilizing recently proposed modifications to 
the FSFI, participants not sexually active over the past four weeks would complete only 
4 items, substantially reducing respondent burden.  The FSFI has high internal 
consistency (Cronbach alpha > 0.8).  This assessment will be administered in a female 
subsample of SPRINT participants. 
 
Patient Satisfaction (Bharmal and others, 2009) A modified Treatment Satisfaction 
Questionnaire for Medication (TSQM) General Satisfaction subscale will be administered 
at baseline (based on current blood pressure medications being taken, if any) and at 1 
and 4 years.  This corresponds with the administration of the Morisky Adherence scale, 
which will allow for analyses of the relationship between satisfaction and adherence at 
these time points.   
 
Patient Health Questionnaire-9 (PHQ-9) The PHQ-9 is a self-report measure of 
depression that has been recommended by the AHA Advisory Panel on Depression and 
Coronary Heart Disease, has a low response burden (9 items; 2-3 minutes to complete), 
excellent reliability, and good sensitivity and specificity with depression diagnoses.  This 
assessment will be done at baseline and annually on all participants. 
 

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7.3.3 Health State Utility Measures 
 
  
 
 
EQ-5D is a self-administered 5-item instrument including mobility, self-care, usual 
activities, pain/discomfort and depression. There are three responses to each question 
(no, moderate, or severe limitations).  This commonly used measure of health utilities 
will be used to convert quality of life and health status into quality adjusted life-years 
(QALYs) for cost-effectiveness analysis.  The EQ-5D will be administered to all 
participants at baseline and annually thereafter.  
 
7.4. 
Cost-Effectiveness Assessment 
 
7.4.1 Rationale  
 
It is expected that the intensive therapy for hypertension will not only reduce 
cardiovascular events but will be more cost-effective over the long-term. The two primary 
measures of cost-effectiveness are the incremental cost per QALY and life-year gained. 
The primary cost-effectiveness hypothesis is that the intensive blood pressure treatment 
will be cost-effective as compared to the standard treatment. This question will be 
addressed by conducting incremental cost-effective analyses in which the net costs and 
net effectiveness of intensive therapy defined by the main trial to standard therapy will 
be calculated and expressed as a series of ratios.  
  
For QALYs, the cost-effectiveness hypothesis is that the ratio of costs per QALY (as 
measured by the EQ-5D) will be significantly less (i.e., more favorable cost-
effectiveness) for the intensive intervention than for the standard intervention. Costs will 
be discounted to weigh future costs less heavily than present ones. 
 
7.4.2 Effectiveness 
 
The primary endpoints defined by the main trial are considered as primary outcome 
measures for this economic evaluation. The primary effectiveness measures will be life-
years gained and QALY gained. The measure of life-year gained is determined by the 
difference in number of life–years between intensive therapy and standard therapy. 
QALYs adjust life-years gained by the quality of the participant’s overall HRQL during 
these life-years gained.   
 
7.4.3 Costs 
 
All direct medical costs associated with treatment of hypertension and its complications 
and costs for treating adverse effects of the therapy will be considered. These costs will 
include costs of inpatient care, outpatient care, medications, medical equipment, 
supplies, laboratory tests, and professional services. The participant's costs such as 
waiting time, transportation, lodging, and informal care arising from the disease will not 
be included. Likewise, opportunity costs of premature death, productivity loss, and long-
term disability will not be considered in this study.   
 
 
 
 
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Hospitalizations are the primary cost drivers in most cost-effectiveness analyses, and 
SPRINT has proposed obtaining hospitalization events via multiple sources.  Patient 
report of hospitalizations, along with emergency department (ED) visits, stays in 
rehabilitation facilities, and day-surgery admissions, are obtained every 3 months during 
scheduled SPRINT study visits.  Discharge summaries and other pertinent records 
(including reason for hospitalization and length of stay) will be obtained from 
hospitalizations, Emergency Department visits, rehabilitation stays, and day-surgery 
admissions related to outcome events and potential adverse events (including 
cardiovascular, renal, and cerebrovascular disorders; dementia; falls) which will 
constitute many of the admissions that might be expected to differ by arm.  Because of 
the large proportion of VA and Medicare patients in SPRINT, we also will be able to 
determine hospitalizations, dates of admission, length of stay, and reason for admission 
via Medicare and VA databases for those hospitalizations for which we do not have 
discharge summaries.  For the limited number of remaining patient reports for which we 
have neither discharge summaries nor database information, we will perform regression 
analyses of reported vs. actual length of stay and costs for all those with such data to 
estimate the costs of the undocumented hospitalizations.  Cost estimates for 
hospitalizations will be based on DRG-specific Medicare cost weights.  For professional 
costs associated with hospitalizations we plan to obtain these costs from Medicare and 
VA databases as available in a subsample and use these data to estimate professional 
costs for the entire sample based on these subsample analyses.  We will also explore 
whether these databases allow us to obtain costs associated with ED visits, stays in 
rehabilitation facilities, and day surgery admissions.   
 
7.4.3.2 Intensive and Standard Therapy Non-Research Costs 
 
For medications, we plan to use study medication logs to obtain the medications 
prescribed by the study.  This log also includes blood pressure lowering medications 
prescribed by other healthcare providers.  Medication costs will be estimated using 
median wholesale price.  We will obtain information on non-study prescribed 
medications (concomitant medications) from participants annually and will estimate costs 
for these medications based on the most commonly used doses in clinical practice.  We 
will not obtain cost data on non-study related labs, as this source of utilization is not 
expected to differ by group.  To estimate non-research related costs for the SPRINT 
office visits, we plan to obtain estimated CPT codes (minus research-specific activities) 
from clinic staff for a random subset of these visits to estimate costs via Medicare 
payment rates.  Non-study outpatient visits will not be obtained but will be estimated with 
non-study medication costs by age using national health care expenditure data. 
 
7.4.3.3 Data Analysis for Cost-Effectiveness 
 
Two methods of cost-effectiveness analysis (CEA) and cost-utility analysis (CUA) will be 
used in the economic evaluation. The ratios of cost to outcome derived from CEA/CUA 
are used to compare cost-effectiveness among treatment strategies. An incremental 
cost-effectiveness ratio (ICER) will be calculated, which provides a summary of the cost-
effectiveness of one intervention relative to the other.  
 
 
 
 

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The basic formula to calculate incremental CEA ratio and CUA ratio of a specific 
treatment A relative to the reference treatment B is presented as following:   
 
ICERCEA    =    (Mean Cost treatment A  - Mean Cost treatment B )  
                       (Mean Effecttreatment A   - Mean Effect treatment B) 
 
ICERCUA    =   (Mean Cost treatment A  - Mean Cost treatment B ) 
(Mean QALY treatment A – Mean QALY treatment B) 
 
The ratio of incremental cost to incremental effectiveness represents cost-effectiveness 
of the intensive BP treatment. Bootstrap methods will be used to calculate confidence 
intervals for cost-effectiveness ratios. All costs will be adjusted to the baseline year using 
the medical component of the Consumer Price Index. Future costs and outcomes will be 
discounted by 3%. Estimates of utilization over time will be adjusted for the presence of 
censored data with variable follow-up. Sensitivity analysis will explore the effect of 
correlations between costs and outcomes, which will also be empirically examined in the 
cost and outcome data.  
 
QALYs will be calculated by summing the area under each individual's QALY curve 
(constructed by plotting the EQ-5D scores for each interview during follow-up). The 
estimates of mean differences in costs and outcomes – which will be used to create net 
health benefits and the cost per QALY ratios -- will be derived from multivariable 
regression analyses. For the evaluation of the difference in costs, the dependent 
variable in the regression will either be costs or the natural log of costs (determination of 
the form of the dependent variable will be based on statistical tests of its distribution). If 
the dependent variable used in the analysis is the log of costs, a smearing 
retransformation will be used to estimate the absolute difference in costs between the 
treatment groups.  

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Chapter 8 – Safety Monitoring and Reporting 
 
 
8.1 
Introduction 
 
The SPRINT trial is testing whether lowering SBP to a goal of <120 mm Hg results in 
better outcomes than a goal of <140 mm Hg in patients at risk for CVD events.  SPRINT 
is not a study of specific anti-hypertensive agents.  All antihypertensive agents provided 
by the trial or recommended by SPRINT have been approved by the Food and Drug 
Administration (FDA) and are routinely prescribed for lowering blood pressure. 
 
Patient safety will be carefully monitored in SPRINT.  Each participating investigator has 
primary responsibility for the safety of the individual participants under his/her care.  In 
addition, an independent Data and Safety Monitoring Board (DSMB) will have primary 
responsibility for monitoring the accumulating study data for signs of adverse trends in 
morbidity/mortality and treatment-related serious adverse events.  
 
8.2 
Participant population 
 
Participants enrolled in SPRINT have elevated risk for CVD outcomes. Inclusion and 
exclusion criteria for SPRINT were set in order to maximize safety while facilitating 
inclusion of a trial population at risk for the major trial outcomes.  Exclusions are outlined 
in Section 3.1.   
 
Potentially Vulnerable populations:  The SPRINT population includes a significant 
proportion of older adults (>75 years), some of whom may become cognitively impaired 
during the course of the trial.  Thus, participants are asked to identify a contact person at 
the time of enrollment that can provide information about the participant as it relates to 
the study.  In addition, participants with CKD may need care coordination or referral to a 
nephrologist during the study.  Various management issues in patients with eGFR 
values lower than 30 ml/min/1.73m2 may arise including dietary issues and the effects of 
CKD on pharmacokinetics, pharmacodynamics and side-effects of various drugs.  All 
participants, including those with CKD, will be managed according to current national 
guidelines.  If patients with this level of renal impairment are not already followed by a 
nephrologist and the investigator feels it is needed, he/she will coordinate with the 
participant's primary care physician regarding the recommendation for renal follow-up. 
 
8.3 
Safety Monitoring  
 
Several types of safety issues and serious adverse events may occur in SPRINT and 
participants will be monitored for these regularly throughout the study.   
 
8.3.1  Expected Events: 
 
The potential adverse effects of the blood pressure drugs used in SPRINT have been 
well documented.  For example, electrolyte abnormalities (hyponatremia or hypokalemia 
are known to be associated with diuretics; hyperkalemia and short-term decline in GFR 
with RAAS blockers, hyperkalemia with potassium-sparing drugs; as well as bradycardia 
with beta blockers and calcium channel blockers). Participants will be monitored 

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routinely with interviews, vital signs, targeted physical examination and laboratory tests 
to ensure safety (Chapter 5, Table 5.1).  In addition, site clinicians may also obtain local 
labs and ECG’s if safety is a concern at non-scheduled intervals.  Clinical alerts are 
generated when safety parameters are exceeded. (Table 8.1).  Expected events are not 
considered serious adverse events (SAEs) unless they meet criteria for an SAE (see 
8.3.2).   
  
Table 8.1  Clinical Safety Alerts  
 
Measure 
Alert Value 
 
 
Serum sodium 
< =132 or >150 mEq/L 
Serum potassium 
<3.0 or >5.5 mEq/L 
Serum creatinine 
Increase by at least 50% to a value >=1.5 mg/dL since 
the last study lab (usually 6 months apart). 
 
 
Heart rate 
<40 
 
 
ECG 
acute MI, complete heart block, or bradycardia <40 bmp 
 
 
PHQ-9  
(depression screen) 
Positive response to question on suicidal ideation 
 
 
Dementia 
Assessment 
Adjudicated dementia 
 
 
8.3.2  Adverse Events and Serious Adverse Events 
 
An adverse event (AE) is defined as any untoward or unfavorable medical occurrence in 
a human subject, including any clinically significant abnormal sign (for example, 
abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in the research, whether or not considered 
related to the subject’s participation in the research. The burden of collecting and 
reporting data on every possible AE in SPRINT is excessive and side effects from the 
drugs to be used in SPRINT have been well defined in previous studies.  Therefore, in 
SPRINT, sites will report all serious adverse events and selected AEs to the 
Coordinating Center.  
 
Consistent with NHLBI guidelines and OHRP policy, SAEs are adverse events that meet 
any of the following criteria: 
• fatal or life-threatening,  
• result in significant or persistent disability,  
• require or prolong hospitalization,  
• result in a congenital anomaly/birth defect, or  
• are important medical events that investigators judge to represent significant 
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intervention to prevent one of the other outcomes listed in this definition (e.g. 
hospitalization, death, persistent disability).  
 
Any adverse event that meets any of these criteria will be documented and reported as a 
serious adverse event.  In addition, a select list of other important events (see manual of 
procedures for details and definitions), regardless of whether they resulted in 
hospitalization, will also be considered SAEs in SPRINT, including: 
• 
Injurious falls  
• 
Syncope  
• 
Unexpected events for which the investigator believes that the SPRINT 
intervention caused the event or contributed to the immediate cause of the 
event 
 
Participants will be queried for SAEs and selected AEs at quarterly clinic visits. 
 
 
8.3.3 Modification of treatment in response to safety concerns 
 
SPRINT is testing two different SBP treatment goals.  The study physician may add, 
increase or reduce the dose, stop, or change antihypertensive drugs in the interest of 
participant safety.  Depending on the situation, the change may be temporary or 
permanent.  Situations that may require temporary reduction or elimination of a study 
medication include: side effects, worsening congestive heart failure, acute kidney injury, 
symptomatic hypotensive episodes, and other illnesses.  Orthostatic hypotension is 
usually related to specific drug classes and not BP level per se and thus should NOT 
usually alter target blood pressure goals.  The MOP contains a section on management 
of symptomatic orthostatic hypotension.   
 
8.4   
Safety Reporting 
 
8.4.1 Clinical Safety Alerts 
 
Clinical Safety Alerts (section 8.3.1. and Table 8.1) are provided to the site clinician for 
his/her action. When any laboratory measurement attains a defined alert level, the 
Central Laboratory will immediately notify the clinical site and the CCN. Site clinicians 
may also obtain local labs if safety is a concern at non-scheduled intervals. Site 
clinicians are responsible for timely review of all labs drawn locally and when central lab 
results become available.  ECGs will be done at specified visits and read by the ECG 
reading center. However, if a participant has one of a short list of abnormalities (reported 
on the ECG by the machine), such as acute MI, complete heart block, or bradycardia 
<40 beats/minute, the ECG will be reviewed by the site clinician immediately (see ECG 
section of the SPRINT MOP). 
 
8.4.2 Serious Adverse Events 
 
At each quarterly visit, SPRINT staff will specifically query participants for serious 
adverse events. In addition, information on serious adverse events may also be reported 
to study staff spontaneously by participants through telephone calls or emails between 
study visits.  In addition to local reporting requirements, all serious adverse events will 
be recorded by clinic staff and forwarded to the CC Medical Safety Officer within 72 
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the end of the study follow-up period for an individual participant.  SAEs will be followed 
until resolution, stabilization, or until it is determined that study participation is not the 
cause.  
 
The Coordinating Center will be responsible for timely reporting to the NIH and the 
DSMB.   The Coordinating Center will provide reports of serious adverse events for 
review by the DSMB at their meetings. 
 
