PALS: Prostate Cancer Active Lifestyle Study
Phase: NA
Conditions: Prostate Adenocarcinoma, Stage I Prostate Cancer AJCC V7, Stage IIA Prostate Cancer AJCC v7
Sponsor: Fred Hutchinson Cancer Center

PALS Protocol V10 
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Clinical Research Protocol 
PALS:  PROSTATE CANCER ACTIVE LIFESTYLE STUDY 
Protocol Number: 
9369 
Version Number: 
V10 
Version Date: 
July 20, 2020 
Development Phase: 
Phase III 
Indication 
Active Surveillance, prostate cancer 
Study sites 
Fred Hutchinson Cancer Research Center 
University of Washington 
Veterans Affairs Puget Sound Health Care System 
Funding Organization: 
National Cancer Institute  
Principal Investigator: 
Jonathan Wright, MD  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
1 
BACKGROUND 
8 
2 
STUDY RATIONALE 
11 
3 
STUDY OBJECTIVES 
10 
3.1 PRIMARY OBJECTIVE 
10 
3.2 SECONDARY OBJECTIVES 
10 
4 
STUDY DESIGN 
11 
4.1 STUDY OVERVIEW 
11 
5 
CRITERIA FOR EVALUATION 
11 
6.1 PRIMARY ENDPOINT 
11 
6.2 SECONDARY ENDPOINTS 
11 
6 
SUBJECT SELECTION 
12 
6.1 STUDY POPULATION 
12 
6.2 INCLUSION CRITERIA 
12 
6.3 EXCLUSION CRITERIA 
12 
6.4 STUDY SPECIFIC TOLERANCE FOR INCLUSION/EXCLUSION CRITERIA 
12 
6.5 SCREEN FAIL CRITERIA 
12 
7 
STUDY PROCEDURES 
12 
7.1RECRUITMENT 
15 
7.2 
CONSENT 
17 
7.3 
RANDOMIZATION 
14 
7.4 
INTERVENTION 
14 
7.5 
CLINICAL ASSESSMENTS 
16 
7.6 
OUTCOMES 
17 
8 
RISK BENEFIT ASSESSMENT 
18 
8.1 POTENTIAL RISKS 
18 
8.2 MEDICAL MONITORING 
18 
8.3 PROTECTION AGAINST RISKS 
18 
8.4 POTENTIAL BENEFITS 
19 
9 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
18 
9.1 
EARLY DISCONTINUATION OF STUDY TREATMENT 
18 
9.2 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
20 
9.3 
REPLACEMENT OF SUBJECTS 
20 
10 
DATA SAFETY MONITORING 
20 
10.1 ADVERSE EVENT REPORTING 
20 
10.2 DATA SAFETY MONITORING COMMITTEE 
20 
11 
STATISTICAL METHODS AND CONSIDERATIONS 
19 
11.1 SAMPLE SIZE AND RANDOMIZATION 
20 
12 
DATA COLLECTION, RETENTION AND CLINICAL MONITORING 
22 
12.1 DATA COLLECTION INSTRUMENTS 
21 
12.2 DATA MANAGEMENT PROCEDURES 
22 
12.3 ARCHIVAL OF DATA 
23 
12.4 AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS 
23 
12.5 MONITORING 
23 
12.6 SUBJECT CONFIDENTIALITY 
23 
12.7 PROTOCOL AMENDMENTS 
23 
12.8 INSTITUTIONAL REVIEW BOARDS AND INDEPENDENT ETHICS COMMITTEES 
23 
12.7 INFORMED CONSENT FORM 
24 
12.10 PUBLICATIONS 
23 
16 
REFERENCES 
25 

 
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List of Abbreviations AND ACRONYMS 
AAFQ 
Arizona Activity Frequency Questionnaire 
AE 
Adverse event 
AS 
Active Surveillance 
BMI 
Body mass index 
BUN 
blood urea nitrogen 
CI 
Confidence Interval 
CRF 
case report form 
DPP 
Diabetes Prevention Program 
DM 
Diabetes Mellitus 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
DXA 
Dual x-ray absorptiometry 
EDC 
Electronic data capture 
EPIC 
Expanded Prostate Cancer Index 
FDA 
Food and Drug Administration 
FHCRC 
Fred Hutchinson Cancer Research Center 
GCP 
Good Clinical Practice 
GXT 
Graded Exercise Treadmill test 
HbA1C 
Hemoglobin A1C 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HR 
Hazard Ratio 
HRQOL 
Health Related Quality of Life 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IGF-BP3 
Insulin like Growth Factor Binding Protein 3 
IGF-1 
Insulin like Growth Factor 1 
IGF-1R 
Insulin like Growth Factor 1 Receptor 
IR 
Insulin Receptor 
IRB 
Institutional Review Board 
MAX-PC 
Memorial Anxiety Scale for Prostate Cancer 
NIH 
National Institute of Health 
PCPT 
Prostate Cancer Prevention Trial 
PE/DVT 
Pulmonary embolism/deep venous thrombosis 
PI 
Principal Investigator 
PCa 
Prostate Cancer 
PCSM 
Prostate Cancer Specific Mortality 
PSA 
Prostate Specific Antigen 
QOL 
Quality of Life 
RP 
Radical Prostatectomy 
RC 
Research Coordinator 
SAE 
serious adverse event 

 
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PROTOCOL SYNOPSIS 
TITLE 
PALS: Prostate Cancer Active Lifestyle Study 
SPONSOR 
R01 CA184075-01A1 
FUNDING 
ORGANIZATION 
National Cancer Institute  
NUMBER OF SITES 
Fred Hutchinson Cancer Research Center 
RATIONALE 
Prostate cancer (PCa) is the most common cancer diagnosis in men today and 
the second leading cause of cancer-related mortality in men, accounting for 
almost 30,000 deaths annually. Obesity contributes to PCa-specific mortality 
(PCSM), increasing risk by 20-160%, but the causal mechanisms remain 
unknown. Men on Active Surveillance (AS), where low risk PCa patients are 
monitored with regular PSA blood tests, physical exams and prostate biopsies, 
provide an ideal population to study the effects of obesity on adverse outcomes in 
relation to a lifestyle intervention: (1) these men are cancer survivors not having 
had aggressive treatment, and may be more able and motivated to undergo a 
lifestyle intervention; and (2) they have intact tumors which allow for ongoing 
tumor tissue based analyses to be conducted. Despite their initial lower risk 
status, 50% of these patients will experience disease progression requiring active 
treatment. We hypothesize that obesity enhances tumor growth, leading to 
conversion of low-risk to high-risk disease. Thus, implementing a lifestyle 
intervention against obesity and understanding the biologic mechanisms linking 
obesity and PCa outcomes could have a profound effect on clinical practice 
through reducing overtreatment and its adverse side effects, reducing health care 
costs, and reducing patient anxiety. Identifying factors that may slow or prevent 
tumor progression in AS patients will have substantial clinical and public health 
impact by improving patient outcomes and reducing health cancer expenditures.  
STUDY DESIGN 
This is a randomized controlled trial to investigate the effects of a 6-month 
lifestyle intervention based on the Diabetes Prevention Program (DPP) on 
glucose regulation biomarkers, health related quality of life and pathologic 
features of follow-up biopsies in overweight and obese men with prostate cancer 
on Active Surveillance 
PRIMARY OBJECTIVE 
The study has the following primary specific aims: 
1. To test whether the DPP lifestyle intervention (vs. control) improves serum 
fasting glucose; 
2. To test whether the DPP lifestyle intervention (vs. control) improves serum 
biomarkers of glucose regulation (insulin, C-peptide, insulin-like growth 
factor-1 (IGF-1), IGF binding protein 3 (IGF-BP3) and adiponectin); 
3. To test whether the DPP lifestyle intervention decreases the levels of 
insulin receptor or insulin-like growth factor-1 receptor (IGF-1R) in PCa 
tissue epithelium on follow-up prostate biopsy; 
4. To test whether PCa patients randomized to the DPP lifestyle intervention 
sustain the lifestyle changes for at least 6 months after the end of the 
intervention period. 
 