8.5   
Data Safety Monitoring Board  
 
A Data Safety Monitoring Board (DSMB) is established, with responsibility to monitor 
all aspects of the study. The Medical Safety Officer reports to the DSMB for issues 
related to participants’ safety.  This independent Data and Safety Monitoring Board will 
be established to monitor data and oversee participant safety.  Members will be 
appointed by the NHLBI to provide oversight of the trial and its ancillary studies. The 
SPRINT DSMB may include experts in cardiovascular medicine (particularly 
hypertension), kidney disease, clinical trials, geriatrics, biostatistics, quality of life, cost 
effectiveness, cognitive function and other areas as needed.  DSMB participants include 
the Steering Committee Chair and Vice-Chair, CC PI and senior staff, and 
representatives from the NHLBI and other NIH sponsors. The DSMB normally meets 
twice a year to monitor safety, to advise the NHLBI about study progress and 
performance, and to make recommendations to the NHLBI regarding study continuation 
and protocol changes. In addition, the CC may provide data to the DSMB Chair to 
ensure early identification of any major adverse outcomes of therapy.  The DSMB has 
the responsibility to recommend to the NHLBI whether the trial should continue, whether 
the protocol should be modified, or whether there should be early termination.  The 
DSMB will provide reports to the NHLBI through the Executive Secretary, who will be 
appointed by the NHLBI.  Recommendations by the DSMB must be approved by the 
NHLBI prior to implementation. 
 
 

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Chapter 9 – Clinical Outcome Measures 
 
9.0 Outcomes  
 
This chapter describes the SPRINT primary and secondary clinical outcomes.  Clinical 
events occurring during follow-up will be ascertained primarily through surveillance of 
self-reported events, laboratory, and ECG data collected by the study and classified by 
members of the Morbidity and Mortality subcommittee masked to treatment assignment.  
Additional sources, including searches of the National Death Index (NDI), will also be 
used to augment follow-up data.  
 
9.1 Primary Outcome  
 
The primary outcome measure for SPRINT will be major CVD events, defined as the 
composite endpoint comprised of the first occurrence of a  
• 
fatal or non-fatal myocardial infarction (MI),  
• 
non-MI acute coronary syndrome (non-MI ACS),  
• 
fatal or non-fatal stroke,  
• 
fatal or non-fatal heart failure (HF), or  
• 
death attributable to cardiovascular disease (CVD).   
MI and non-MI ACS are defined in Section 9.1.1; stroke is defined in Section 9.1.2; HF is 
defined in Section 9.1.3, and CVD death is defined in Section 9.1.4.  The SPRINT 
Manual of Procedures contains the full details of these definitions.   
 
9.1.1 MI and Non MI ACS 
 
9.1.1.1 MI: Defined as the death of part of the myocardium due to an occlusion of a 
coronary artery from any cause, including spasm, embolus, thrombus or rupture of a 
plaque.  SPRINT will use standard case definitions for both fatal and nonfatal MI based 
on the combination of symptoms, elevation in biomarkers, and/or ECG findings.  The 
algorithm for classifying MI includes elements of the clinical presentation (signs and 
symptoms), results of cardiac biomarker determinations, and ECG readings, and is 
based on a 2003 Scientific Statement (Luepker and others, 2003).  The definition 
includes MI that occurred during surgery/procedure and MI aborted by thrombolytic 
therapy or procedure.  SPRINT adjudicators will be guided by specific, pre-specified 
definitions and operational rules. Adjudicators will use their clinical interpretation of the 
ECGs and other available evidence for the event to classify MI cases as definite, 
probable, or possible, with all included in the primary outcome (Luepker and others, 
2003).  MI will be ascertained both from adjudication of hospital records for clinical 
events and also from the finding of new significant Q waves from the standardized 
interpretation of the study visit-obtained ECG (silent or unrecognized MI).  MIs that 
present clinically will include Q wave, ST elevation and non-ST elevation infarctions 
(segment elevation myocardial infarction (STEMI) and Non-ST Segment elevation 
myocardial infarction (NSTEMI), as well as aborted MI and post-intervention MI.   
 
9.1.1.2 Non-MI ACS: Defined as hospitalization for evaluation and treatment of an 
accelerating or new symptom pattern consistent with coronary artery insufficiency 
without meeting the definition of MI, but requiring evaluation to rule-out MI on clinical 
presentation.  Non-MI ACS in SPRINT will also require objective findings of coronary 
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significant obstruction or previous revascularization; significant obstructive lesion(s) on 
coronary catheterization during index hospitalization and/or intervention for 
revascularization; ischemic ECG changes or imaging findings on exercise or 
pharmacologic stress testing associated with the index hospitalization; or resting ECG 
findings consistent with ischemia occurring with symptoms during the index 
hospitalization.       
 
9.1.2 Stroke  
 
9.1.2.1 Stroke: SPRINT will use standard case definitions for both fatal and nonfatal 
stroke.  Stroke will be defined based on all available data, including symptoms and 
signs, imaging of the brain and large vessels, and cardiac testing, e.g., 
echocardiography. Adjudicators will use their clinical judgment based on the available 
evidence to classify each case, and will be guided by pre-specified definitions and 
operational rules. Stroke is GENERALLY defined as neurological deficit of 
cerebrovascular cause that persists beyond 24 hours or is interrupted by death within 24 
hours. (World Health Organization, 1978 Cerebrovascular Disorders (Offset 
Publications).  Geneva: World Health Organization. ISBN 9241700432.  Exclusionary 
conditions for stroke include major brain trauma, intracranial neoplasm, coma due to 
metabolic disorders or disorders of fluid or electrolyte balance, peripheral neuropathy, or 
central nervous system infections.  Stroke will be classified as brain infarction, 
subarachnoid hemorrhage, intraparenchymal hemorrhage, other hemorrhage, other 
type, or unknown type.  In SPRINT, brain infarction (ischemic stroke) is defined as a new 
lesion detected by computed tomography or magnetic resonance imaging or, in the 
absence of a new lesion ON AVAILABLE IMAGING, clinical findings consistent with the 
occurrence of stroke that lasted for more than 24 hours (N Engl J Med 2001;345:1444-
51).   Brain infarctions will be further sub-typed using the Causative Classification of 
Stroke system as evident, probable, or possible cases of large artery atherosclerosis, 
cardio-aortic embolism, small artery occlusion, other causes, and undetermined causes 
(Ay and others, 2007).  Strokes following invasive cardiovascular interventions will also 
be classified as such. 
 
9.1.3 HF  
 
9.1.3.1 HF: Defined as hospitalization, or emergency department visit requiring treatment 
with infusion therapy, for a clinical syndrome that presents with multiple signs and 
symptoms consistent with cardiac decompensation/inadequate cardiac pump function. 
Adjudication will use the ARIC study adjudication system (Rosamond and others, 2009).  
The SPRINT HF outcome will include definite or possible acute decompensation, 
including HF with preserved left ventricular ejection fraction as well as HF with reduced 
ejection fraction.  HF cases may also be adjudicated as chronic stable HF but this is not 
considered a SPRINT outcome. In SPRINT, HF will include a variety of clinical 
presentations, including acute or subacute HF as the primary reason for hospital 
admission or for emergency department visit where HF was diagnosed and intravenous 
treatment was given.   The identification and classification of HF cases will rely on 
multiple pieces of key clinical data as well as adjudicators’ clinical judgment, guided by 
specific, pre-specified definitions and operational rules.  No identification of HF should 
rely on a single piece of data such as the presence of dyspnea or of edema, a low 
ejection fraction, or an increased brain naturetic peptide (BNP) value. Adjudicators will 
use both the data available and clinical judgment to distinguish between “definite” and 
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decompensation is clearly present based on available data (satisfies criteria for 
decompensation). “Possible” decompensation will be assigned when decompensation is 
possibly but not definitively present, typically where the presence of co-morbidity could 
account for the acute symptoms (chronic obstructive pulmonary disease (COPD) 
exacerbation, for example).    
 
For participants with advanced CKD with or without chronic dialysis, the ascertainment 
of HF can be particularly difficult, since the fluid overload can be purely the consequence 
of fluid retention by the kidney or absence of kidneys.  Under these circumstances, the 
adjudicators will again use their best judgment, utilizing all available information.   
 
9.1.4 CVD Death  
 
9.1.4.1 CVD Death: SPRINT will use standard case definitions for classification of CVD 
death. Definite CVD events will be defined based on temporal relationship to a 
documented event (e.g., hospitalization for MI or for stroke), or postmortem findings of 
an acute CVD event.  Probable coronary heart disease (CHD) death (Luepker, 2003) will 
be defined based on autopsy findings consistent with chronic CHD, prior history of CHD 
or documented symptoms consistent with CHD prior to death, and the absence of 
another likely cause of death.  Possible fatal CHD will be adjudicated based on death 
certificate information consistent with an underlying CHD cause and no evidence of a 
non-coronary cause.  Stroke deaths will be categorized based on the temporal 
relationship between the stroke event and death, in cases where the underlying cause of 
death is attributed to stroke.  Proximal stroke death is a death attributed to stroke and 
occurring within 30 days of stroke; remote stroke death is underlying cause attributed to 
stroke and more than 30 days from stroke to death.  Other forms of CVD death will also 
be adjudicated and include ruptured abdominal aortic aneurysm, and documented 
arrhythmia. 
 
9.2 Secondary Outcomes 
 
In addition to the primary outcome, SPRINT will assess additional clinical outcomes in 
order to more fully evaluate the relative effects of treating to a SBP goal lower than the 
currently recommended goal.  In order to do so, data will be collected on secondary and 
other trial outcomes.   Main secondary outcomes are included in the analysis plan in 
Chapter 10. 
 
9.2.1 Main secondary cardiovascular composite outcome: The main secondary 
composite outcome of SPRINT is comprised of the first occurrence of any of the 
components of the primary outcome and all cause mortality.  A major and analogous 
secondary outcome of CVD-free survival, defined as survival without any of the primary 
or secondary CVD outcomes, will also be examined because of the significant proportion 
of elderly in the trial and the public health importance of the issue of CVD in that age 
group.   All cause mortality and components of the primary outcome will also be 
examined. 
 
9.2.2  Main secondary renal outcome: The main secondary renal outcome of SPRINT 
will be the composite of a 50% decrease in eGFR or development of ESRD requiring 
chronic dialysis or kidney transplantation.  This outcome applies to the CKD subgroup 
only.  
 

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9.2.3  Main secondary cognitive outcomes:  SPRINT MIND will evaluate the incidence 
of all-cause dementia as adjudicated by an expert panel as the most important outcome 
for the MIND study.  The second most important outcome is cognitive impairment among 
the Extensive Cognitive Assessment Battery participants will be tested with the full 
assessment battery (6.4.1.3 and 6.6.2).  Each test score from the full assessment 
battery will be classified as indicating “impairment (1)” or “no impairment (0)” based on 
norms.  A sum of impairment scores will be calculated indicating the total number of 
impairments.  Detailed definitions of these outcomes are contained in chapter 6. 
 
9.2.4 Additional secondary outcomes:  In addition to the secondary outcomes 
specified in Chapter 10, other outcomes will also be examined separately and combined 
with other outcomes in composites (e.g., CVD-free survival defined above): 
• 
Peripheral arterial disease, including carotid and peripheral revascularization, 
abdominal aortic aneurysm repair, and other objectively defined PAD events  
• 
Coronary revascularization 
• 
Transient Ischemic Attack (TIA): TIA in SPRINT will be defined as one or more 
transient episodes of the sudden onset of a focal neurological deficit, no lesion on 
brain imaging consistent with the deficit, and no signs or symptoms consistent with 
seizures, migraine, or other non-vascular causes.   
• 
ECG diagnosed Left Ventricular Hypertrophy (LVH): ECG-diagnosed LVH will be 
defined primarily using the sex-specific Cornell voltage criteria. Other ECG-LVH 
criteria mentioned in the American Heart Association (AHA)/American College of 
Cardiology (ACC) statement on ECG changes associated with cardiac chamber 
hypertrophy (Hancock and others, 2009) will be also considered. 
• 
Atrial fibrillation or flutter: In SPRINT, atrial fibrillation/flutter will be primarily detected 
from the scheduled study ECGs using Minnesota ECG classification (Minnesota 
code 8.3). Other sources of detection include hospital discharge ICD code (ICD-10 
code 148 or ICD-9 code 427.3) and self-report. 
• 
Other renal outcomes 
o Incident CKD, defined as a >30% decrease in eGFR and an end value of <60 
ml/min/1.73M2.  This outcome applies only to the non-CKD subgroup.  This 
decrease in eGFR requires a confirmatory value in the next available official 
SPRINT lab check.  
o Incident albuminuria, defined as a doubling of urinary albumin-to-creatinine 
(ACR) ratio from a value <10 mg/g to a value of >10 mg/g.  This outcome 
applies to CKD and non-CKD subjects.  This increase in ACR requires a 
confirmatory value in the next available official SPRINT lab check. 
 
 
 
 

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Chapter 10 – Statistical Considerations  
 
The SPRINT Trial has a single primary objective and several key secondary objectives, 
some of which will be addressed within a number of subgroups whose target size has 
been guided by power computations.   The primary objective is to determine whether the 
intensive BP treatment strategy will, when compared to a standard BP treatment 
strategy, reduce the incidence of serious cardiovascular events, defined as MI, stroke, 
heart failure, non-MI acute coronary syndrome or other cardiovascular death.  This will 
be tested in all SPRINT participants. 
 
The key secondary objectives are to determine whether the intensive BP strategy 
reduces the incidence of: 
1) total mortality, 
2) progression of CKD, 
3) probable dementia, 
4) cognitive impairment, and 
5) white matter lesions detected by MRI. 
The primary analysis of each of these objectives will be in different groups of 
participants.  The analysis plan to address the primary and each secondary objective is 
described below, followed by estimates of the required sample size for each. 
 
10.1 Analysis Plan 
 
This section describes some of the key pre-specified analyses directed at the study’s 
primary and key secondary objectives.  Many other outcomes and measurements, such 
as blood pressure, adverse event experiences, health related quality of life, cost, and 
results of assays performed on blood and urine specimens will also be analyzed. 
 
10.1.1 Analysis of the Primary Outcome in all Randomized Participants 
 
The primary analysis will apply Cox proportional hazards regression (Cox, 1972) to all 
randomized participants to compare the time from randomization to the first occurrence 
of the primary CVD composite endpoint between the randomized BP groups. The model 
will include an indicator for intervention arm as its sole predictor variable.  Clinical site at 
randomization will be a stratifying factor.  Follow-up time will be censored at the last date 
of event ascertainment.  The p-value from the primary analysis will be based on the chi-
square statistic from a likelihood ratio test obtained from proportional hazards models 
with and without the term for intervention arm.  This likelihood ratio test will constitute the 
primary test of statistical significance for the primary analysis. 
 
Primary comparisons of intervention groups will be performed according to the intention-
to-treat principle. All randomized participants in these analyses will be grouped 
according to their intervention assignment at randomization, regardless of adherence.  
 
10.1.2 Secondary analyses supporting the primary analysis 
 
 
10.1.2.1 Secondary outcomes.   A number of secondary outcomes will be analyzed to 
clarify the interpretation of the results of the primary analysis.  These will include: 
a) all myocardial infarction, 
b) all stroke, 

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c) non-MI acute coronary syndrome, 
d) all heart failure, 
e) CVD mortality, 
f) total mortality, and 
g) a composite of total mortality and the primary composite outcome (i.e. major 
CVD event- free survival). 
 
Each of these will be analyzed using a proportional hazards model as described for the 
primary analysis.  These will be reported with 95% confidence intervals and nominal p-
values without an adjustment for multiple comparisons, since the intent is to articulate a 
pattern of effects closely related to the primary outcome, rather than to provide additional 
tests of efficacy. 
 
10.1.2.2  Subgroup analyses.  In addition to the analysis of the secondary outcomes 
described above, a set of analyses will be reported to explore whether intervention 
effects on the primary and confirmatory secondary outcomes are consistent across 
subgroups of interest.  These subgroups are: 
a) CKD (defined as eGFR < 60 at randomization) vs. non-CKD, 
b) senior vs. non-senior (aged >75 at randomization vs. aged <75), 
c) male vs. female, 
d) black vs. non-black, 
e) with and without a history of CVD at randomization (as defined in Chapter 3), and 
f) tertiles of systolic blood pressure at baseline. 
 
The subgroups defined by CKD, age and race are motivated by biologically plausible 
hypotheses. For each subgroup analysis, a proportional hazards model will be used that 
is similar to the one described for the primary analysis above, but with additional terms 
identifying subgroup membership and the intervention by subgroup interaction.  The 
nominal p-value for the interaction term using a likelihood ratio test will be reported along 
with within subgroup estimates of the intervention effect and associated nominal 95% 
confidence intervals.  We will report the Hommel adjusted p-values for the interaction 
effects.   
 
10.1.3  Non-cardiovascular clinical outcomes 
 
10.1.3.1. Acute vs. chronic effects of intervention 
 
It is possible that the intervention will have some acute adverse effects due to under-
perfusion of various organs, notably the kidney and the brain, which are major targets of 
SPRINT.  In the long term, however, lower SBP may protect these organs from 
hypertension-related damage. We will examine the possibility of acute effects as part of 
the data monitoring plan, particularly if differential adverse effects are observed early in 
the trial; we also will examine the possibility of acute effects as part of the data analysis 
at the end of the trial. 
 
10.1.3.2 Renal outcomes 
 
Renal outcomes are of particular importance in SPRINT, both to assess the incidence of 
new kidney disease among participants free of CKD at baseline and to assess the 
progression of kidney disease among those with CKD at baseline.  Because some 

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outcomes are more interpretable in either people with CKD or without CKD at baseline, 
some analyses will be restricted to these subgroups. 
 
The primary hypothesis for the renal outcomes is whether, in the subgroup with CKD at 
baseline, the rate of a composite of a 50% decrease in eGFR or ESRD undergoing 
chronic dialysis or kidney transplantation is lower in the intensive intervention arm.  The 
decline in eGFR must be seen on two visits at least three months apart.  This will be 
analyzed using a proportional hazards model as described for the primary CV analysis. 
 
A number of additional analyses related to this hypothesis will also be performed.  These 
will include: 
a) incident CKD in the non-CKD subgroup, defined as a 30% decline from baseline 
eGFR to a value of <60 mL/min/1.73m2 (observed on two visits at least 3 months 
apart.  There must be a decrease of at least 30% AND the end value of this 
decrease must be <60 ml/min/1.73m2 in order to satisfy this endpoint criterion) or 
ESRD 
b) incident albuminuria, defined as a doubling of urinary albumin-to-creatinine 
(ACR) ratio from a value <10 mg/g to a value of >10 mg/g.  This outcome applies 
to CKD and non-CKD subjects.  This increase in ACR must be observed at two 
visits at least 3 months apart. 
 
Subgroup analyses.  Analyses of the renal outcomes will be by CKD and non-CKD 
strata.  Within each strata, assessments of the renal composite endpoint will be by 
subgroups.  The analytical approach will be the same as for the primary CV analysis as 
described in 10.1.2.2.  The renal subgroups are: 
a) urinary albumin/creatinine ratio (>300 mg/g and ≤ 300 mg/g),  
b) black vs. non-black, 
c) senior vs. non-senior (aged 75+ at randomization vs. aged <75), 
d) male vs female, 
e) eGFR (median split) 
The subgroups defined by albumin/creatinine ratio, age and race are motivated by 
biologically plausible hypotheses. The main renal outcome composite is defined 
differently for the CKD and non-CKD strata, so that these will be separate analyses.   
 
10.1.3.3 Dementia and cognitive outcomes. 
 
The primary outcome for SPRINT MIND will be the first identification of adjudicated 
dementia.  Cox proportional hazards models (as described above for the SPRINT 
primary outcome) will be used to compare the time from randomization to the first 
identification of dementia between the two treatment arms.  All participants will be 
screened for dementia at baseline. 
 
Secondary analyses.  Secondary analyses in the areas of cognitive function, small 
vessel ischemic disease (SVID) lesion load, and mild cognitive impairment will also be 
performed to support the primary analysis. 
 
Cognitive Function.  A cognitive assessment battery will be administered at baseline and 
2 and 4 years post-randomization in a subsample of 2800.  The primary outcomes will 
be composite scores for two domains: 1) Memory, consisting of the Hopkins Verbal 
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Processing Speed, consisting of Trails Making Tests and Digit Symbol Coding Test.  
Changes in impairment over time will be compared between the two treatment arms. 
 
Supporting analyses will also be conducted on the effect of the interventions on 
individual domains of memory over 48 months. Follow-up test scores will be compared 
using mixed-effects analysis of covariance models (Laird, 1982).  Mixed-effects models 
allow for departure from linearity in the relationship between the outcome and time.  
Estimates of the difference in mean levels of the outcome between control and 
intervention groups will be obtained using maximum likelihood techniques.  Sensitivity of 
results to missing data will be investigated through the use of multiple imputation 
techniques (Rubin, 1987).  
 
Magnetic Resonance Imaging (MRI).  Other than age, hypertension is the strongest 
correlate of SVID.  Total SVID lesion load including abnormal white matter, abnormal 
gray matter and abnormal basal ganglia will be the SPRINT measure of total SVID lesion 
load.  Differences in total SVID lesion between treatment groups at 48 months will be the 
main outcomes of the MRI component.  Furthermore, differences in total brain volume 
will also be compared after 48 months.  These measures are continuous and will be 
analyzed using mixed effects analysis of covariance models as described above.  
 
Mild Cognitive Impairment (MCI).  This outcome is defined as the time to the first of  
two consecutive occurrences of MCI.  Analytical methods used for dementia will be 
applied to the analyses of MCI, in those free of MCI at baseline.  Furthermore, these 
same methods will be applied to the analyses of the first cognitive impairment defined as 
the first event classified either as MCI or dementia in those free of MCI at baseline. 
 
Subgroups.  Analyses of the cognitive outcomes will also explore the intervention effects 
within subgroups.  The analytic approach will be the same as for the primary CV analysis 
as described in 10.1.2.2.  The subgroups are: 
a) CKD (defined as eGFR < 60 at randomization) vs. non-CKD, 
b) senior vs. non-senior (aged 75+ at randomization vs. aged <75), 
c) male vs. female, 
d) black vs. non-black, 
e) with and without a history of CVD at randomization (as defined in Chapter 3),  
f) tertiles of systolic blood pressure at baseline, 
g) MCI at baseline (yes vs. no),  
h) orthostatic hypotension (yes vs. no). 
 
The subgroups of CKD, age, and MCI are motivated by biologically plausible 
hypotheses. 
 
10.1.4  Other analyses 
 
We expect to explore fully the rich set of data that SPRINT will obtain.   Exploratory 
analyses of biologically plausible subgroups are of particular interest.  Some of these will 
be further articulation of supporting subgroup analyses described above, such as 
analysis of continuous baseline factors as continuous variables rather as pre-specified 
categorical variables.   Other analyses will involve baseline variables that are not listed 
in the pre-specified subgroup but which may modify treatment effect, such as diastolic 
blood pressure or presence of the metabolic syndrome.   
 

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10.1.5  Missing data 
 
Consistent with an intention-to-treat analysis, we will categorize all participants by their 
randomization group, regardless of compliance, in our primary analyses.  For those 
participants lost to follow-up, we plan to use all available information until the time of 
death or loss to follow-up.   
 
Our approach to handling missing outcomes in clinical trials is consistent with the 
opinion of Molenberghs and Kenward (2007, p9), who state that while ignorable, 
missing-at-random (MAR) analyses are reasonable for the primary analysis, exploration 
of the sensitivity of conclusion to the MAR assumption may include models which allow 
for missingness that is not random.  If loss to follow-up is related to the level of the 
outcome being analyzed (e.g. as often occurs when analyzing health related outcomes), 
then results obtained under the assumption of independent loss to follow-up may be 
biased.  The magnitude of this problem will be investigated by using measurements 
taken at previous visits to predict loss to follow-up.  Variables determined to predict loss 
to follow-up will be included in our predictive models in order to satisfy the conditions 
described by Little and Rubin (1987) for the data to be considered MAR.  Maximum 
likelihood techniques will be used to estimate parameters.  If necessary, other 
approaches may be examined in consideration of how robust the results will be and 
whether they provide appropriately conservative estimates for the trial. 
 
In order to explore the possibility of a relationship between ESRD and CV outcomes, we 
will conduct sensitivity analyses which treat ESRD as a censoring point for the primary 
outcome.  This exploration may include an auxiliary composite outcome combining the 
events in the primary outcome and ESRD. 
 
Robustness of inferences to missing outcome data will be further explored in sensitivity 
analyses.  These analyses will include examination of several “worst-case” scenarios, 
including opposite and pooled imputation approaches (Wittes, Lakatos & Probstfield 
1989; Proschan et al., 2001).  These types of scenarios are members of a broad class 
that can be parameterized as pattern mixture models (Little 1993) and allow for 
examination of sensitivity of conclusions to missing-not-at-random (MNAR) mechanisms 
(Mohlenberg and Kenward, 2007). 
 
The MRI substudy involves two assessments—one at baseline and one at 48 months—
in 640 participants, thus limiting the range of analytic strategies.  We recommend using 
maximum likelihood based general linear models for analyzing outcomes. Intracranial 
volume will be included as a covariate. The validity of the MAR assumption can be 
improved by including baseline covariates that predict missingness.  If loss to follow-up 
is related to the unobserved cognitive outcome then our results may be biased.  Again, 
some modeling and sensitivity analysis options may be considered if necessary. 
 
10.2 
Sample Size Estimation and Power Calculations  
 
10.2.1 Primary Outcome 
 
We have assumed a 2.2 %/yr event rate of the primary outcome in the standard group, a 
20% effect size for the intervention (hazard ratio of 0.8), a two-year uniform recruitment 
period, a total study length of 5 years and 10 months, a 2 %/yr rate of loss to follow-up, 

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and a two-sided test at the 5% level.  With these assumptions, power for a variety of 
sample sizes is presented in Table 1.  Power is also presented for hazard ratios of 0.78 
and 0.82 and for event rates of 2.0 and 2.4 %/yr.  A sample size of 9250 provides high 
power for a hazard ratio of 0.8 (representing a 20% effect) and a 2.2 %/yr event rate.  
This sample size would also provide over 80% power for an effect of 18% (hazard ratio 
of 0.82) with an event rate of 2.2 %/yr and would have reasonable power of 77.3% even 
with a smaller than assumed event rate of 2.0 %/yr and an 18% effect.  Depending on 
the observed event rate and treatment effect, the table below shows that sample sizes of 
8500 to 10000 would be consistent with study goals. 
 
Table 1:  Power for the SPRINT primary outcome. 
 
Event Rate 
 
2.0 %/yr 
2.2 %/yr 
2.4 %/yr 
N\Hazard Ratio 0.78 
0.8 
0.82 0.78 
0.8 
0.82 0.78 
0.8 
0.82 
8500 
89.4 82.7 73.7 91.9 85.9 77.6 93.9 88.6 80.9 
8750 
90.3 83.7 75.0 92.6 86.9 78.7 94.5 89.5 82.0 
9000 
91.0 84.7 76.1 93.3 87.8 79.8 95.0 90.3 83.0 
9250 
91.7 85.7 77.3 93.9 88.7 80.9 95.5 91.0 84.0 
9500 
92.4 86.6 78.3 94.4 89.4 81.9 95.9 91.7 85.0 
9750 
93.0 87.4 79.4 94.9 90.2 82.9 96.4 92.4 85.9 
10000 
93.6 88.2 80.4 95.4 90.9 83.8 96.7 93.0 86.7 
 
If the event rate in the standard therapy arm is substantially less than 2.2%, we may ask 
that the DSMB consider recommending a two year extension of the trial.   
 
10.2.2 Summary 
 
For the primary outcome under the assumptions detailed below, with 9250 participants, 
the SPRINT study is designed to have 
• 
88.7% power to detect a treatment effect of 20% of intensive blood pressure 
control compared with standard blood pressure control, 
• 
81.9% power to detect a treatment effect of 20% of intensive blood pressure 
control compared with standard blood pressure control among participants with 
estimated glomerular filtration rates of <60 ml/min/1.73m2 at baseline, 
• 
84.5% power to detect a treatment effect of 25% of intensive blood pressure 
control compared with standard blood pressure control among participants at 
least 75 years old at baseline, 
• 
96% power to detect a 20% effect and 80% power to detect a 15% effect for 
incident dementia, the primary outcome for SPRINT MIND. 
 
These estimates of power are valid under the following assumptions: 
• 
The primary outcome for SPRINT is a composite of fatal CVD, MI, stroke, heart 
failure, and non-MI acute coronary syndrome. 
• 
The event rate for this composite outcome is 
o 2.2 %/yr in the standard BP arm, 
o 4 %/yr among participants with eGFR <60 ml/min/1.73m2, and 
o 3.5 %/yr among participants ≥75 years old. 
• 
The event rate for the SPRINT MIND primary outcome of incident dementia is 
3.1%/yr. 
• 
There are 

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o 9250 participants in SPRINT, 
o 4300 participants with eGFR < 60 ml/min/1.73m2, and 
o 3250 participants ≥75 years old. 
• 
Participants are recruited uniformly over 2 years. 
• 
Minimum follow-up is 3 years, 10 months which assumes that closeout visits 
occur uniformly over a 4 month period. 
• 
Two-sided tests at the 0.05 level are used. 
• 
Annual loss to follow-up is 2 %/yr (3 %/yr for incident dementia). 
 
Additional computational details and a justification for the assumed event rates are 
included in the appendix. 
 
10.2.3 Power for the MIND primary outcome 
 
Power for the MIND primary outcome is presented in Table 10.2 for a range of event 
rates with 9250 participants, 5 years and 10 months of follow-up, 2 years of recruitment, 
and 3 %/yr loss to follow-up.  Details of the event rate estimation are given in Appendix 
3. 
 
Table 10.2.  Power for the SPRINT MIND primary outcomes. 
 
Event Rate (%/yr) 
Hazard Ratio 
3.1 
3.2 
3.3 
3.4 
3.5 
0.80 
96.3 
96.7 
97.1 
97.4 
97.7 
0.85 
79.0 
80.2 
81.3 
82.4 
83.4 
 
 
10.3 
Statistical Reports  
10.3.1 Steering Committee Reports 
 
Periodic reports will be generated for the Steering Committee, CCNs  and Clinical Sites.  
These reports will include information on recruitment, loss to follow-up, adherence, 
baseline covariate information on the comparability of treatment groups, and adverse 
events.  Information will be stratified by CCNs and Clinical Sites.  Other reports will 
include information on quality control for central facilities and data entry. 
 
10.3.2 Data and Safety Monitoring Board Reports 
 
The role and composition of the Data and Safety Monitoring Board are described 
elsewhere (Chapter 13.6).  Meetings of the DSMB will be held at least annually.  Material 
for these meetings will be distributed two weeks in advance of the meetings.  Up-to-date 
statistical analyses will be provided to the DSMB in preparation for their meetings.  The 
analyses will include data on recruitment, outcome measures, any side-effects or safety 
concerns, adherence, and quality control, and will be designed in cooperation with the 
DSMB.  Interim analyses of the intervention effectiveness will be performed at times 
coinciding with the meetings of the DSMB, and will be controlled to protect the overall 
Type I error of the trial.  These results will be for the use of the DSMB and will not be 
revealed to the investigators.  The purpose of these analyses will be for the DSMB to 
assess the trial progress with respect to intervention efficacy and safety, for possible 
recommendations regarding early termination of the trial. 
 