SECONDARY 
OBJECTIVES 
The secondary objectives are to: 
1. To evaluate whether the DPP lifestyle intervention improves health-related 
quality of life; 
2. To evaluate whether the DPP lifestyle intervention effects on pathologic 
features of follow-up prostate biopsies. 

 
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NUMBER OF 
SUBJECTS 
200 
SUBJECT SELECTION 
CRITERIA:  
Inclusion Criteria 
Inclusion Criteria: 
1. histologically confirmed adenocarcinoma of the prostate, clinically localized, 
low or low-intermediate risk disease (T1C/T2a, Gleason≤7 (3+4), PSA < 20);  
2. Primary treatment is AS with planned annual surveillance biopsies; 
3. BMI≥25 kg/m2; and  
4. Able to make the required dietary changes 
5. Physically able to undertake an exercise program. 
SUBJECT SELECTION 
CRITERIA:  
Exclusion Criteria 
Exclusion Criteria: 
1. Current, recent (<1 year), or planning to join a weight loss program, undergo 
weight loss surgery, or take appetite suppressants;  
2. Steroid hormone (ADT) use within past 12 months;  
3. Significant cardiovascular disease precluding an exercise program, including 
recent (within 6 months) myocardial infarction or stroke, pulmonary edema, 
myocarditis, pericarditis, unstable angina, PE/DVT, uncontrolled hypertension 
(SBP>200; DBP>110), uncontrolled arrhythmia, heart failure; or  
4. Insulin dependent DM and/or metformin use. 
5. MD confirmed cognitive impairment 
6. Current alcohol or narcotic abuse 
DURATION OF 
SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
Subjects will be on study for up to 1 year 
Treatment:  6 months 
Follow-up:  6 months 
The total duration of the study is expected to be 4 years 
PRIMARY ENPOINTS 
 
Primary Aims 1 and 2: Compare change in fasting glucose, C-peptide, insulin, 
IGF-1, IGF-BP3, and adiponectin levels relative to baseline between the 
intervention and control arms.  
Primary Aim 3: We will test whether the change in expression of IR, IGF-1R, and 
AKT on prostate cancer epithelial cells from follow-up surveillance biopsy (6 
months post-randomization) relative to ‘baseline’ (biopsy ~6 months prior to 
randomization). 
Primary Aim 4: We will test whether PCa patients randomized to the intervention 
arm are able to sustain the beneficial changes in weight and glucose regulation 
an additional 6 months after the active intervention. 
SECONDARY 
ENDPOINTS 
Secondary Aim 1.  We will test whether the change in HRQOL, namely urinary 
and sexual QOL and bother, relative to baseline, differs between the intervention 
and control arms  
Secondary Aim 2. We will use a two-sample test of proportions to determine 
whether the proportion of participants with adverse pathology (Gleason 
upgrading, increase in number of positive cores, cores>50% positive) on follow-
up surveillance biopsy differs between intervention and control arms. 

 
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STATISTICS 
Primary Analysis Plan 
Aims 1 and 2:  Global assessment of intervention effects will be evaluated using 
a two-sided t-test or Wilcoxon rank sum test if normality of the measurement is 
questionable (as determined by QQ-normal plots). Further analysis will quantify 
effects of patient age, BMI and other body composition measures on change in 
fasting glucose using linear regression. Differential effects between intervention 
and control arms will be quantified using interaction terms. All analyses will 
compare effects based on intention-to-treat. 
Aim 3:  Global assessment of intervention effects will be evaluated using a two-
sided t-test (or Wilcoxon rank sum test). Linear regression will be used to assess 
associations of IR, IGF-1R, and AKT expression with systemic measures of 
glycemic control at 6 months.   
Aim 4:  We will follow the DPP research group characterization of sustained 
weight loss as maintenance of a 7% reduction in weight and sustained glucose 
regulation as maintenance within 5% of 6-month levels. Because not all 
participants will achieve 7% weight loss at 6 months, we will look in the subset of 
participants who did and did not achieve this goal both separately and combined.  
A one-sample test of proportions will be used to determine whether the proportion 
of participants that are able to sustain lifestyle changes differs from zero.   
Rationale for Number 
of Subjects 
Our power calculations give the minimally detectable intervention effects for 
endpoints in Primary Specific Aims, setting two-sided alpha error at 5% and 
power at 80%. We have set a sample size of 100 in each of the intervention and 
control arms, based both on our overall evaluation of minimum detectable 
differences across the range of study endpoints and on a reasonable estimate of 
the number of men we can recruit. The sample size allows for a drop-out rate of 
5%, and power calculations assume correlations of 0.70 between baseline and 
follow-up measures.   
 

 
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1 BACKGROUND 
Obesity prevalence in the U.S. has risen dramatically over the past 20 years. Presently, more than one-third of 
adults are obese (body mass index (BMI) ≥ 30 kg/m2) and among older men, approximately 40% are obese.1 
Obesity is linked with an increase in cancer-specific mortality and an estimated 14% of cancer deaths in U.S. 
men are due to obesity.2 Epidemiologic studies have consistently associated obesity with an increased risk of 
prostate cancer (PCa) progression and PCa-specific mortality (PCSM).2-18 In a study of 731 men with organ-
confined, margin-negative PCa after radical prostatectomy (RP), the most obese men had a 4-fold increased 
risk of progression after adjusting for Gleason grade.10 As shown in Table 1, obesity is associated with a 20% 
to 160% elevation in PCa-specific mortality. Pooled/meta analyses report that for every 5-point increase in 
BMI, there is a corresponding 20% increase in PCSM (95% CI 0.99-1.46) and conclude that “cumulative data 
is compelling for a strong positive association between obesity and fatal prostate cancer”.19 A 2011 Institute of 
Medicine Workshop on Obesity and Cancer Report noted: “evidence is building that obesity and weight gain 
are risk factors for poor outcome in prostate cancer”.20 
 
Table 1:  Studies of Obesity and PCa-Specific Mortality 
Study, year 
No.  
Patients 
Hazard Ratios (95% Confidence Intervals) 
P trend 
BMI ≤ 25 
BMI 26 – 29 
BMI ≥ 30 
Andersson, 1997 18 
2,368 
1.00 (ref) 
1.3 (1.0-1.7)* 
1.4 (1.1-1.8)* 
0.04 
Calle, 2003 2 
3,314 
1.00 (ref) 
1.1 (1.0-1.2) 
1.2 (1.1-1.4) 
< 0.001 
Wright, 2007 3 
9.986 
1.00 (ref) 
1.3 (0.9-1.8) 
1.5 (0.9-2.3) 
0.02 
Efstathiou, 2007 9 
945 
1.00 (ref) 
1.5 (1.0-2.3) 
1.6 (1.0-2.7) 
-- ^ 
Gong, 2007 6 
752 
1.00 (ref) 
1.1 (0.6-2.3) 
2.6 (1.2-5.9) 
0.03 
Ma, 2008 16 
2,456 
1.00 (ref) 
1.3 (1.0-1.6) 
2.0 (1.2-3.2) 
< 0.001 
* BMI (kg/m2) quartiles used;   ^ p Trend not provided 
    
The mechanisms underlying the obesity-PCa progression relationship are unknown. However, a number of 
metabolic changes that occur in obese men may be responsible, including impaired glucose regulation and 
insulin resistance. Studies have shown that obesity is strongly associated with hyperinsulinemia21 and weight 
loss both improves insulin sensitivity and prevents incident diabetes in high-risk individuals.22   
   The societal impact of PCa is significant, as the 2010 cost of care estimate was $11.9 billion.23  The highest 
costs are during the first year after diagnosis, typically including treatment with either surgery or radiation.24 
However, there is growing awareness of overtreatment of men with low-risk PCa (the most common type of 
PCa) who are increasingly managed with active surveillance (AS).  AS involves monitoring of the PCa with 
plans to intervene if the cancer progresses, thus avoiding expensive treatment with significant side- effects in a 
large proportion of men. AS has been shown to have lower 5-year costs compared to other PCa treatments 
with a potential net per-patient savings of $12,194 at 5-years.25 Therefore, reducing progression on AS has the 
potential to have profound impacts on both an individual and societal perspective.  Targeted weight reduction 
is a viable opportunity.  
 
1.2 Dietary Studies in Prostate Cancer 
   Observational studies provide compelling evidence that dietary factors post-PCa diagnosis may affect 
disease progression. In the Health Professionals Follow-up Study, the consumption of specific food types by 
men with PCa was associated with disease progression suggesting that dietary intake can influence disease 
outcome.26 Specifically, replacing 10% of energy intake after the diagnosis of PCa from carbohydrate with 
vegetable fat was associated with a significant reduction in the risk of PCSM (HR 0.71, 95% CI 0.51-0.98), 
whereas substituting 5% of saturated fat intake for carbohydrate significantly increased the PCSM risk (HR 
1.30 95% CI 1.05-1.60).27 A recent analysis of these men reported that men with a higher healthy lifestyle 
index (based on BMI, diet and physical activity) had a 40% reduction in the risk of lethal PCa (HR 0.61, 95% CI 
0.42-0.88).28 In a study of 1,560 men with PCa, those with the highest cruciferous vegetable intake post-
diagnosis had a lower risk of disease recurrence.29 Finally, patients with high vs. low saturated fat diets had a 
2-fold increased risk of PCa recurrence (HR 2.0, 95% CI 1.2-3.2).30 
   Weight gain also increases the risk of progression after radical prostatectomy (RP).15, 31, 32  In a study of 526 
men, weight gain >1.5 kg/year between age 25 and PCa diagnosis was associated with a two-fold increased 
risk of recurrence vs. men who were weight stable (HR 2.3, 95% CI 1.1-5.1).15  Similarly, among 359 men, 

 
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weight gain ≥2.5 kg the year before RP increased risk of PCa recurrence (HR 1.7, 95% CI 1.0-2.6).31  Finally, 
in a study of 1,337 men, weight gain >2.2 kg between 5 years pre- and 1 year post-RP increased risk of 
recurrence nearly 2-fold (HR 1.9, 95% CI 1.1-3.3) vs. those who maintained their weight.32  In addition to 
dietary changes, exercise also reduces the risk of PCSM, with men who do >3 hours of vigorous exercise per 
week having a 61% reduction in the risk of PCSM (HR 0.39, 95% CI 0.18-0.84).33   
   Studies in men with PCa have also demonstrated that dietary change leads to changes in serum markers 
that affect PCa cell growth.34, 35  In a study of 12 men participating in a 6-month low-fat/high fiber diet with soy 
supplements, serum from participants was incubated with LnCaP PCa tumor cells and the intervention arm had 
a 20% inhibition of LnCaP cell growth (p<0.05) compared to the control arm.34 In a second study of a vegan 
diet, moderate aerobic activity and stress management, LNCaP cell growth declined an average of 70% in the 
lifestyle intervention arm, compared to a 9% decline in the control arm (p<0.001).35  In a study of 30 men 
undergoing a 3-month intensive nutritional and lifestyle intervention, which achieved a mean 2.6 unit decline in 
BMI, changes in gene expression from pre- and post-intervention prostate biopsies included down-regulation of 
IGF-1R genes.36  In summary, diet and dietary change post-PCa diagnosis can impact disease progression. 
Thus, a lifestyle intervention in men with PCa is timely, and studies identify glucose regulation as an important 
biomarker of this intervention effect. 
 