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We will work with the DSMB to finalize the monitoring plan.  We include here a potential 
starting point for those discussions. 
Interim analyses will be performed periodically for the DSMB.  Monitored parameters will 
include the following: 
1. SBP separation between groups 
2. SBP distribution within groups 
3. Primary outcome results 
4. Adverse events 
5. Laboratory alerts 
6. Recruitment progress 
7. Other event rates, and event rates by subgroups 
8. Enrollment overall and by subgroups such as level of eGFR and CKD category 
 
Sequential monitoring and early stopping.  Incidence rates of outcomes will be monitored 
throughout the trial and used for interim analyses of efficacy and futility. Group 
sequential methods for event rates will be used to control the Type I error to be 0.05 
across these repeated analyses.  Critical values for interim testing will be defined based 
on an O'Brien-Fleming type bound and will use a spending function to allow flexibility in 
the number and timing of interim analyses.  With this approach, interim tests early in the 
trial are conservative and the reduction in the overall power of the trial caused by interim 
testing is small. If needed, conditional power calculations will be used to assess the 
futility of continuation in the presence of a negative treatment effect. 
 
The monitoring plan will include consideration of the hypothesis that early adverse 
effects may occur and then be followed by long-term beneficial effects.  Because kidney 
function will be measured at baseline, 1, 3, and 6 months, we will be able to analyze the 
acute impact of our intervention on kidney function.  Because of the study design, 
episodes of acute kidney injury (AKI) that are of more than a transient nature will be 
identified as changes in chronic kidney function, consistent with contemporary 
paradigms acknowledging the interrelationships between AKI and CKD. Episodes of AKI 
will be specifically sought in review of medical records in appropriate patients as adverse 
events.  Regarding the possibility of acute cognitive decline, spontaneously reported 
SAEs would be the source of such information. 
 
At each meeting, the DSMB will review data on adverse events and other safety issues 
to make an overall recommendation to the NIH concerning the safety of continuing 
SPRINT.  Consistent with NIH policy, each SPRINT CCN Principal Investigator will 
receive a report summarizing the DSMB review of the adverse event data. Principal 
Investigators are responsible for providing this report to their sites and institutional IRB.   
 
10.3.3 Website Reports 
 
The Coordinating Center will prepare many reports and place them on the SPRINT 
website.  These reports enable a user to click on a static link which starts a real-time 
report processed by SAS and returned as output in the user’s web browser. These 
reports access live data and run within seconds.  Examples of real-time reports on 
randomization and screening activities include: number of clinics actively recruiting, 
percent at target (overall, to date, and by demographic subgroups such as women and 
race/ethnic group).  Clinical Sites will have access to live data showing exactly where 
their clinic stands in relation to their recruitment goals and those of the other Clinical 
Sites, as well as projections of activity needed to meet their goals. Committee members 

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will have expanded access to information across all Clinical Sites for the purpose of 
monitoring recruitment performance for the trial as a whole. 

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Chapter 11 – Data Management 
 
11.1 
Overview:  Use of the World Wide Web 
 
All Clinical Center Networks and Clinical Sites will use the World Wide Web (WWW) to 
enter SPRINT data collected on forms from participants seen within the Clinical Sites.  
Each Clinical Site will have a password protected area on the SPRINT home page 
through which data will be entered.  Documentation of the data entry system will be 
maintained at the CC.  In addition, training materials for measurement and data entry 
personnel will be available in downloadable format on the SPRINT web site.  Site-
specific reports relating to participant demographics, recruitment goals, etc., among 
other reports, will be available on the web site. 
 
Data security in the web-based data system uses 128-bit encryption and Secure Socket 
Layer (SSL).   Once data has been received at the CC, recovery from disasters such as 
natural phenomenon (water, fire, or electrical) is possible through the ability to 
reconstruct both the database management system and the data up to the last back-up 
through the use of nightly backups.  This will ensure optimal recovery of data systems in 
the event of a disaster. Back-up tapes are kept in a locked, fire and waterproof storage 
cabinet away from the computer room. Additional back-up tapes will be stored at another 
location on the Wake Forest University Health Sciences campus.   CCNs and clinical 
sites have local procedures for back-up and recovery of data following a disaster.  As a 
supplement to those plans, the SPRINT CC will have all participant contact information 
to minimize the chance for disruption of communication with participants regarding study 
medications and test results. 
 
11.2       Flow of Data from Trial Units to Databases 
 
11.2.1 Data from Clinical Sites and Clinical Center Networks 
 
Participant Randomization:  SPRINT will use an internet-based, web browser 
randomization procedure.  Clinical Sites access the randomization application through 
the study web site.  Access to this application is password protected and its 
communications are encrypted.  Once security requirements are satisfied, a series of 
questions identify and verify the eligibility of the participant.  When the session is 
complete, an e-mail is sent to the Clinic Coordinator, the appropriate CCN, and the CC 
indicating that the participant has been properly randomized and appended to the 
database. 
 
Participant Tracking: The Participant Tracking System (PTS) is a fully integrated tracking 
and notification system that advises clinic staff about participant follow-up windows, and 
projects clinic and laboratory workload for a week at a time (longer if necessary).  
Tracking a participant begins at screening and continues automatically throughout the 
project by integrating participant follow-up data with predetermined follow-up "windows". 
When a participant is enrolled into the study, a schedule of target dates for each of the 
visits is automatically generated.  The report details the recommended "windows" that 
each visit should fall into and a case file is created for the participant.   
 
Data Entry:  The images on the data entry screens mirror the data collection forms for 
ease and accuracy of entry.  Typically, as participant visits are completed, and hard copy 

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forms are filled out, the clinic coordinator reviews each form for accuracy and 
completeness, including laboratory reports and any supporting documentation (hospital 
records, etc.). Once any data problems have been resolved, data are entered by clinic 
staff into the computer via the web-based browser application.  During data entry, a 
variety of programmed edit checks are performed for key variables.  When the edit 
checks fail, data may be flagged for further review or prevented from becoming part of 
the study database.  Also, a sample of key forms may be double-keyed for additional 
quality control. 
 
11.2.2 Data from Central Laboratory and ECG Reading Center 
 
Laboratory specimens and electrocardiographic data are sent to the Central Laboratory 
and ECG Reading Center from the Clinical Sites on a fixed schedule.  The Central 
Laboratory and ECG Reading Center provide results to the CC on live internet feed.  
Depending on clinic needs, reports will be sent to assist in the clinical functions (e.g., 
providing timely feedback to the clinic on any measurement that exceeds a predefined 
alert level). 
 
11.2.3 Central Database Edits 
 
At regular intervals, data queries will be carried out on the computerized databases at 
the CC to perform consistency checks on key variables and forms.  Although much of 
this will have been done at the data entry level in the clinic, this additional pass through 
the data serves as a quality control check. 
 
11.3 
Feedback to Clinical Sites and Clinical Center Networks 
 
Data edit reports will be generated to help ensure that data are entered in timely and 
complete manner.  These reports will include both the assessment for each Clinical Site 
of the time between data collection and entry, and the generation of reports by the CC of 
missing items.  These reports will be provided to the Clinical Center Networks, Clinical 
Sites, and study committees on a regular basis so that data collection items that are 
troublesome can be identified and Clinical Sites not meeting study standards can be 
notified.  CCN Coordinators will be copied on all data reports for Clinical Sites within 
their network and asked to follow-up on any action that needs to be taken. 
 
11.4 
Confidentiality 
 
The confidentiality of all participant information (including but not limited to any genetic 
analysis) must be protected at the Clinical Sites, the CCNs, and the CC.  Paper records 
and computer files must be appropriately safeguarded from unauthorized access. 
 
Paper and/or electronic records for study participants will be stored at the Clinical Sites. 
Copies of records identified by participant identification number pertaining to SAEs and 
study-defined clinical events, including necessary medical records, will be stored at the 
CC.  These records will receive the same care as would ordinary medical records.  They 
will be stored in locked filing cabinets and/or filing rooms within secure office space.  
Only study personnel who have completed SPRINT training in data handling will have 
access to study forms. 
 

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Similar care will be used in the handling of the computer records of study data stored at 
each Clinical Site.  Access to the data in any local SPRINT database will be controlled 
by a system of user identification names and passwords.  Each Clinical Site staff 
member must complete the SPRINT data handling training program before being given 
an ID and password to use the data system. The privileges allowed to each ID can be 
individually specified by the local CCN Coordinator.  All passwords stored within the 
system will be encrypted using SSL encryption. 
 
Confidentiality of information within the CC will be protected through a variety of 
procedures and facilities: 
 
1. The confidential nature of the data collected, processed, and stored at the CC is 
explained to all new personnel. 
 
2. All access to CC office space containing data is controlled through a single door, 
which is locked with a keypunch lock.  This door remains locked at all times.  
 
3. All participant data sent to the CC is encrypted as described above.   
 
4. All participant data stored on the Wake Forest University’s mainframe computers 
are likewise encrypted.  In addition, all such databases are protected by 
passwords that must be supplied before the data can be accessed.  Passwords 
are released only to CC staff with a need to use the particular file, and are 
changed on a regular schedule. 
 
5. All printouts, plots, and reports containing individually identifiable data are 
produced on printers and plotters within the CC’s secure office space.   
 
6. The CC will obtain a Certificate of Confidentiality for SPRINT, which prevents 
researchers from being forced to disclose identifying information by certain legal 
proceedings. 
 
 
 
 

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SPRINT Protocol 
Chapter 12 – Quality Control 
 
12.1 Introduction 
 
Data integrity and quality are among the highest priorities in SPRINT.  This feature is 
reflected in the details provided in the protocol regarding initial screening and 
recruitment of participants, data acquisition at baseline and follow-up visits, outcome 
definition and assessments, reading and/or interpretation of the results, and their 
analysis and publication. There are two primary purposes for quality control: to 
document the level of quality and to provide feedback to the clinical, reading and 
laboratory centers in order to maintain and improve the quality of the study data over the 
course of the trial.  The Measurement Procedures and Quality Control Committee will 
establish guidelines for quality assurance and quality control, detailed in the Manual of 
Procedures.  
 
Quality control monitoring in SPRINT will involve the CC, the CCN hubs, and various 
SPRINT committees and other groups, although the Measurement Procedures and 
Quality Control Subcommittee will monitor quality control and quality assurance activities 
for the study overall, integrating input from these other groups.  For example, the 
Recruitment, Retention and Adherence Subcommittee will monitor progress toward 
achieving recruitment goals, and the SPRINT MIND subcommittee will monitor the 
quality of assessment with the cognitive battery.  The CC will generate reports and 
supply them to the CCN hubs for their sites, to the Measurement Procedures and Quality 
Control Subcommittee for all sites and entities, and to other involved groups for the 
activities in their purview.  The CCN hubs will be responsible for tracking the 
performance of sites within their Networks, and for following up with their sites on areas 
of concern.  The Measurement Procedures and Quality Control Subcommittee will 
conduct monitoring for the trial overall, will raise issues on specific sites and 
communicate them to the CCN hub for follow-up, will monitor the central facilities (ECG 
reading center and central lab), and will report any areas of concern to the Steering 
Committee for consideration, as needed. 
 
This chapter outlines the type of quality assurance activities that will be conducted in the 
SPRINT Trial.  Two phrases are used.  The first, quality assurance, is the collection of 
manuals and procedures that will be in place to assure the integrity of the data.  A 
subset of these procedures is referred to as quality control, which describes the 
monitoring and analytic activities that assess performance during data collection and its 
processing. 
 
12.2 Manual of Procedures  
 
As with any multicenter study, standardization of study procedures is very important in 
the SPRINT Trial.  The MOP includes the detailed descriptions of all trial procedures.  
This MOP is used for training purposes and as a reference for all study investigators and 
staff.  The MOP is an important aspect of efforts to standardize study procedures across 
clinical sites in the SPRINT Trial.   
 
Key study procedures will be standardized; these include the use of a central lab and 
ECG reading center, and standard forms, equipment, and procedures in the clinics for 

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BP measurement and other data collection procedures.  Furthermore, standard event 
definitions and event validation procedures will be used. 
 
12.3 
Study Forms and Data Entry Procedures 
 
Quality assurance concepts were employed during the development of forms.  Forms 
are printed with accompanying question-by-question instructions for easy reference.   
Web-based data entry screens will be developed from the forms, and enable the 
incorporation of range and logical checks at the time of data entry.  These features will 
contribute to quality assurance. 
 
12.4 
Training 
 
Training of staff and pilot testing of procedures will be crucial to standardize procedures 
and assure data quality. SPRINT uses two different training models: central training for 
study staff and the train-the-trainer approach. In the central training aspects of the 
SPRINT training effort, all relevant staff members from all clinical sites will be convened 
in a single, centrally administered face-to-face training session. This approach is cost-
efficient and contributes to uniformity of the training experience and thereby to uniformity 
of data quality across sites. In the train-the-trainer aspect of the SPRINT training effort, 
CCN hub staff will provide training sessions to persons who were unable to attend the 
central training session and to newly hired staff as turnover occurs. In addition, the CCN 
hubs will organize training and refresher training sessions, as needed, including CCN 
remedial training in specific areas targeted by quality control monitoring for a specific 
site.  
 
12.5 Data Queries 
 
The Coordinating Center will be responsible for data editing, which will include checks 
for missing data, unrealistic values, and crosschecks for inconsistencies.  Data will be 
checked on form submission and any data queries presented to the data entry staff for 
immediate resolution, if possible. The CC will also produce data query reports on the 
website that summarize the number and types of queries by clinic and network. Clinical 
center staff will be responsible for reviewing and resolving the data queries in a timely 
manner. Reports, including reports on timeliness of data entry and query resolution, will 
be shared with the Measurement Procedures and Quality Control Subcommittee and the 
corresponding CCN hub investigators and staff for quality control purposes. 
 
12.6 Quality Control Reports 
 
The Measurement Procedures and Quality Control Subcommittee will develop quality 
indicators, both to document data quality and to provide feedback to individual clinical 
sites, that will be tracked in routine quality control reports in the SPRINT Trial. All reports 
will be generated by the CC and distributed to the Subcommittee, to the corresponding 
CCN hub, and/or to other relevant groups (e.g., the SPRINT MIND subcommittee for 
those measures).  Investigators and staff at the CCN hubs will be responsible for 
disseminating reports and feedback to the appropriate investigators and staff at the 
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place during regularly scheduled telephone contacts and site visits.  Additional 
information about these processes is contained in the MOP. 
 
Quality Control reports will focus on measures of process, impact, and outcomes.  
Examples of process measures that will be tracked for quality control purposes include: 
1. Days between data collection and data entry 
2. Percent of forms with late data entry  
3. Number of participants with missed or late visits by contact,  number of missed 
or late visits clinic-wide, and number of participants missing two or more 
consecutive visits 
4.  Number, name and dose of prescribed antihypertensive medications for 
individual participants 
 
Examples of impact measures that will be tracked for quality control purposes include: 
1. Number (and percent) of participants at goal according to the BP target 
assignment as assessed by in-clinic BP measurements. 
 