1.3 Glucose Regulation and Prostate Cancer Outcomes 
Preclinical and observational studies demonstrate that glucose regulation affects PCa outcomes. 
Preclinical studies.  Insulin and glucose are critical for cancer cell growth37 and preclinical studies provide 
evidence of the role of glucose regulation  in PCa.38, 39  In one study, LnCaP tumor cells were injected and 
tumor growth was compared in mice with induced hyperinsulinemia through a high carbohydrate feeding to 
mice fed a low carbohydrate diet without resultant hyperinsulinemia.39  After 9 weeks, the tumors in the mice 
with hyperinsulinemia were significantly larger than those tumors in mice without hyperinsulinemia (p < 0.001).  
In a second preclinical study, mice with LAPC-4 xenografts were fed either a western diet or a no carbohydrate 
diet.  Tumor cell volume after 7 weeks was 33% lower in the mice fed the no carbohydrate diet.38  These 
preclinical studies demonstrate the potential role of aberrant glucose regulation in PCa cell growth. 
   Several different cancers have been shown to overexpress the insulin receptor (IR),40-43 including PCa.44  
The IR is structurally similar to the IGF-1 receptor (IGF-IR) and both are considered to be important in cancer.  
Activation of these receptors leads to mitogenic activity via RAS and MAPK and anti-apoptotic action through 
the AKT and mTOR pathway, with phosphorylated-AKT representing a measurable downstream signaling 
molecule for the IGF-IR and IR (Fig. 1)45.  A study of 161 men undergoing RP for PCa found two-fold higher 
levels of IR staining on PCa cells compared to benign prostate cells.44  This finding, combined with animal 
models demonstrating that dietary restriction in animals with PCa decreases expression of IGF-1R, IR and 
downstream signaling with phosphorylated-AKT (Table 2),39 suggests that IR could be a target for therapy and 
tumor receptor expression/activation may serve as a biomarker of lifestyle modifications. 
Human studies.  Small 
studies have evaluated 
serum biomarkers of glucose 
regulation and PCa 
aggressiveness and cancer 
outcomes.  In studies of men 
with diabetes undergoing RP, 
higher pre-RP HbA1C levels 
were associated with a 
greater risk of extracapsular disease and aggressive PCa.50, 51  In an analysis of the control arm of the Prostate 
Cancer Prevention Trial (PCPT) by one of our investigators (MN), higher C-peptide (an insulin surrogate) levels 
were associated with an 88% increased risk of aggressive PCa.52  In addition, longitudinal studies of men 
treated for PCa have found direct associations between markers of glucose regulation and PCSM.16, 53 In one 
study, a higher mean fasting insulin level at diagnosis was found in those who died of PCa.53 In the Physicians 
Health Study, PCa cases with the highest C-peptide concentrations (>2.7) had more than a 2-fold increased 
risk of PCSM (HR 2.4, 95% CI 1.3-4.3) vs. those with the lowest concentrations (<1.0).16  
   In previous studies, we determined that elevated glucose levels at PCa diagnosis independently predicted 
risk of recurrence. Men with PCa undergoing local therapy who had glucose ≥100 mg/dL at diagnosis had a 
50% increased risk of recurrence (HR 1.5, 95% CI 1.1-2.0) vs. those with glucose level <100 mg/dL.54 These 
findings are in line with results from studies in several other cancers, including breast, colon, liver and brain 
Table 2: Animal studies of diet and resultant PCa tissue receptor changes 
Author, year 
Diet 
Receptor levels in diet arm 
Narita, 200846 
Low fat 
↓ IGF-1R 
Powolny, 200847 
Caloric Restriction 
↓ IGF-1R 
Venkateswaran, 200739 
Low fat, low carb 
↓ IR and ↓ phos-Akt 
Kobayashi, 200848 
Low fat 
↓ phos-Akt 
Mavropoulus, 200949 
No carb 
↓ phos-Akt 

 
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cancers, which have also found that higher glucose levels are associated with a greater risk of tumor 
progression.55-59  In summary, markers of glucose regulation may foreshadow PCa progression and glucose 
control may be a modifiable risk factor for PCa recurrence.    
   Considering the increasing prevalence of both obesity60 and PCa, and the relationship of impaired glucose 
regulation with increased obesity and adverse PCa outcomes, a weight reduction lifestyle program to improve 
glucose regulation in PCa patients holds promise for reducing adverse PCa-specific outcomes. One of the 
most successful ways to lose weight is through a structured program of diet and exercise such as the Diabetes 
Prevention Program (DPP), which is individualized to take into account individual preferences and includes 
behavioral modifications that are important for dietary adherence.61 AS patients represent an ideal population 
to study for this intervention. Cancer survivors on AS have untreated cancer which allows for comparisons of 
the intervention’s effects on tumor tissue to be performed with repeat surveillance biopsies. Thus, the effect of 
the intervention on changes in cancer biomarkers can be ascertained.  It would not be appropriate to delay 
definitive therapy for >6 months in men with higher risk PCa to obtain post-intervention tumor tissue. However, 
as AS patients have untreated cancer, they may be at a higher functional level since they are not recovering 
from surgery or radiation that could limit their abilities to fully participate in dietary and exercise interventions. 
Finally, as the men on AS do not have advanced disease, they are not suffering the consequences of 
metastatic disease and advanced therapy (androgen deprivation), which can influence metabolic biomarkers. 
Thus, men with PCa on AS offer a unique population in which to investigate a weight reduction intervention on 
biomarkers of tumor progression. Since 50% of men on AS progress to  eventually requiring treatment,62 a 
lifestyle modification that could delay or prevent this disease progression would represent a significant savings 
of heath care expenditures from surgery and other treatments as well as lowering morbidity and mortality in the 
patients requiring further treatment.  
 
1.4 Diabetes Prevention Program 
   The DPP studied over 3,000 participants with elevated fasting glucose levels randomized to metformin, a 6-
month lifestyle modification program or placebo.22, 61 The goal of the lifestyle modification program was a 7% 
reduction in body weight through a structured dietary program and at least 150 minutes of weekly physical 
activity.  The lifestyle intervention decreased incident diabetes mellitus (DM) by 58% vs. controls, while 
metformin reduced incident DM by 31%. Fasting glucose declined from a mean of 107 to 101 mg/dl in the 
lifestyle group whereas no change was seen in the placebo group. Long term follow-up of the DPP has 
demonstrated sustained weight loss at 10 years,63 which is an important consideration as other studies of 
dietary interventions in men with PCa have used diets that are difficult to maintain over the long-term (e.g., 
vegan35, low glycemic64 and prepared meals65).  The results of the lifestyle intervention have also been found 
to be cost-effective and cost saving.66, 67 A meta-analysis of weight loss studies based on the DPP lifestyle 
modification program consistently shows statistically significant and clinically relevant reductions in weight; 
however, the majority of participants in those studies were women and no studies to date have been 
conducted in older men with cancer.68 Despite this, there are indications that older men may be an ideal 
population for the DPP lifestyle intervention.  Older participants (≥60 years) compared to younger groups (25-
44 yrs. and 45-59 yrs.), had the greatest weight loss (mean -6.4 kg vs. -4.1 and -5.0 kg respectively, p<0.001) 
and more commonly met the exercise goal (48% vs. 34% and 38% respectively, p<0.001).69  The lifestyle 
intervention was more effective than metformin at weight loss with increasing age (p=0.005).69  In addition, 
compared to women, men lost more weight (p<0.01) and performed higher levels of physical activity (p<0.05) 
in the lifestyle intervention. 70  However, since only 20% of participants were older than 60 years of age, fewer 
than 1/3 of participants were men, and none of the participants had cancer, whether these results will have 
similar effects in a PCa population are unknown, but certainly these data provide evidence that the DPP 
intervention can succeed in this population. Thus, the DPP intervention offers a novel strategy to improve PCa 
patient outcomes and yield insights on biological pathways by which obesity may delay or prevent disease 
progression.   
 
1.5 Active Surveillance (AS) 
   An emerging area of PCa management is AS. PCa will be diagnosed in over 200,000 men this year.71  PCa 
is a cancer of older men (mean age at diagnosis of 67 years).71  Because of the long natural history of PCa, 
many men will die of competing causes, the most common being cardiovascular disease. Considering the 
significant quality of life and functional side effects of PCa treatment, there is increasing pressure to reserve 
treatment for those most likely to experience PCa related morbidity and mortality.  In AS, men with lower risk 
PCa are monitored regularly with PSA tests, physical exams and surveillance prostate biopsies. Men who 

 
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show evidence of disease progression (Gleason upgrading, increase in amount of cancer present) are 
recommended treatment (e.g., RP, radiation or androgen deprivation therapy) with curative intent.   
   Progression during AS occurs in 33% (range 14-49%) of patients at 5 years and 55% (range 40-59%) at 10 
years,62 suggesting that efforts to slow the growth of PCa while on AS are needed.  In fact, delaying curative 
intervention in men with localized PCa remains a concern as men on AS who undergo delayed RP are found to 
have adverse features (pT3, Gleason ≥7 disease) on final pathology approximately 25% of the time.72-74  
Further, obese men represent an even greater risk population, as data have shown that obese men eligible for 
AS have an increased risk of upstaging (OR 4.2, 95% CI 1.7-10.6),75 upgrading (OR 1.9, 95% CI 1.0-3.6)76 and 
biochemical recurrence (HR 1.9, 95% CI 1.0-3.4).13  In a recent study of men on active surveillance, a 5-point 
increase in BMI was associated with a 50% increased risk of pathologic progression (95% CI 1.1-2.1).77  In a 
randomized study in 93 men on AS, the intervention arm was encouraged to eat a low-fat, plant based diet, to 
exercise and to participate in group support sessions, the proportion of men who progressed to require 
treatment within 2-years was greater in the control arm (13/49) compared to the intervention arm (2/43, 
p<0.05).78  Mean weight loss was significantly greater in the intervention arm (4.5kg vs. 0kg, p<0.001).  These 
findings support our theory that improving body weight in men on AS can positively influence PCa outcomes.   
   Men on AS have anxiety levels and mental health scores that are similar or worse compared to men treated 
with RP79, 80, 81  However, men on AS can have improvements in their anxiety, as seen in a trial of dutasteride 
or placebo.82  In that study, anxiety significantly declined over the course of the study in the dutasteride group 
compared to the placebo group (p = 0.036).  Importantly, a study of lifestyle changes in men on AS 
demonstrated better mental and physical scores (from the generic HRQOL instrument, the Short Form 36 (SF-
36)) in addition to sexual function compared to controls.83  In a study of 30 men on AS undergoing a 3-month 
nutritional and lifestyle intervention, a 6.5 mean increase in mental component summary score was observed36 
along with decreased perceived stress.  Analyses of the DPP have demonstrated HRQOL benefits with 
lifestyle intervention compared to placebo for health utility index and physical component summaries of the 
Short-Form-36 health survey.84, 85  Therefore, the AS population represents a unique group of cancer survivors 
to study the effects of a lifestyle intervention.  
 
2 STUDY RATIONALE 
Obesity is associated with PCa recurrence and one potential mechanism is hyperglycemia and impaired 
glucose regulation, with both preclinical and observational data demonstrating this relationship.  The DPP is a 
diet and exercise lifestyle intervention with a successful track record of improving glucose regulation, although 
it has not been extensively studied in an older male population with cancer. Men with PCa on AS represent an 
important group in which to test a lifestyle intervention. Approximately 50% of men on AS will experience 
disease progression requiring treatment and the associated complications/side effects.  Thus, this study has 
the potential to improve overall survival and HRQOL in men by reducing PCa progression. 
 
3 STUDY OBJECTIVES 
 
3.1 Primary Objective 
The study has the following primary specific aims: 
1. To test whether the DPP lifestyle intervention (vs. control) improves serum  fasting glucose; 
2. To test whether the DPP lifestyle intervention (vs. control) improves serum biomarkers of glucose 
regulation (insulin, C-peptide, insulin-like growth factor-1 (IGF-1), IGF binding protein 3 (IGF-BP3) and 
adiponectin); 
3. To test whether the DPP lifestyle intervention decreases the levels of insulin receptor or insulin-like 
growth factor-1 receptor (IGF-1R) in PCa tissue epithelium on follow-up prostate biopsy; 
4. To test whether PCa patients randomized to the DPP lifestyle intervention sustain the lifestyle changes 
for at least 6 months after the end of the intervention period. 
 
3.2 Secondary Objectives 
We will also assess the following secondary aims: 
1. To evaluate whether the DPP lifestyle intervention improves health-related quality of life; 
2. To evaluate whether the DPP lifestyle intervention effects on pathologic features of follow-up prostate 
biopsies 
 

 
PALS Protocol V10 
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4 STUDY DESIGN 
 
4.1 Study Overview 
This will be a 6-month, prospective, randomized trial in overweight (BMI = 25-29 kg/m2) and obese (BMI > 30 
kg/m2) men with PCa (n=200) who have elected AS.  Patients will be randomized to either:  
1. Lifestyle intervention (a structured diet and exercise program based on the DPP); or  
2. Control (oral and written information based on general U.S. dietary and physical activity guidelines). 
 
Following randomization, men will be followed for 12 months, and the 12 month start and end dates will 
coincide with the yearly prostate biopsies that are part of routine clinical care for AS patients (thus no extra 
biopsies will be performed solely for the study; Fig. 3).  Baseline and post-intervention (at 6 and 12 months) 
measures of glucose regulation will be compared along with BMI, physical activity, caloric intake, additional 
insulin related biomarkers, function and quality of life and pathologic endpoints. 
 