Examples of outcome measures that will be tracked for quality control purposes include: 
1. 
Submission of medical record documentation for reported study events by the 
clinical site (e.g., timeliness, completeness) 
2. 
Proportion of participants with ECG submitted to central ECG Reading Center 
overall and by quality grade 
3. 
Proportion of participants with urine samples submitted for albuminuria 
assessment 
4. 
Proportion of participants with blood samples submitted to central lab 
5. 
Percent agreement of individual study adjudicators with the final outcome 
assignments for cases adjudicated 
 
Details of the various quality control procedures are contained in the Manual of 
Procedures.  In general, the CC will generate reports and analyses on progress at the 
clinical sites on an agreed upon schedule appropriate to the study phase.  Reports will 
most often be developed at the level of the clinical site but may also include patient-level 
reports by site, technician-level reports by site, and summary reports study-wide and 
within and across CCNs.  The CC will supply these reports to the Measurement 
Procedures and Quality Control Subcommittee, to other relevant Subcommittees, and to 
the corresponding CCN hub investigators and staff.   
 
12.6.1 Deviations from protocol 
 
Adherence to the study protocol is crucial to collection of high quality data and to the 
internal validity of the trial.  Thus, the Intervention Subcommittee will define important 
deviations from the intervention protocol for tracking purposes.  A clinic-site-specific 
report describing important protocol deviations will be disseminated by the CC to the 
respective CCNs for quality control purposes.  Copies of these reports and a summary 
report describing important protocol deviations and plan for corrective actions on a 
study-wide basis will be shared with the Measurement Procedures and Quality Control 
Subcommittee and the Steering Committee. 
 

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12.6.2 Monitoring the Clinical Centers in the Networks 
 
Primary responsibility for clinical site monitoring in SPRINT will be assigned to the 
corresponding CCN hub.  CCN hub investigators and staff will be responsible for 
monitoring performance at each of their clinical sites.  The CCN hub monitoring team will 
coordinate research activities of the study within their network and maintain effective 
communications with clinical sites, other clinical center networks, the coordinating 
center, project office and study central units (Central Lab, ECG Reading center, MRI 
Reading Center and Drug Distribution Center).  One of the primary roles of CCN hubs is 
to monitor clinical sites in all aspects of trial operations and performance and to assist in 
problem solving related to all aspects of the main study and ancillary studies.  Site 
monitoring can and will be performed using regular communications including email, 
conference calls, site visits and other means.      
 
12.7  Site Initiation 
 
Clinical site initiation to enroll and randomize participants is dependent upon completion 
of a series of preliminary tasks.  These include completion of appropriate regulatory 
approvals (IRBs), and letters of agreement.  Site staff training, certification, and receipt 
of all study supplies including medications will need to be completed as well as the 
development of a recruitment plan.  CCNs will provide the appropriate assistance to their 
clinical sites toward these ends, which may include site visits to ensure that the study 
enrollment and randomization process follows proper study procedures.   
 
12.8 
Site Visits 
 
12.8.1  CCNs to clinical sites 
 
During the course of the trial, clinical center network personnel will site visit clinical sites 
in their network at specified intervals, and as needed.  The scope of these visits is broad 
and can include but is not limited to regulatory requirements, study communications, site 
initiation, site staffing, and general site performance.  A minimum standard for all site 
visits content and frequency is detailed in the MOP; however, areas of emphasis and/or 
additional monitoring may vary according to the circumstances of a specific site and site 
visit.  Site visits may be conducted to evaluate performance deficits in one or more 
critical areas, such as consistent departures from the protocol or MOP.  Site visits are 
also an opportunity for refresher training and/or training of new staff, as needed.  Site 
visit frequency and visit procedures can be found in more detail within the appropriate 
section of the MOP. 
 
Site visitors will include CCN hub and site staff and investigators as deemed appropriate. 
As needed, representatives from the coordinating center, project office, other CCNs, and 
study committees may attend these visits. 
 
A summary of the site visit will be presented to the clinical site investigator and staff at 
the conclusion of the site visit.  The CCN staff will prepare a written site visit report within 
a reasonable time-frame post visit.  Copies of the site visit report will be sent to the 
clinical site investigator, the coordinating center, the project office, and the CCN.  
Additional copies of the site visit report may be requested by other SPRINT Study 
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A sample of site visit reports may be reviewed by the Measurement Procedures and 
Quality Control Committee or other study committees with recommendations for follow-
up actions and/or reporting changes as needed. 
 
12.8.2  Coordinating Center to CCN hubs 
 
The SPRINT Coordinating Center will periodically site visit each CCN hub in order to 
monitor and ensure high performance throughout the trial.  Representatives from the 
NIH SPRINT project office (including NHLBI, NIA, NIDDK, and NINDS) and study 
leadership may also attend. 
 
12.8.3  Project Office to Coordinating Center 
 
Representatives from the NIH SPRINT project office and study leadership will visit the 
coordinating center in order to monitor and ensure high performance throughout the trial. 
 
12.9 
Laboratory and ECG Center Quality Control  
 
The SPRINT Measurement Procedures and Quality Control Subcommittee will work with 
the Coordinating Center, the Central Laboratory and the ECG Reading Center to 
develop quality control procedures to ensure high quality data, including monitoring 
clinical site performance as well as performance of the Central Laboratory and ECG 
Reading Center.  The results of quality control procedures performed at the Central 
Laboratory and the ECG Reading Center will be reported on a regular basis to the 
Measurement Procedures and Quality Control Subcommittee and by them to the 
Steering Committee.  
 
Core Laboratory for Blood and Urine Assays 
Clinical site performance in acquisition, handling, storage and shipping of specimens will 
be tracked by the Central Laboratory and the Measurement Procedures and Quality 
Control Subcommittee.  The first step in quality assurance at the site level consists of the 
training and certification process for staff within the clinical sites.  Other steps include 
maintaining logs of equipment checks at each clinical site according to the Manual of 
Operations; observation of technicians performing all steps of sample collection and 
processing during site visits; reviewing study forms, documentation of staff certification/re-
certification, and other records to ensure only certified staff are obtaining and processing 
specimens; reviewing and tracking the condition of samples received at the Central 
Laboratory for problems in shipment; and periodic analysis of the study data for participant 
compliance with fasting, where required, and for signs of problems in drawing or 
processing, such as hemolysis.  Reports on clinical center performance will be submitted 
regularly by the Central Laboratory to the CCN hubs and the SPRINT Measurement 
Procedures and Quality Control Subcommittee. 
 
Performance of the Central Laboratory will be monitored regularly by the SPRINT 
Measurement Procedures and Quality Control Subcommittee.  Quality Control 
procedures in the laboratory for assays include the use of the internal Laboratory 
Manual, training and certification of Laboratory staff, Laboratory participation in external 
standardization and certification quality control programs, and implementation of the 
SPRINT internal quality control program.  Process measures, such as turn-around time 
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monitored. Particular attention will be paid to the feed-back of pre-specified laboratory 
alerts to the Clinical Sites by the Central Laboratories. 
 
As part of the internal quality control program specified in the manual of operations, the 
Central Laboratory will regularly provide summaries of the internal quality control results to 
the Coordinating Center, including the following information for each assay: (1) monthly 
summary statistics (n, mean, and standard deviation) on all quality control pools, including 
new pools being overlapped to replace established QC pools; (2) summaries of any 
unusual problems or conditions noted. The SPRINT Measurement Procedures and 
Quality Control Subcommittee will review these reports for evidence of trends with time 
in results on these pools. 
 
ECG 
Clinical site performance in acquisition and submission of ECG tracings will be tracked by 
the Reading Center and by the Measurement Procedures and Quality Control 
Subcommittee.   The first step in quality assurance at the site level consists of the training 
and certification process.  All SPRINT staff acquiring ECGs must be certified, consisting 
of the successful recording and transmission to EPICARE of three successive, adequate 
quality ECGs.  The ECG Reading Center will continuously monitor ECG quality and will 
identify errors in acquisition.   Each tracing submitted will be graded for quality and used 
to compile continuous quality trend analysis data for each clinical site.  Quality control 
grade reports will be regularly submitted to the CCN hubs and to the SPRINT 
Measurement Procedures and Quality Control Subcommittee. 
 
The ECG Reading Center has an internal quality control protocol that monitors 
performance of ECG coding and measurement.  This includes regular monitoring of the 
repeatability and accuracy of editing ECG waveforms of the digital (electronic) ECGs, 
and procedures to safeguard against change in trends due to change in ECG reading 
software.  The SPRINT Measurement Procedures and Quality Control Subcommittee will 
monitor performance of ECG coding and measurement within the ECG Reading Center 
by regularly reviewing the results of the center’s quality control reports.  
 
 
 

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Chapter 13 – Study Organization 
 
13.1 
Overview 
 
The SPRINT organizational structures and responsibilities are similar to those of other 
large multicenter clinical trials sponsored by government or industry.  The National 
Heart, Lung, and Blood Institute (NHLBI) initiated this study, and the National Institute of 
Diabetes and Digestive and Kidney Diseases (NIDDK) is a co-sponsor of the main 
SPRINT trial.  The National Institute of Neurological Disorders and Stroke (NINDS) and 
the National Institute on Aging (NIA) are jointly sponsoring the SPRINT MIND study.  
Five Clinical Center Networks and a Coordinating Center work together through the 
Steering Committee to successfully design and conduct the trial (see Figure 13.1).  In 
addition, there is a Central Laboratory, an ECG Reading Center, an MRI Reading Center 
and a Drug Distribution Center. Scientific leadership is provided by the Steering 
Committee.  External oversight is provided by Institutional Review Boards and a Data 
and Safety Monitoring Board. 
 
13.2 
Clinical Center Networks and Clinical Sites 
 
SPRINT participants will be recruited, randomized, treated, and followed through a 
system of five CCNs.  Each CCN consists of collaborating clinical sites, which are 
medical facilities and/or individual practices involved in the initial evaluation, enrollment, 
treatment and follow-up of participants in the trial.  Each CCN and clinical site will be 
responsible for timely recruitment and protocol adherence in accordance with the 
SPRINT protocol and MOP.  In addition, the CCNs will contribute to the study’s scientific 
leadership and operational management, and each CCN Principal Investigator (PI) will 
participate in Steering Committee and other investigator meetings.  The clinical sites will 
collect data at the local level in accordance with the study protocol and the manual of 
operations, and will manage each participant’s hypertension treatment.  For all 
participants recruited, the CCNs and clinical sites will be responsible for achieving the 
goals specified in the protocol for adherence to study treatment and retention of study 
participants.  The CCN will have the primary responsibility for overseeing their clinical 
sites and timely evaluation and correction of recruitment, adherence, and retention 
problems, including development and implementation of alternative strategies to achieve 
the stipulated goals, and funding the related activities.  It is anticipated that each CCN 
will conduct periodic site visits within its network of clinical sites to supervise recruitment, 
adherence, and retention activities and to ensure high quality performance.  The CCN 
activities will be coordinated with the CC, and may include site visits conducted by the 
CC, along with other organizational components of the study. The CCNs will collaborate 
closely with and assist the CC in implementation and standardization of the protocol 
within its network.   
 
13.3 
The Coordinating Center  
 
The CC, with input from the SPRINT Steering Committee, will be responsible for 
coordinating protocol writing activities, including protocol drafting and finalization; 
developing and distributing forms and the MOP; training trial personnel in standardized 
protocol implementation and data collection; generating and distributing numerous 
reports (including specific recruitment goals and projections); providing rapid feedback to 
the CCN and Central Units on the quality of data submitted and proposed corrections; 

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developing and maintaining trial databases and related internal and public websites; 
collecting, managing, and analyzing all trial data; developing and overseeing the web-
based adjudication of clinical events and endpoints; preparing reports for the DSMB; 
ensuring that the provisions of the manual of operations are carried out by all 
investigating groups; and providing timely and high quality statistical analysis expertise 
as required to prepare presentations and manuscripts.  The CC will conduct periodic 
visits to each CCN in order to monitor and ensure high performance throughout the trial.   
 
The CC will oversee 4 Central Units: the Drug Distribution Center, the Central 
Laboratory, the ECG Reading Center, and the MRI Reading Center.  
 
The Central Laboratory will serve as a repository for immediate and future analyses of 
urine and blood specimens.  The Central Laboratory will be responsible for the 
development and distribution of specific measurement procedures, and laboratory 
analyses, and for participating in quality assurance activities related to laboratory 
measures.  Periodic reports will be generated to address sample acquisition quality for 
each clinical site and assay performance, and these will be provided to the CCNs and 
the Measurements, Procedures and Quality Control (MPQC) Subcommittee for review. 
 
The ECG Reading Center will provide central interpretation of ECGs.  The ECG Reading 
Center will develop procedures for obtaining and transmitting ECG data from the clinical 
sites to ensure the highest quality data collection. Periodic reports will be generated to 
address ECG quality for each clinical site, and these will be provided to the CCNs and 
the MPQC for review.  
 
In collaboration with each CCN participating in the MRI study, the MRI Reading Center 
will identify an MRI site which is located in geographic proximity to the CCN’s clinical 
sites.  The MRI Reading Center will develop a detailed protocol and manual of 
procedures to ensure that the MRIs taken over time are of the highest quality with the 
smallest variation due to changes in technique and to allow the most precise estimate of 
change over time. The MRI Reading Center will provide training and certification for MRI 
site staff in order to ensure uniformity of methods, and will monitor carefully the quality of 
their work. Working with the CC, the MRI Reading Center will develop an analytical plan 
to estimate as precisely as possible the change in brain MRI over time for each SPRINT-
MIND-MRI participant. Periodic reports will be generated to address MRI quality for each 
scanning site, and these will be provided to the CCNs and the MPQC for review. 
 
The Drug Distribution Center will be responsible for developing and implementing plans 
for cost-effective drug acquisition; packaging, labeling, and dispensing drugs according 
to the study protocol; and providing data to the CC for further analyses.  The DDC will 
design the technical aspects of drug packaging and labeling to facilitate participants’ 
ability to understand and adhere to the drug regimen.  The DDC will work with the 
clinical sites and CCNs to develop cost-effective inventory management procedures. 
 
13.4 
NHLBI Project Office and Other Government Representatives 
 
The NHLBI Project Office will be responsible for the scientific conduct and administration 
of SPRINT.  Representatives from the Project Office participate in the scientific, general 
organizational and fiscal management of the trial.  NHLBI staff includes scientific 
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and the Office of Biostatistics Research.  In addition, the NIH SPRINT team includes 
scientific staff from the NIDDK, the NINDS and the NIA.  
 
13.5 
The SPRINT Steering Committee, Executive Committee, Conflict of Interest 
Committee and the Subcommittees of the Steering Committee 
 
The SPRINT Steering Committee provides the overall leadership for the study and 
establishes scientific and administrative policy.  It is composed of the Principal 
Investigators from the five Clinical Center Networks, the Principal Investigator from the 
Coordinating Center, the NHLBI Project Officer, representatives from NIDDK, NINDS, 
NIA, the Steering Committee Chair, and the Steering Committee Vice-Chair.  This 
committee oversees the overall conduct of the trial throughout all phases, develops the 
trial design, prepares the final protocol, and approves the study forms and manual of 
operations.  During the data collection phases of the trial, this committee oversees data 
collection practices and procedures to identify and correct deficiencies.  The Steering 
Committee also will consider and adopt changes in the study protocol or procedures as 
necessary during the course of the trial. 
 
The SPRINT Steering Committee is chaired by the Steering Committee Chair, who 
serves as the senior executive officer of the investigative group.  A Vice-Chair assists 
the Chair with Steering Committee responsibilities. Voting Steering Committee members 
are the Principal Investigators from the five CCNs, the Principal Investigator from the 
Coordinating Center, and the NHLBI Project Officer.  If a CCN PI or the CC PI cannot 
make a meeting at which a vote is taken, then the Co-Principal Investigator may vote 
(with the understanding that the Co-PI is fully informed about the issue). The Steering 
Committee Chair, or Vice-Chair in his/her absence, votes only to break a tie.  CCN and 
Site Co-investigators and Coordinators, CC staff, NIH staff, consultants, and opinion 
leaders may also be invited to attend meetings. 
 