Month 0 
1 
2 
Month 3 
4 
5 
Month 6 
7 
8 
9 
10 
11 
Month 12 
PALS STUDY VISIT TIMELINE 
CLINIC VISIT 
1 
 
CLINIC VISIT 2 
 
CLINIC VISIT 3 
 
CLINIC VISIT 4 
• Informed Consent 
• Blood draw  
• Height/weight 
• Waist/hip measures 
• Questionnaires 
• DXA scan 
• Exercise test 
• Meet with Nutritionist 
 
• Blood draw 
• Weight 
• Waist/hip measures 
• Questionnaires 
 
 
• Blood draw 
• Weight 
• Waist/hip measures 
• Questionnaires 
• Exercise test 
 
• Blood draw 
• Weight 
• Waist/hip measures 
• Questionnaires 
• DXA scan 
 
Standard of care 
BIOPSY 
• Tissue collection 
 
PALS Lifestyle Intervention group only 
 
PALS Sessions 
• Up to 11 one-on-one healthy eating  instruction sessions 
• Up to 24 supervised exercise sessions 
• Maintenance of healthy eating  and physical activity 
 
5 CRITERIA FOR EVALUATION 
 
5.1 Primary Endpoint 
The primary endpoints for each of the primary aims are: 
Primary Aim 1:   change in fasting glucose levels relative to baseline between the intervention and control 
arms.  
 
Primary Aim 2:   change in fasting C-peptide, insulin, IGF-1, IGF-BP3, and adiponectin levels relative to 
baseline between the intervention and control arms.  
 
Primary Aim 3:   change in expression of IR, IGF-1R, and AKT on prostate cancer epithelial cells from follow-
up surveillance biopsy (6 months post-randomization) relative to ‘baseline’ (biopsy ~6 months prior to 
randomization). 
 
Primary Aim 4:   will test whether PCa patients randomized to the intervention arm are able to sustain the 
beneficial changes in weight and glucose regulation an additional 6 months after the active intervention. 
 
5.2 
Secondary Endpoints 
Secondary Aim 1.  We will test whether the change in HRQOL, namely urinary and sexual QOL and bother, 
relative to baseline, differs between the intervention and control arms  

 
PALS Protocol V10 
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Secondary Aim 2.  
We will use a two-sample test of proportions to determine whether the proportion of 
participants with adverse pathology (Gleason upgrading, increase in number of positive cores, cores>50% 
positive) on follow-up surveillance biopsy differs between intervention and control arms. 
6 SUBJECT SELECTION 
 
6.1 Study Population 
Subjects with a diagnosis of localized prostate cancer who meet all of the inclusion and none of the exclusion 
criteria will be eligible for participation in this study.   
 
6.2 Inclusion Criteria 
1. histologically confirmed adenocarcinoma of the prostate, clinically localized, low or low-intermediate risk 
disease (T1C/T2a, Gleason≤7 (3+4), PSA < 20);  
2. primary treatment is AS with planned annual surveillance biopsies; 
3. BMI≥25 kg/m2; and  
4. physically able to undertake a diet and exercise program 
 
6.3 Exclusion Criteria 
1. current, recent (<1 year), or planning to join a weight loss program or take appetite suppressants;  
2. Steroid hormone use (ADT) within the past 12 months;  
3. significant cardiovascular disease precluding an exercise program, including recent (within 6 months) 
myocardial infarction or stroke, pulmonary edema, myocarditis, pericarditis, unstable angina, PE/DVT, 
uncontrolled hypertension (SBP>200; DBP>110), uncontrolled arrhythmia, heart failure; or  
4. 4) insulin dependent DM and/or metformin use. 
5. MD confirmed cognitive impairment 
6. Current alcohol or narcotic abuse 
 
6.4 Study Specific Tolerance for Inclusion/Exclusion Criteria 
Subjects who fail to meet one or more of the inclusion criteria or who meet any of the exclusion criteria will not 
be enrolled in this study. Waivers of any of the above study entry criteria will not be granted. 
 
6.5 Screen Fail Criteria 
Any consented patient who is excluded from the study before randomization is considered a screen failure. All 
screen failures must be documented with the reason for the screen failure adequately stated. Screen failures 
will not be re-screened for this study. 
 
7 STUDY PROCEDURES  
7.1a Recruitment from collaborating urology clinics 
Clinic study staff will identify potential eligible participants from urologic clinics at the University of Washington, 
Valley Medical Center and the Veterans Affairs Seattle Puget Sound Heath Care System.  Clinic study staff will 
pre-screen men to determine medical eligibility.  Recruitment efforts will be targeted towards medically eligible 
men living in the greater Seattle area.  All of our recruitment messages will outline the parameters of the 
project and will stress the time commitment necessary in order to participate.  UW, Valley and VA clinic staff 
will approach eligible prospective participants to tell them about the study.  Interested men will be provided a 
study brochure, and will be asked to sign consent to allow their personal contact information to be reported to 
FHCRC study staff for formal recruitment.   
 
7.1b Recruitment from community urology clinics 
If a patient from outside UW, Valley and VA contacts study staff directly about participating, PALS study staff 
will first obtain authorization (HIPAA) to allow access to the patients’ medical records to confirm medical 
eligibility requirements are met before completing the final eligibility screening. FHCRC study staff will contact 
eligible and interested men by phone to further review the study procedures, and to conduct the final eligibility 
screening verbally.  Men who meet all eligibility requirements and agree to participate will be scheduled to 
attend Visit 1 at the FHCRC Prevention Center clinic. 
 
7.1c Recruitment from CSS 

 
PALS Protocol V10 
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Direct case recruitment from CSS will follow the IRB-approved “Cancer Surveillance System Protocol for Direct 
Case Recruitment”. Briefly, CSS will identify potential case participants and notify study staff. We will contact 
local urologists known to the study PI to first determine whether potential case patients meet the study 
eligibility requirements. Potential case patients who are known to not meet the study eligibility requirements will 
not be contacted. Potential case patients will be sent a ‘Prior Notification’ letter that describes the CSS, informs 
them that they are being invited to participate in PALS. Included with this letter is a letter from the PALS study 
team and a study brochure introducing the PALS study. After 10 days, if a potential case participant has not 
opted out of contact and there is no evidence to suggest that the prior notification letter could not be delivered; 
PALS study staff will contact the potential case participant. During this call, PALS study staff will introduce the 
PALS study, review study procedures and to conduct a verbal eligibility screen. Men who are interested in 
participating and meet the eligibility requirements will be asked to sign and return a HIPAA authorization to 
allow access to medical records to confirm medical eligibility. Once these procedures are complete, potential 
case participants will be schedule to participate in the study.  
 
7.2 Consent 
A waivers of HIPAA authorization has been obtained to allow the University of Washington and the Veterans 
Affairs Seattle Puget Sound Heath Care System urology clinic study staff to pre-screen patients for eligibility. 
Clinic study staff will obtain informed consent from medically eligible and interested men to allow their personal 
contact information to be sent to the FHCRC for recruitment into this study.   
 
Men who self-refer to the study (from outside the VA/UW/Valley health care systems) or who are recruited via 
CSS will be asked to sign a HIPAA authorization to allow access to medical records to confirm medical 
eligibility to participate in PALS.  
 
Eligible men will be asked to sign the study l consent to participate in the intervention trial at clinic visit 1. 
Participants who are recruited from UW/VA/Valley will also complete a HIPAA authorization to allow access to 
the medical information required to meet study objectives (Participants who self-refer to the study  or who are 
recruited via CSS will already have signed the HIPAA authorization prior to Visit 1).  
 
 
 
7.3 Randomization 
Participants will be randomly assigned to either the intervention or control arm using a computerized program.  
In order to evenly distribute men to treatment arm, randomization will be blocked on BMI (25-29.9 or 30+) and 
age (<65years or 65+). 
 
7.4 Intervention 
Intervention.  The DPP intervention entails both a dietary program and an exercise component with goal 
based behavioral teaching. The goal is for participants to lose 7% total body weight over a 6 month time period 
at a pace of 1-2 pounds per week. Participants will be weighed at the start of each session.  The program 
involves 16, 30-minute to one-hour sessions led by a dietitian over a 24-week period.  Each session has a 
curriculum for the lifestyle coach/dietitian 
(http://www.cdc.gov/diabetes/prevention/recognition/curriculum.htm#3). These sessions are designed to help 
the patient adopt, and reinforce, lifelong skills for healthy living. The structured sessions provide training on 
nutrition, physical activity and behavioral self-management.  Over the first 8 sessions, the focus is on teaching 
the fundamentals of energy intake modification and increasing energy output while learning self-monitoring 
skills.  The last 8 sessions focus on the social, psychological and motivational hurdles to maintain these 
healthy lifestyle skills.  During months 6-12, intervention participants will receive a monthly newsletter to keep 
them engaged in the study and actively trying to achieve or maintain their weight loss goal. These newsletters 
will build upon the diet instruction participants received during the first 6 months of the study. 
 
Diet and exercise arm. The diet and exercise intervention is a caloric reduction program aimed at helping 
participants reduce total intake by 500-1000 calories/day, depending on one’s initial body weight, with no more 
than 25% of calories from fat, and to expend at least 700 calories a week through exercise.  The DPP teaches 
nutrition and behavior change skills: setting calorie and fat gram goals, counting calories of foods, self-
monitoring, and coping with challenges to eating behavior changes. Several tools are provided, such as graphs 
for monitoring weight, participant worksheets, cooking and shopping for lower-fat eating, and etc. Participants 

 
PALS Protocol V10 
14 
 
will attend 11 sessions with a study dietitian during the first 6 months of the study (once a week for 4 weeks, 
then every other week for 8 weeks, then once a month for 3 months) to receive diet and exercise instruction. If 
necessary, diet instruction can occur via telephone.   During each session the dietitian will weigh the participant 
(or ask the participant to weigh themselves), collect and review calorie-count and physical activity journals, 
review the participant’s dietary changes from the previous week and discuss any issues that may have arisen, 
providing appropriate behavioral counseling. The intervention will be individualized to the person’s dietary 
preferences. It is important to note that the DPP curriculum includes lessons related to compliance, retention 
and motivation. 
 
Supervised exercise. In addition, participants will complete up to 24 exercise sessions under the supervision of 
an exercise physiologist. The first two sessions will be one on one with the exercise physiologist to introduce 
exercises and provide teaching.  The subsequent weekly visits will be supervised, but not one on one. If 
necessary, exercise instruction and supervision can via telephone.  Many of the exercise sessions will coincide 
with the dietitian sessions.  
 
Exercise test. All participants will undergo a submaximal graded exercise treadmill test (GXT) to 85% predicted 
heart rate reserve at baseline and at 6 months. The purpose of the GXT is to measure fitness level (predicted 
aerobic capacity), establish exercise heart rate for training, and ensure safety of exercise training. A screening 
questionnaire will be administered prior to the GXT to determine whether any contraindications to exercise 
testing are present.  A brief heart and lung exam will also be conducted and the resting ECG reviewed. There 
will be physician on-call for all of these procedures. 
 
Heart rate monitor. Participants randomized to the diet and exercise group will be asked to wear a heart rate 
monitor during exercise sessions for one week a month.  They will be asked to put the monitor on prior to their 
daily exercise session. At the end of the exercise session (on average about 30 minutes) they will record the 
maximal heart rate that appears on the monitor screen.  Men in the control group will not wear the heart rate 
monitor. This tool will allow participants to monitor their exercise intensity with an individual heart rate range, 
provided by the exercise physiologist based on the GXT, to stay in while they exercise. This will help to ensure 
that the participant exercises at an appropriate intensity level. We have chosen to use heart rate monitors 
because they measure kcals and time in activity directly as heart rate increases linearly with activity intensity. 
Heart rate monitors are also ideal to use for this intervention because they yield data on the time in specific 
heart rate zones during exercise and sedentary time. This approach will allow us to directly measure number of 
minutes/week (goal = 150 minutes/week) and whether individual goals are being met. The heart rate monitor 
data will be downloaded to the study database.  
 
Compliance. Compliance to dietary and physical activity goals will be evaluated both formally and informally. 
The primary formal tool to assess overall study compliance will be participant weight loss; weight will be 
measured at each session (using a research scale and a standardized protocol) and if participants are meeting 
weight loss goals then compliance is achieved.  Other formal compliance tools to assess compliance will 
include study dietitian-directed proactive check-ins and completion of a 3-day diet record (at 6 mo). At each 
intervention session the dietitian will review progress and any potential barriers, and individual dietary goals will 
be adjusted as needed.104  Formal measures for adherence to physical activity goals will include reviewing 
heart rate monitor data and formal check-ins with the exercise physiologist. Informally, compliance to diet, 
physical activity and weight loss goals will be assessed by self-monitoring through logs and journaling.111 In 
addition, global-study wide tailored messages with diet, physical activity and behavioral strategies content will 
be delivered by text message and e-blasts. This multi-tiered approach has been shown to maximize adherence 
and retention during intervention trials.111   
 
Controls.  Written information on standard healthy lifestyle recommendations will be provided along with a 20-
30 minutes individual session with a dietitian including 1) US Dietary Guidelines (www.dietaryguidelines.gov); 
2) Activity goal of 30 minutes of physical activity 5 days/week; and 3) Discussion of the health benefits of 
weight loss along with general behavior change suggestions for weight loss. 
 