The SPRINT Executive Committee will oversee the day-to-day operations of the trial as 
an extension of the Steering Committee to ensure efficient and quality performance. The 
members include the Steering Committee Chair, Steering Committee Vice-Chair, 
Coordinating Center personnel, Project Office personnel, and one CCN PI (rotated 
annually so that each PI has the opportunity to serve).  Other key study personnel (e.g., 
Chair of the Operations/Project Coordinators Subcommittee, Director of the DDC) may 
be asked to participate as either ad hoc or regular members.  
 
The SPRINT Conflict of Interest Committee reviews potential conflict of interest issues.  
The NIH Project Office, Steering Committee Chair, and CC PI comprise this committee, 
which has the overall responsibility for the trial’s ethical oversight policy and procedures. 
 
There are a number of standing subcommittees and working groups which report to the 
Steering Committee.  These subcommittees and groups and their charges are detailed 
in Appendix 5.   
 
13.6 
The Data and Safety Monitoring Board  
 
An independent Data and Safety Monitoring Board will be established to monitor data 
and oversee participant safety.  Members will be appointed by the NHLBI to provide 
oversight of the trial and its ancillary studies. The SPRINT DSMB may include experts in 
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geriatrics, biostatistics, bioethics, quality of life, cost effectiveness, cognitive function and 
other areas as needed.  DSMB participants include the Steering Committee Chair (who 
is unblinded) and Vice-Chair (who is blinded), CC PI and senior staff, and 
representatives from the NHLBI and other NIH sponsors. The DSMB normally meets 
twice a year to monitor safety, to advise the NHLBI about study progress, including 
contractor performance, and to make recommendations to the NHLBI regarding study 
continuation and protocol changes. In addition, the CC may provide data to the DSMB 
Chair to ensure early identification of any major adverse outcomes of therapy.  The 
DSMB has the responsibility to recommend to the NHLBI whether the trial should 
continue, whether the protocol should be modified, or whether there should be early 
termination.  The DSMB will provide reports to the NHLBI through the Executive 
Secretary, who will be appointed by the NHLBI.  Recommendations by the DSMB must 
be approved by the NHLBI prior to implementation. 
 
13.7 
Role of Industry 
 
Industry may contribute resources to the study and will be acknowledged appropriately.  
However, the scientific decisions and governance of the trial will be determined by the 
Steering Committee, as per NHLBI Policy. 
 
13.8 
Conflict of Interest Policy 
 
The SPRINT investigators have established a policy regarding Conflict of Interest, which 
is presented in the MOP.  This policy was developed to meet two goals.  First, the 
investigators wished to maintain the confidence that advice was being given, and 
decisions made, in as unbiased and fully informed manner as possible.  Second, the 
investigators wished that the processes and results of the trial would meet public 
standards of conduct.  
 
13.9 
Timeline 
 
SPRINT will begin recruiting and randomizing during the fall of 2010.  Recruitment will 
continue for approximately two years.  The minimum length of participant planned follow-
up will be four years, and maximum length of follow-up will be approximately six years, 
so the final study visits will occur in late 2016 or early 2017.  If the event rate in the 
standard therapy arm is substantially less than 2.2%, we may ask that the DSMB 
consider recommending a two year extension of the trial.   
 
13.10 Ancillary Studies 
 
13.10.1 Introduction 
 
In addition to the main SPRINT protocol, investigators may wish to perform Ancillary 
Studies using the SPRINT population, blood or urine samples, or other collected data. 
An ancillary study is an investigation not initiated by the SPRINT Steering Committee, 
with objectives that are not within the main SPRINT specific objectives and not part of 
the SPRINT protocol but uses SPRINT participants, samples, and/or data collected by 
SPRINT. In most cases, an ancillary study will involve acquisition of additional data that 
are not compiled as part of the SPRINT data set. An ancillary study may or may not use 
all randomized participants. Investigators are encouraged to propose and conduct 
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ensure the continued interest of the diverse group of investigators who are critical to the 
success of the trial as a whole. These studies provide an exceptional opportunity for 
investigators, either within or outside of SPRINT, to conduct additional projects at 
relatively low cost. In general, ancillary studies will require additional funding from the 
NIH or other sources. 
 
13.10.2 Application Review Process 
 
To protect the integrity of SPRINT, all ancillary studies must be reviewed and approved 
by the SPRINT Steering Committee before access to SPRINT data, samples, or 
participants is permitted. Investigators will not be allowed access to the SPRINT 
participants, samples, or database without approval. New ancillary study proposals will 
be submitted to the SPRINT Ancillary Science (AS) Subcommittee, which will review all 
ancillary study proposals and make a recommendation to the Steering Committee.  In 
the event that investigators wish to modify an ancillary science protocol that have 
already been approved by the SPRINT SC, they will need to first obtain AS 
Subcommittee and SC approval.  Ancillary study forms can be obtained by contacting 
the Coordinating Center or accessing the SPRINT website. 
 
Studies submitted for approval less than four months prior to a funding application 
deadline may not receive timely approval.  When the application is complete, the study 
proposal will be sent to the AS Subcommittee for review. The AS Subcommittee will 
have monthly calls to discuss proposals, which will be circulated at least one week prior 
to the calls.  After review and approval by the AS Subcommittee, preliminary 
approval/disapproval will be made by the Steering Committee, with a final 
recommendation for approval/disapproval made by the Data and Safety Monitoring 
Board to the NHLBI Director. Ancillary Science investigators must include one or more 
SPRINT investigators in their ancillary study proposals.  
 
The Coordinating Center will usually be responsible for all data management and 
analysis for all ancillary studies.  Specialized expertise external to the coordinating 
center (e.g., processing of images) may be needed at the coordinating center’s 
discretion.  Costs associated with ancillary study data management and analysis must 
be budgeted into each ancillary study, even if the applicants have the necessary 
expertise in data management and analysis. 
 
Prior to grant submission (or study initiation if no external funding is required), the CCN 
PI must approve participation of sites in her/his network.  This is required as the CCN PI 
is responsible for the conduct of all aspects of SPRINT within her/his network.  Part of 
this is management and oversight of clinic and participant burden.  As needed, the CCN 
will include funding for oversight (e.g., investigator, coordinator, and fiscal personnel 
time, travel).  The SPRINT Steering Committee also reserves the right to review the 
burden of ancillary studies on an on-going basis and take appropriate actions as 
necessary.  Investigators with approved ancillary studies will report the status of the 
studies annually to the Chair of the AS Subcommittee.   
 
Additional detail on the review process and criteria for judging proposals can be found in 
the MOP. 
 

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13.10.3 Additional Requirements of Ancillary Science Investigators 
 
All ancillary study investigators will be required to budget adequately for all necessary 
resources for their studies.  This includes, but may not be limited to, costs for data 
collection, sample collection, sample shipping, sample extraction, sample analysis, data 
entry, website development, data analysis, dataset preparation, data storage and 
publication of results.  The final budget may be determined after AS and SC approval. 
 
Each ancillary study will cause an increase in utilization of main SPRINT study 
resources, particularly by the SPRINT Presentations and Publications 
(P&P)Subcommittee.  To help with study operations, each ancillary science proposal 
team should budget for and may be asked to contribute efforts to the main SPRINT 
study by, for example, assigning a person to serve as a reviewer for the P&P 
Subcommittee.   
 
Investigators proposing the use of laboratory measurements are encouraged to use the 
SPRINT Central Laboratory if at all possible.  This will facilitate sample processing and 
shipping and may reduce the amount of sample required. 
 
All images (e.g., MRI) or tracings (e.g., ECG) must be available for other investigators to 
use in the spirit of the NIH policy available at http://grants.nih.gov/grants/sharing.htm.  
To achieve this goal, ancillary studies must budget for the costs associated with 
archiving these images and making them available to others.  If there are legitimate 
reasons why this cannot be accomplished, this can be discussed on a case-by-case 
basis by the investigators, the funding agency, and the SPRINT SC. 
 
13.11  Publication Policy 
 
The purpose of the policy is to encourage and facilitate the presentation and publication 
of SPRINT Study background, rationale, design, and analyses; ensure appropriate use 
of the SPRINT data, timely completion of manuscripts and presentations, equitable 
access to authorship, and adherence to established principles of authorship; and 
coordinate the reporting of trial results.  The policy applies to all investigators analyzing, 
presenting, and publishing data from main SPRINT, SPRINT-MIND, SPRINT-Senior 
(hereafter collectively called “SPRINT”)and ancillary studies, except for those using the 
NHLBI Data Repository data (see https://biolincc.nhlbi.nih.gov/home/).  
 
There are several principles underlying this policy: 
 
1. Research questions and hypotheses to be addressed using SPRINT Study data 
should be formulated a priori and clearly stated in a manuscript proposal to reduce 
the likelihood that study results are attributable to type I error. 
 
2. Publication of scientific findings from the SPRINT Study should proceed in a timely 
fashion once relevant analyses are complete. 
 
3. The publications arising from the SPRINT Study should avoid overlap and conflicting 
representation of SPRINT Study findings.  Overlaps are, however, acceptable for 
review articles. 
 

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4. Recognition through authorship will be distributed among the SPRINT investigators 
so that: 
i) all SPRINT investigators and team members have equitable opportunity to 
lead and co-author SPRINT publications and, if appropriate, publications from 
ancillary studies; 
ii) all Ancillary Study investigators have the opportunity to lead and be co-
authors on publications resulting from their ancillary studies. 
 
5. The SPRINT Study should promote the career development of trainees and junior 
faculty by providing them the opportunity to lead and be recognized as co-authors of 
SPRINT publications, as appropriate. 
 
6. Standards for authorship on SPRINT publications will adhere to the Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals of the International 
Committee of Medical Journal Editors (NEJM 1997;336:309-315) and those 
established by the destination journals. 
 
7. The concept, in the form of a proposal, for all manuscripts must be approved by the 
P&P Subcommittee prior to preparation. 
 
 
There are three categories of manuscripts and anticipated authorship: 
 
i) Main results developed based on core SPRINT data and study 
aims/hypotheses (which will bear the corporate authorship, “The SPRINT 
Research Group”).  The design and main baseline papers will also be 
corporate authored. 
 
ii) Manuscripts developed and authored by investigators using data that are not 
considered to be main SPRINT results. 
 
iii) Ancillary study results led by investigators bringing external funding or 
resources into SPRINT for a specific project. 
 
(1) Unless specific justifications and alternative arrangements are made, all 
SPRINT analyses will be performed by the Coordinating Center (CC), with 
specialized expertise external to the Coordinating Center as needed at 
the Coordinating Center’s discretion.  Ancillary study budgets should 
include funds allocated to the CC for that purpose. 
 
(2) Ancillary study manuscripts are subject to similar review and tracking 
procedures as other SPRINT manuscripts.  
 
During the operational phase of the trial, manuscripts proposing to use data other than 
baseline data will be reviewed closely to ensure that the SPRINT study objectives are 
not compromised.  In general, the following will not be allowed: 
 
(1) Publication of follow-up data according to randomized group 

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(2) Longitudinal analyses of outcomes pre-specified in the main protocol 
 
All such proposals will be considered on a case-by-case basis, with input from the Data 
and Safety Monitoring Board. 
 
The final responsibility for review and approval of manuscript proposals, including 
composition of writing committees, readiness for submission, and abstracts and material 
for presentations at meetings and conferences, rests with the Steering Committee.  The 
P&P Subcommittee will oversee and facilitate these processes, assisted by a 
Publications Coordinator based at the Coordinating Center. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Clinical
Sites
UAB
VA
Southeast
Ohio-CWR 
Clinical Center Networks
Data and Safety
Monitoring Board
Clinical
Sites 
Clinical
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Protocol Review 
Committee 
NHLBI/NIH
Clinical
Sites
Coordinating 
Center 
Utah 
Clinical
Sites
Central 
ECG 
Lab 
Drug 
Distribution 
Center 
MRI 
Reading 
Center 
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Lab 
 
Steering 
Committee 
Figure 13.1:  SPRINT Organizational Chart

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Engl J Med 2000 Mar 9;342(10):748 and 2000 May 4;342(18):1376]: N Engl J 
Med, v. 342, p. 145-153. 
 
 

 
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APPENDIX 1:  Abbreviations Used 
 
AAA: 
Abdominal Aortic Aneurysm 
AASK: 
African American Study of 
Kidney Disease and 
Hypertension 
ABI: 
Ankle Brachial Index 
ACC: 
American College of 
Cardiology 
ACCORD: 
Action to Control 
Cardiovascular Risk in 
Diabetes 
ACE: 
Angiotensin Converting 
Enzyme 
ACR: 
Albumin to Creatinine Ratio 
ACS: 
Acute Coronary Syndrome 
AD: 
Alzheimer’s Disease 
AE: 
Adverse Event 
AHA: 
American Heart Association 
ALLHAT:  
Antihypertensive and Lipid-
Lowering Treatment to Prevent 
Heart Attack Trial 
ARB: 
Angiotensis Receptor Blocker 
ARIC: 
Atherosclerosis Risk in 
Communities 
AS: 
Ancillary Science 
ASCOT: 
Anglo-Scandinavian Cardiac 
Outcomes Trial 
BID: 
Twice Daily 
BNT: 
Boston Naming Test  
BP: 
Blood Pressure 
BPH: 
Benign Prostatic Hyperplasia 
CABG: 
Coronary Artery Bypass 
Grafting 
CAD: 
Coronary Artery Disease  
CAMELOT: 
Comparision of Amlodipine vs 
Enalapril to Limit Occurrences 
of Thrombosis Trial 
CC: 
Coordinating Center  
CCB: 
Calcium Channel Blockers 
CCN: 
Clinical Center Network 
CE: 
Carotid Endarterectomy 
CEA: 
Cost-Effectiveness Analysis 
CHD: 
Coronary Heart Disease 
CHF: 
Chronic Heart Failure 
CHS: 
Cardiovascular Health Study 
CKD: 
Chronic Kidney Disease 
Co-PI: 
Co-Principal Investigator 
CPT: 
Current Procedural 
Terminology 
CUA: 
Cost-Utility Analysis 
CV: 
Cardiovascular 
CVD: 
Cardiovascular Disease 
 
 
 
DASH: 
Dietary Approaches to Stop 
Hypertension 
DBP: 
Diastolic Blood Pressure 
DDC: 
Drug Distribution Center 
DHP: 
Dihydropyridine 
DQ: 
Dementia Questionnaire 
DSC: 
Digit Symbol Coding test 
DSMB: 
Data Safety Monitoring 
Board 
DSM-IV: 
Diagnostic and Statistical 
Manual of Mental Disorders -
Fourth Edition 
DSST: 
Digit Symbol Substitution 
Test 
DST: 
Digit Span Test 
ECG: 
Electrocardiogram 
ED: 
Erectile Dysfunction  
eGFR: 
Estimated Glomerular 
Filtration Rate 
EnaC Inhibitor: 
Epithelial Sodium Channel 
Inhibitor 
EPICARE: 
Epidemiological Cardiology 
Research Center 
EQ-5D: 
EuroQol 5 Dimensional 
Descriptive System 
ESRD: 
End Stage Renal Disease 
EUROPA: 
European Trial on Reduction 
of Cardiac Events with 
Perindopril in Stable 
Coronary Artery Disease 
FAQ: 
Functional Activities 
Questionnaire  
FDA: 
Food and Drug 
Administration 
FES-I: 
Falls Self-Efficacy Scale 
International 
FRS: 
Framingham Risk Score 
FSFI: 
Female Sexual Function 
Assessment 
GCP: 
Good Clinical Practice 
GEMS: 
Gingko Evaluation of 
Memory Study 
GFR: 
Glomerular Filtration Rate 
GXT: 
Graded Exercise Test 
HDFP: 
Hypertension Detection and 
Follow-up Program 
HF: 
Heart Failure 
 
HIPAA: 
Health Information Portability 
and Accountability Act 
HOPE: 
Hospital Outcomes Project 
for the Elderly  

 
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HOT: 
Hypertension Optimal 
Treatment trial 
HRQL: 
Health Related Quality of Life 
HTN: 
Hypertension 
HVLT: 
Hopkins Verbal Learning Test 
HYVET: 
Hypertension in the Very 
Elderly Trial 
HYVET COG: 
Hypertension in the Very 
Elderly Trial – cognitive 
function assessment 
ICER: 
Incremental Cost-Effectiveness 
Ratio 
ID: 
Identification 
IIEF: 
International Index of Erectile 
Function 
IRB: 
Institutional Review Board 
ISH: 
Isolated Systolic Hypertension 
JNC: 
Joint National Committee 
JNC-7: 
The Seventh Report of the 
Joint National Committee on 
Prevention, Detection, 
Evaluation, and Treatment of 
High Blood Pressure 
LMT: 
Logical Memory Test 
LVH: 
Left Ventricular Hypertrophy 
MAP: 
Mean Arterial Pressure 
MAR: 
Missing-at-Random Analyses 
MCI: 
Mild Cognitive Impairment 
MDRD: 
Modification of Diet in Renal 
Disease Study 
MI: 
Myocardial Infarction 
MIND: 
Memory and Cognition In 
Decreased Hypertension 
MoCA: 
Montreal Cognitive 
Assessment 
MOP: 
Manual of Procedures 
MPQC: 
Measurement Procedures and 
Quality Control 
mRey-O: 
Modified Rey-Osterrieth 
Complex Figure 
MRI: 
Magnetic Resonance Imaging 
NEJM: 
New England Journal of 
Medicine 
NKF: 
National Kidney Foundation 
NHANES: 
National Health and Nutrition 
Examination Survey 
NHLBI: 
National Heart, Lung, and 
Blood Institute 
NIA: 
National Institute on Aging 
NIDDK: 
National Institute of Diabetes 
and Digestive and Kidney 
Diseases 
NIH: 
National Institutes of Health 
NINDS: 
National Institute of 
Neurological Disorders and 
Stroke 
OH: 
Orthostatic Hypotension 
P&P: 
Publications and 
Presentations 
PAD: 
Peripheral Artery Disease  
PCI: 
Percutaneous Coronary 
Intervention 
PEACE: 
Prevention of Events with 
Angiotensin Coverting 
Enzyme 
PHI: 
Private Health Information 
PHQ: 
Patient Health Questionnaire 
PI: 
Principal Investigator  
PKD: 
Polycystic Kidney Disease 
PROGRESS: 
Perindopril Protection 
Against Recurrent Stroke 
Study 
PTS: 
Participant Tracking System 
QALY: 
Quality Adjusted Life Years 
QC: 
Quality Control 
RAAS: 
Renin-angiotensin-
aldosteribe system 
RAS: 
Renin Angiotensin System 
SAE: 
Serious Adverse Event 
SBP: 
Systolic Blood Pressure 
SCOPE: 
Study on Cognition and 
Prognosis in the Elderly 
SHEP: 
Systolic Hypertension in the 
Elderly Program 
SPRINT: 
Systolic Blood Pressure 
Intervention Trial 
SPRINT MIND: 
SPRINT Memory and 
Cognition In Decreased 
Hypertension  
SSL: 
Secure Socket Layer 
SVID: 
Small Vessel Ischemic 
Disease 
Syst-Eur: 
Systolic Hypertension in 
Europe Trial 
TICS-M: 
Modified Telephone Interview 
for Cognitive Status 
TMT: 
Trail Making Test 
UKPDS: 
United Kingdom Prospective 
Diabetes Study 
WHI: 
Women’s Health Initiative 
WHIMS: 
Women’s Health Initiative 
Memory Study 
WWW: 
World Wide Web 
 

 
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APPENDIX 2:  Computational Details and Sensitivity Analyses for the CVD 
outcome 
 
Power computations were developed using event rates observed in ALLHAT.  The ALLHAT 
Coordinating Center provided us with summary data across all three arms allowing us to 
calculate event rates using different combinations of baseline characteristics.  Event rates were 
calculated using a composite outcome including fatal CVD, non-MI acute coronary syndrome, 
and nonfatal MI, stroke, and heart failure.  For ALLHAT participants without diabetes, the annual 
event rate was 4.39 %/yr.  (Note:  ALLHAT used hospitalized angina rather than non-MI acute 
coronary syndrome.) 
 
This rate of 4.39 %/yr provides a starting point for the estimation of event rates we will expect in 
SPRINT.  Several factors can be considered which suggest that these rates should be either 
increased or decreased.  Factors arguing for an increased event rate include (1) SPRINT will 
have an older cohort of participants than did ALLHAT, (2) SPRINT will use the Framingham risk 
score of ≥15% 10-year CVD risk as an inclusion criterion, and (3) inclusion of a substantial 
group of participants with Stage 3 or Stage 4 CKD.  Factors that are expected to reduce the 
event rate include (1) the temporal trend towards a reduction in CVD event rates in the U.S. and 
(2) a more rigorous definition of non-MI acute coronary syndrome that will be used in SPRINT.  
It is difficult to precisely estimate the impact that these five factors will have on the SPRINT 
event rate. 
 
In ALLHAT, event rates increased substantially with age.  The event rate for participants 70 to 
<75 years old was 5.19 %/yr; for participants ≥75 years old, the event rate was 6.99 %/yr.  In 
ALLHAT 17.7% of the participants were 70 to <75 years old, while 18.5% were ≥75 years old.  
We expect that participants in these age categories will represent a greater fraction of the 
SPRINT cohort.  Approximately 50% (4625 participants) are expected to be at least 70 years 
old, while 35.1% (3250 participants) are expected to be ≥75 years old.  This will likely yield a 
higher event rate in SPRINT, compared to ALLHAT. 
 
The event rate in ALLHAT among participants with 10-year Framingham risk ≥15% at baseline 
was 4.67 %/yr.  Our including people with ≥15% 10-year risk will help to ensure a higher event 
rate. 
 
We expect that 4300 SPRINT participants will have eGFR 20 to <60 mL/min/1.73m2 with equal 
numbers above and below 45 mL/min/1.73m2.  In ALLHAT, the event rate was 5.89 %/yr for 
those with eGFR 45 to <60 mL/min/1.73m2.  Among those <45, the event rate was 8.24 %/yr.  In 
ALLHAT, 18.6% had eGFR <60 mL/min/1.73m2 as compared with the expected 46.7% in 
SPRINT.  Increasing the numbers of participants with CKD in SPRINT will help increase the 
event rates. 
 
We compared ALLHAT participants with diabetes to participants in the ACCORD BP trial (all of 
whom have diabetes) using outcome variables that are as similar as possible.  In ALLHAT the 
event rate was 5.90 %/yr.  The corresponding event rate in ACCORD was 3.43 %/yr.  The 
reduction in event rates between ALLHAT and ACCORD could be due to a temporal trend 
(ALLHAT was 1994—1999, ACCORD was 2001—2009), because ALLHAT participants were 
older (mean 67 years) than ACCORD (mean 62.2 years), or for other reasons.   

 
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Exactly how we should use the ALLHAT data to estimate the event rates for SPRINT is unclear.  
Since the rates in ACCORD were approximately half of those in ALLHAT, for the purposes of 
power we will assume that the SPRINT rates will also be half of the ALLHAT rates.  This 
assumption balances the possibility of a further temporal trend in event rate reduction with the 
fact that participants recruited for SPRINT will be older, have lower kidney function, and have 
greater Framingham CVD risk scores than those recruited in either ALLHAT or ACCORD.  We 
expect that this may be slightly conservative.  Thus, we assume that the event rate in SPRINT 
will be approximately 2.2 %/yr for the composite outcome including non-fatal MI, non-fatal 
stroke, cardiovascular death, hospitalized heart failure, and non-MI acute coronary syndrome. 
 
We have assumed a 2-year uniform accrual period, 3 years 10 months minimum follow-up 
(assumes that closeout visits occur uniformly over a 4-month period), and a 2 sided significance 
level of 0.05.  The effect size for the primary outcome is assumed to be 20% in the entire 
sample and the CKD subsample, and 25% in the Senior subsample.  Loss to follow-up and 
events are assumed to follow an exponential model. We expect that the annual rate of loss to 
follow-up will be approximately 2% but have included rates up to 3% to be conservative. 
Calculations made using two methods (Lachin and Foulkes, 1986;Lakatos, 1988) were similar.  
Power for the primary outcome for a range of event rates and annual loss rates is presented in 
Table 1 for the assumed effect size of 20%. 
 
Table 1. Power for the primary outcome in entire sample of  
9250 participants for a 20% effect (Hazard Ratio of 0.8). 
Annual  
Loss  
Rate (%/yr) 
Annual Standard Arm Event Rate (%/yr) 
1.8 
2.0 
2.2 
2.4 
2.6 
1 
82.9 
86.5 
89.4 
91.7 
93.5 
2 
82.0 
85.7 
88.7 
91.0 
93.0 
3 
81.1 
84.8 
87.9 
90.4 
92.4 
 
In ALLHAT the event rates were 5.89 %/yr and 8.24 %/yr for people whose eGFR was 45 to 
<60 or <45 mL/min/1.73m2.  We will assume that the event rate for the primary outcome in 
SPRINT will be 4 %/yr among participants with eGFR <60 mL/min/1.73m2.  Power for the 
primary outcome among SPRINT participants with CKD for a range of event rates and annual 
loss rates is presented in Table 2 for the assumed effect size of 20%.   
 
Table 2. Power for the primary outcome in CKD 
subsample (eGFR < 60 mL/min/1.73m2) of 4300 
participants for a 20% effect (Hazard Ratio of 0.8). 
Annual 
Loss 
Rate 
(%/yr) 
Annual Standard Arm Event Rate (%/yr) 
3.5 
3.75 
4.0 
4.25 
4.5 
1 
77.9 
80.5 
82.7 
84.8 
86.6 
2 
76.9 
79.5 
81.9 
83.9 
85.8 
3 
75.9 
78.6 
80.9 
83.1 
85.0 
 
 
In ALLHAT, the event rate was 6.99 %/yr among participants at least 75 years old.  Applying the 
same halving as was done above for the entire sample, we will assume that the event rate in 

 
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SPRINT will be 3.5 %/year among participants ≥75 years old.  Power for the primary outcome 
among SPRINT Senior for a range of event rates and annual loss rates is presented in Table 3 
for the assumed effect size of 25%. 
 
 
Table 3. Power for the primary outcome in Senior subsample (≥75 
years old) of 3250 participants for a 25% effect (Hazard Ratio of 
0.75). 
Annual 
Loss 
Rate 
(%/yr) 
Annual Standard Arm Event Rate (%/yr) 
3.0 
3.25 
3.5 
3.75 
4.0 
1 
79.9 
82.8 
85.3 
87.5 
89.4 
2 
79.0 
81.9 
84.5 
86.7 
88.6 
3 
78.0 
81.0 
83.6 
85.9 
87.9 
 

 
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APPENDIX 3:  Computational Details and Sensitivity Analyses for the MIND 
outcomes 
 
Dementia.  The primary outcome for SPRINT MIND is all-cause dementia.  Table 1 summarizes 
dementia rates from HYVET-COG (Peters, 2008), the Ginkgo Evaluation of Memory Study 
(GEMS) (DeKosky, 2008), the Cardiovascular Health Study (CHS) (Fitzpatrick, 2004) and the 
Women’s Health Initiative Memory Study (WHIMS) (Shumaker, 2004).  In HYVET-COG, there 
was a 14% non-significant decline in dementia.   Overall annual dementia rate varied from  
0.13% to 3.86%.  The Women’s Health Initiative Memory Study (WHIMS) (Shumaker, 2004) 
recruited women 65 and older with a mean age of 69 in two hormone replacement therapy 
interventions.  Both trials were stopped early because of unexpected increased health risks in 
women receiving the hormone therapy.  Of the studies reported here, WHIMS may be the least 
similar to SPRINT.  
 
 
Table 1. Annual rates of dementia from previous studies. 
Age 
eGFR 
HYVET-COG 
GEMS 
 
CHS 
WHIMS 
<75 
 
 
 
1.29 
0.08 
 
 
 
 
 
 
75+ 
 
 
3.09 (3.86)1 
4.55 
0.81 
 
<45 
 
4.87 (6.39) 
 
 
 
45-59.9 
 
3.02 (3.20) 
 
 
 
60-89.9 
 
2.87 (3.70) 
 
 
 
90+ 
 
3.86 (4.51) 
 
 
 
 
 
 
 
 
80+ 
 
3.50 
 
 
 
 
 
 
 
 
 
ALL 
 
3.50 
3.09 (3.86) 
2.62 
0.13 
1 With prior CVD 
 
Based on these data and the expected number of SPRINT participants 75 or older, and with 
CKD or MCI at baseline, we expect the annual event rate in SPRINT to be 3.1%-3.5%.  In meta-
analyses performed by the HYVET investigators, three of the four trials had hazard ratios 
ranging from 0.84 to 0.90.  A reasonable goal for SPRINT MIND is to detect a relative difference 
between arms expressed by a hazard ratio of 0.5 to 0.8 for dementia.  Using a 2-sided 
proportional hazards regression test of time until first incidence of dementia, we can expect at 
least 79% power for annual dementia rates of 3.1%-3.5% and an effect size of 0.15 and 96% 
power for annual dementia rates of 3.2%-3.5% and an effect size of 0.20. 
 
Cognitive Function.  SPRINT will include 2,800 participants receiving the extended cognitive 
battery at baseline, and years 2 and 4 post randomization.  We obtained the standard deviations 
for several of the tests included in the SPRINT battery to determine detectable differences.  The 
standard deviation for the Digit Symbol Substitution Test is from actual ACCORD MIND data 40 
months post randomization adjusted for baseline and stratifying factors.  Actual means were not 
available so we used the ACCORD MIND assumptions in their sample size calculations based 
on CHS data.   GEMS provided us with standard deviations and means for Trails A & B, Digit 

 
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Span and the Boston Naming Test.  Table 2 shows that we can detect mean differences for 
each test of 5.1% or less between the two SPRINT treatment groups at year 4, with 90% 
statistical power, assuming 3%/year loss to follow-up.  The statistical power will even be 
increased when combining the scores for these tests in each domain.   
 
Table 2.  Means, standard deviations and power for cognitive tests. 
Cognitive Test 
Mean (STD) 
Power 
 
 
80%  
90% 
Effect Size 
 
0.114 
0.132 
Digit Symbol Substitution 
Test 
39.51 (7.9)2 
0.90 (2.4%) 
1.05 (2.7%) 
Trails A3 
47.5 (18.1) 
2.07 (4.4%) 
2.40 (5.1%) 
Trails B3 
124.4 (40.6) 
4.65 (3.7%) 
5.38 (4.3%) 
Digit Span3 
13.9 (2.6) 
0.30 (2.2%) 
0.34 (2.4%) 
Boston Naming Test3 
26.2 (2.6) 
0.30 (1.1%) 
0.34 (1.3%) 
1 From ACCORD MIND assumptions in sample size calculations based on CHS data 
2 From actual ACCORD MIND data at 40 months post randomization 
3 From GEMS at 48 months post randomization 
 
MRI.  We will perform MRI in 640 of SPRINT MIND participants.  The standard deviations for 
total abnormal tissue volume and total brain volume from the ACCORDMIND study 40 months 
post randomization adjusted for baseline and cranial size are 2.77 cm3 and 16.45 cm3.  The final 
analysis of the MRI data collected in SPRINT MIND will compare the mean total abnormal 
tissue and mean total brain volumes between the groups, controlling for the baseline MRI value 
and cranial side.  With 640 participants (320 participants in each treatment group), after 
accounting for a 3%/yr loss to-follow-up, and assuming a 0.05 two-sided significance level, we 
will be able to detect group differences in total abnormal vascular lesion volumes of 0.65 cm3 
and 0.76 cm3, and in total brain volumes of 3.9 cm3 and 4.5 cm3 over 4 years, with 80% and 
90% power, respectively.

 
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APPENDIX 4:   SPRINT Organizational Chart 
Committees and Subcommittees 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Steering 
Committee 
Executive 
Committee 
CKD 
Working 
Group 
Geriatrics 
Working 
Group 
Genetics 
Working 
Group 
Design & 
Analysis 
Subcommittee 
Health-Related 
Quality of Life/ 
Economic 
Evaluation 
Subcommittee 
Operations/ 
Project 
Coordinators 
Subcommittee 
Intervention 
Subcommittee 
Ancillary 
Science 
Subcommittee 
Morbidity & 
Mortality 
Subcommittee 
MIND 
Subcommittee 
Recruitment, 
Retention & 
Adherence 
Subcommittee 
Measurement, 
Procedures & 
Quality Control 
Subcommittee 
Publications & 
Presentations 
Subcommittee 
Lifestyle/ 
Background 
Working 
Group 
Blood 
Pressure 
Working 
Group 
Safety 
Subcommittee 

 
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APPENDIX 5 
SPRINT Charges & Membership of Committees & Subcommittees 
 
Below are the charges of the committees and subcommittees to the Steering Committee.  Each 
subcommittee will assume additional responsibilities as deemed necessary by the SPRINT 
Steering or Executive Committee.   
 
SPRINT Steering Committee (SC) provides the overall leadership for the trial and establishes 
the scientific and administrative policies.  It will be led by the independent Study Chair, who is 
also the Chair of the Steering Committee.  The Vice Chair of the Steering Committee, who may 
be a CCN or a clinical site PI, will be a permanent SC member and also will be the Vice Chair of 
the Executive Committee.  Other members of the Steering Committee include the Principal 
Investigators (PIs) from the Clinical Center Networks (CCNs), NIH representatives (from the 
NHLBI, NIDDK, NIA and NINDS), Coordinating Center (CC) staff, and other subcommittee 
chairs as needed.  This committee oversees the overall conduct of the trial throughout all 
phases.  The SC provides the leadership for the trial design, the protocol, Manual of Procedures 
(MOP), and study forms, all of which require final SC approval.  This committee oversees 
recruitment, intervention, follow-up, and data collection practices and procedures to identify and 
correct deficiencies.  They will consider adopting changes in the study protocol or procedures as 
necessary during the course of the SPRINT trial.  Voting members will include the CCN PIs, the 
CC PI, and the NIH Project Office (which includes the joint interests of the four NIH funding 
institutions – NHLBI, NIDDK, NIA, and NINDS).  The Steering Committee Chair will vote in the 
case of a tie. 
 
SPRINT Executive Committee (EC) is the operational arm of the Steering Committee and 
makes decisions on behalf of the Steering Committee (SC) on day-to-day operational issues 
that require immediate action.  This committee will consist of the Study Chair, SC Vice Chair, 
CC PI, NIH Project Office staff, Drug Distribution Center director, Project Coordinators/ 
Operations Subcommittee Chair, one rotating CCN PI, CC Program Coordinator, CC staff, and 
other subcommittee chairs as needed.  This committee will meet by conference call every other 
week or as needed.  The Executive Committee will develop the SC meeting agenda and 
timeline for completion of tasks.  Important study issues, protocol changes, and other items will 
be discussed by the EC prior to presentation to the full SC for review and approval.   
   
SPRINT Conflict of Interest Committee:  This committee reviews potential conflict of interest 
issues.  The NIH Project Office, Steering Committee Chair, and CC Chair comprise this 
committee, which has the overall responsibility for the trial’s ethical oversight policy and 
procedures. 
 
Subcommittees: 
 
In general, each subcommittee will have representative(s) from the Coordinating Center, from 
each CCN, and from the NIH Project Office.  Together the Steering Committee and each 
subcommittee should determine the expertise required for the given subcommittee.  For 
example, the Intervention Subcommittee should include experts in hypertension, nephrology, 
neurology, and geriatrics.  In addition, the various subcommittees may form working groups to 
address major issues within their charge (e.g., Genetics Working Group, CKD Working Group).  
The subcommittee and the CC will decide what periodic reports the subcommittee needs to 
perform its charge. 
 

 
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Ancillary Science Subcommittee (AS): This subcommittee is charged with developing 
procedures for review and approval by the SC for ancillary studies and substudies.  The AS will 
review proposals for feasibility and compatibility with the main study protocol and aims.  Specific 
evaluation criteria include participant and study burden.  There will be substantial statistical 
support to the development of ancillary studies through this committee.  It is suggested to have 
all 5 CCNs represented on this committee.  
 
Design and Analysis Subcommittee (D&A):  This subcommittee will review the currently 
proposed and alternative designs for the trial, including the analysis plan, the impact on sample 
size, statistical power and patient recruitment, as well as sequential monitoring, subgroup 
monitoring, and adjustments for multiple comparisons.  This subcommittee will work closely with 
the Intervention Subcommittee and the Recruitment, Retention and Adherence Subcommittee 
on the development of analysis plans for recruitment and adherence monitoring.   
 
Economic Evaluation/Health Related Quality of Life Subcommittee:  This subcommittee will 
develop the protocol for the economic evaluation of the SPRINT interventions and the protocol 
for assessing the impact of these interventions on health-related quality of life. This will allow the 
study to estimate overall costs, cost effectiveness and cost utility for the SPRINT interventions.  
This subcommittee also will train the CCNs regarding collection of human resource costs, 
quality of life data and plans for analyses of these data, and provide interim reports to the SC.   
 
Intervention Subcommittee:  This subcommittee is charged with generating all of the blood 
pressure (BP) intervention plans for the trial, including materials, medications, titration 
algorithms and schedules, visit schedules, adherence strategies to the medications protocol and 
all BP monitoring including reports.  This committee will consider issues concerning the SPRINT 
intervention on high-risk groups such as the elderly, CKD patients, and groups at highest risk for 
heart failure. The Intervention Subcommittee will provide guidelines on the standard of care for 
both treatment arms, as well as lifestyle choices, such as exercise, limiting salt, smoking 
cessation and medical management strategies.  An additional charge for this subcommittee is to 
monitor the safety of the interventions and to make recommendations regarding any possible 
changes to the protocol and MOP for patient safety reasons.  This subcommittee will likely have 
working groups such as a Medications Working Group and Lifestyle/Background Working Group 
to provide plans for standard of care.   
 
Measurements, Procedures and Quality Control Subcommittee (MPQC): This subcommittee is 
charged with developing and implementing the quality assurance and control mechanisms for 
the study.  The MPQC Subcommittee will work with the Central Lab in developing procedures 
for biological sample collection, processing, shipping, storage, and analysis – as well as a blood 
drawing and aliquoting scheme to reflect the storage of specimens for future use.  This 
subcommittee will work with the ECG Reading Center to develop quality control procedures to 
ensure high quality data. Initially, this subcommittee will establish criteria under which the study 
will be expected to perform.  This subcommittee will require communication with the CC in 
overseeing the quality assurance procedures, such as the standardized collection of data at all 
CCNs and clinical sites.  They will monitor all quality control as well, and will work closely with 
the CC in producing quality control reports.  The CC will provide the necessary information to 
the subcommittee, such as data entry quality control and missing data reports.  If quality control 
is an issue based on site visits reports, the MPQC Subcommittee will be alerted and requested 
to provide recommendations to the Steering Committee, as all site visit reports are reviewed by 
this subcommittee to determine if any action is warranted.  This subcommittee will develop site 
visit protocols and CCN “report cards.”  Clear definitions of the boundaries for the CC and CCN 
monitoring responsibilities will be drafted.   

 
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Mortality and Morbidity Subcommittee (M&M): This subcommittee will initially be responsible for 
developing event definitions and classifications and coding guidelines, then subsequent 
adjudication procedures.  The M&M Subcommittee will be responsible for establishing the 
guidelines for cause of death; diagnosis of MI, stroke, and heart failure; and evaluating other 
cardiac events and the trial endpoints.  They will jointly monitor all classifications of events, 
oversee the data collection of events, including forms design, and will serve as the liaison 
between the CCNs, clinical sites and the CC for the events ascertainment data collection.  This 
subcommittee will require expertise in neurology, nephrology, and cardiology. The M&M 
subcommittee will function as an adjudication subcommittee once the trial gets underway.   
 
Presentations and Publications Subcommittee (P&P): This subcommittee is charged with 
developing procedures for review and approval by the SC, and will review all publications, 
presentations, abstracts, and slides of the SPRINT trial and substudy results.  The CC and this 
subcommittee will develop procedures to track the development of publications and 
presentations (P&P), as well as strategies for stimulating P&P productivity.  Additionally, the CC 
will provide analyses for publications and presentations, and the study web site will provide P&P 
tracking reports and study presentations and publications.   
 
Project Coordinators/Operations Subcommittee:  This subcommittee facilitates communication 
and collaboration among clinical sites, the CCNs, and the Coordinating Center.  It focuses on 
recruitment, retention, adherence, and implementation issues, identifying problems early to 
promptly implement solutions.  In addition, the Operations subcommittee addresses specific 
CCN and clinic requests for tracking and scheduling reports, missed appointment reports, data 
entry updates or issues requiring attention, and coordinates certification updates and numerous 
data management issues.  This subcommittee will include representatives from the CC (e.g., 
project managers) and from the MRI and ECG Reading Centers, Central Laboratory and Drug 
Distribution Center. The CCN Coordinator Chair of this committee can be rotated annually as 
needed and will serve as a member of the Executive Committee. 
 
Recruitment, Retention and Adherence Subcommittee:  This subcommittee will be charged with 
developing the eligibility criteria, recruitment, retention and adherence to the protocol and 
procedural strategies.  Generation of the SPRINT template informed consent and HIPAA 
authorizations will be done in conjunction with other subcommittees, such as PC/Operations, 
MPQC, and Intervention subcommittees.   Recruitment and retention strategies will be 
developed with special emphasis on issues pertinent to recruitment of ethnic groups, women, 
those with CKD and the elderly.  The subcommittee will develop educational and recruitment 
materials and will provide the culture-specific central training in recruitment strategies.  During 
the follow-up phase, this subcommittee will monitor all aspects of retention, including visit and 
procedure adherence, and will provide input on necessary retention tracking reports.  This 
subcommittee will collaborate with the Intervention subcommittee to develop strategies and 
tactics to enhance and monitor intervention adherence.  This subcommittee also will assist the 
Coordinating Center in monitoring recruitment at the CCNs and clinical sites in order to identify 
recruitment difficulties.   
 
Safety Subcommittee:  This subcommittee is charged with responding to concerns about the 
safety of study participants that may arise during the course of the SPRINT study. Concerns 
related to safety of study intervention, study medication or study procedures will be reviewed by 
the committee and either by addressed directly or referred to another subcommittee/ working 
group as appropriate. Additionally, this committee will help triage issues raised by clinic IRBs 
that are related to safety and review any clinical practice issues that may arise. They may also 
review summaries of study data related to the overall safety of study participation, but not 

 
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reported by treatment assignment, and develop related reports for or respond to concerns from 
the Data and Safety Monitoring Board. The Safety Committee will include the Safety Officer, 
representatives from the Intervention Committee, the CKD working group, the MIND Committee, 
the Geriatrics working group, and may be joined by other experts for specific issues as needed. 
 
SPRINT-MIND Subcommittee:  This subcommittee will provide the scientific leadership for 
SPRINT-MIND and will include cognitive functioning, dementia and MRI representatives from 
the CC, CCNs, the NIH (NINDS, NHLBI, NIDDK, and NIA) and the site PI of the MRI Reading 
Center. This subcommittee will monitor all 3 areas of MIND: dementia, cognitive functioning and 
MRI scans, as well as selection of the data collection instruments and training of clinical staff.  
The SPRINT-MIND Subcommittee will serve as the adjudicators for cognition outcomes as 
members of the M&M subcommittee. This subcommittee may utilize working groups as needed, 
such as MIND Operations or MIND Geriatrics Working Group.  

 
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APPENDIX 6 
Participating Sites 
 
SPRINT CLINICAL CENTER NETWORKS  
 
Ohio/Case Western Reserve CCN 
Network Hub: Case Western Reserve (PI: Jackson Wright, MD) 
Bolwell Suite 2200 
11100 Euclid Ave 
Cleveland, OH 44106-6053 
 
Southeast CCN 
Network Hub:  Wake Forest University Health Sciences (PI: Michael Rocco, MD) 
Wake Forest University Health Sciences 
Section on Nephrology 
Medical Center Blvd 
Winston-Salem, NC 27157-1063 
 
University of Alabama – Birmingham CCN 
Network Hub:  University of Alabama, Birmingham (PI: Suzanne Oparil, MD) 
703 19th St South 
ZRB 1034 
Birmingham, AL 35294 
 
Utah CCN 
Network Hub:  University of Utah (PI: Alfred Cheung, MD) 
Dialysis Program/University of Utah 
Ezekiel R & Edna Dunke Bldg 
84 N Medical Dr East, Room 201 
Salt Lake City, UT 84108 
 
Veteran’s Administration (VA) CCN 
Network Hub:  Memphis, TN (PI: Bill Cushman, MD) 
Hypertension and Lipids Research 
111Q/1030 Jefferson Ave 
Memphis, TN 38104-2193 
 
SPRINT COORDINATING CENTER 
(PI:  David M Reboussin, PhD) 
Wake Forest University Health Sciences 
Division of Public Health Sciences 
Department of Biostatistical Sciences 
Medical Center Blvd, Wells Fargo-21 
Winston-Salem, NC 27157 
 
 
 
SPRINT CENTRAL RESOURCE CENTERS 

 
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Drug Distribution Center (PI: Mike Sather, Rob Ringer) 
VA Cooperative Studies Program  
Clinical Research Pharmacy Coordinating Center 
2401 Centre Ave SE 
Albuquerque, NM 87106  
 
ECG Reading Center (PI: Elsayed Soliman) 
EPICARE 
Wake Forest University Health Sciences 
Medical Center Blvd, Wells Fargo-13 
Winston-Salem, NC 27157 
 
MRI Reading Center (PI: R. Nick Bryan) 
Brain Magnetic Resonance Imaging Reading Center 
University of Pennsylvania 
Section of Biomedical Image Analysis 
3400 Spruce St 
Philadelphia, PA 19104 
 
Central Lab (PI: Tony Killeen) 
University of Minnesota Collaborative Studies Clinical Lab 
420 Delaware St SE 
Minneapolis, MN 55455 
 
 
FEDERAL SPONSORS 
 
National Institutes of Health (NIH) 
National Heart, Lung, and Blood Institute (NHLBI) 
            National Institute of Neurological Disorders and Stroke (NINDS) 
National Institute on Aging (NIA) 
            National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)