Follow-up Visits. All participants will come to the Fred Hutch Cancer Prevention Center for study visits at 
baseline (0), 3, 6 and 12 months.  A description of the clinical assessments performed at each follow-up visit is 
provided below. 
 

 
PALS Protocol V10 
15 
 
7.5 Clinical Assessments 
Study visits will occur at baseline, 3, 6 and 12 months.  During study visits, participants will undergo 
anthropometrics, fasting blood studies and/or complete physical activity, food diaries and HRQOL 
questionnaires.  Assessments at 6 months will be used to evaluate the effectiveness of the intervention, and at 
12 months will evaluate maintenance of the intervention.   
 
Anthropometric Measurements. Height will be measured at baseline only, and weight, waist (1” above 
umbilicus), hip circumferences will be measured at baseline, 3, 6 and 12 months.  Dual x-ray absorptiometry 
(DXA) using a GE Lunar iDXA will be obtained to measure overall percent body fat, lean mass and total bone 
density at baseline and 12 months. 
   
Twelve-hour fasting blood. Fasting blood samples will be collected at baseline, and at 3, 6, and 12 months.  
Vacutainers will be labeled with participants’ study ID and date, processed within 1 hour of collection and 
stored at -70ºC.   
 
Prostate Tissue. As part of the consent to participate in this study, participants are asked to give permission to 
investigators to allow a) the collection of two extra prostate biopsy cores during their standard-of-care biopsy 
(UW and VA participants only), and b) access to pathology tissue from a pre-study biopsy (that was already 
collected as part of routine medical care for diagnostic purposes) to be used for this study (UW and VA 
participants only). For VA patients, separate consent allowing the collection of extra biopsy cores during a 
standard-of-care biopsy, and allowing access to biopsy tissue after used for diagnostic purposes will be 
obtained at the VAPSHCS by VA study staff on the day of their scheduled biopsy. For participants who are not 
patients at UW or the VA, since the collection of extra biopsy cores is not possible, they will be asked to sign a 
separate “Release of Information” allowing access to prostate biopsy tissue collected as part of their routine 
care.  Tissue blocks, fixed in formalin and embedded in paraffin (standard for AS biopsies), will be sent to Dr. 
Colm Morrissey’s laboratory.  Participants will be enrolled on study so that the intervention calendar coincides 
with routine clinical care; no extra biopsies will take place outside of the routine clinical care. Tissue blocks will 
be cut and sections mounted on charged slides.   
 
Questionnaires (see Appendix).  
 
Food Diary. All participants will complete a 3-day food diary at baseline and 6 months. For men in the diet and 
exercise arm, the baseline food diary will be used together with information on the participant’s body weight, 
age and usual physical activity level to calculate usual energy intake using the Nutrition Data Systems for 
Research (NDS-R, University of Minnesota Nutrition Coordinating Center, version 2012). The study dietitian 
will then compute the average calorie reduction needed to meet study goals individualized for each participant. 
This calorie level will be explained to each participant as incorporated into the DPP curriculum.  At the end of 
the 6 month intervention, all participants will again complete a 3-day food diary to assess compliance.  
 
Physical Activity. Physical activity will be assessed at baseline and 6 months with a self-administered 
administered physical activity questionnaire, the Arizona Activity Frequency Questionnaire (AAFQ) (see 
appendix).  The AAFQ is a 59-item scannable questionnaire. The AAFQ has been validated in an eight-day 
doubly labeled water protocol to measure total energy expenditure.113 It has been upgraded with the 
compendium of physical activity codes and MET intensities.114 The AAFQ categorizes physical activity by 
leisure, recreational, household, and "other” activity categories. At randomization the AAFQ will assess 
participants’ baseline activity level. These baseline data will inform the types of exercises that the exercise 
physiologist will prescribe for each participant to meet the intervention physical activity goal of >150 
minutes/week of at least 700 kcal of physical activity.  
 
Lifestyle. Demographics, lifestyle habits and family history of prostate cancer will be assed at baseline only.  
Self-assessments of Lower Urinary track symptoms will be completed by participants at baseline, 3, 6, and 12 
months, and medication use will be completed at baseline, 6 and 12 months.. 
 

 
PALS Protocol V10 
16 
 
Quality of life. Self-administered quality of life (QOL) questionnaires will be  completed by participants at 
baseline, 3, 6 and 12 months.  We will assess the following: 1) anxiety related to PCa with the Memorial 
Anxiety Scale for Prostate Cancer (MAX-PC)115 ; 2) PCa-specific QOL with the Expanded Prostate Cancer 
Index (EPIC) Short Form116; and 3) generic QOL with the extensively validated EQ-5D-5L,118  
 
7.6 Outcomes 
Serum Biomarkers. 
Glucose.  Plasma glucose concentrations will be measured in duplicate by an automated glucose oxidase 
method using SVR glucose test (Behring Diagnostics) Glucose assays will be performed in the Diabetes 
Research Lab. 
 
Insulin.  Insulin concentration will be determined using an immunoenzymatic assay as per manufacturer’s 
instructions (Invitrogen).  Insulin assays will be performed in the Diabetes Research Lab. 
 
C-peptide.  C-peptide is the cleaved sub-unit of pro-insulin.  Levels will be quantified using a solid phase 
sandwich-type ELISA as per the manufacturer's protocol. The assay uses monoclonal antibodies directed 
against distinct epitopes of C-peptide (Beckman Coulter). C-peptide assays will be performed in Dr. Plymate’s 
lab. 
 
IGF-1. IGF-1 levels are quantified using a solid phase sandwich-type Enzyme Linked-Immuno-Sorbent Assay 
(ELISA) as per the manufacturer's protocol. The assay uses monoclonal antibodies directed against distinct 
epitopes of IGF-1 (R&D Systems). IGF-1 assays will be performed in Dr. Plymate’s lab. 
 
IGFBP-3. IGFBP-3 levels will be quantified using in vitro enzyme-linked immunoabsorbent assays following 
manufacturer’s protocol (RayBiotech).  IGFBP-3 assays will be performed in Dr. Plymate’s lab. 
 
Adiponectin. Adiponectin is quantified using in vitro enzyme-linked immunoabsorbent assays following 
manufacturer’s protocol (RayBiotech). Adiponectin assays will be performed in Dr. Plymate’s lab. 
 
Tissue Biomarkers.  pIR/IR, pIGF-IR/IGF-IR and pAKT/AKT protein expression will be assessed by IHC. 
Sections will be rehydrated and incubated with 3% H2O2, blocked with avidin/biotin blocking solution (Vector 
Laboratories Inc.) and then 5% goat serum. The sections will be incubated with either rabbit anti-IGF-1R 
(1:100; Santa Cruz Biotechnology), rabbit anti-phospho-IGF-1R (1:50; Abcam), mouse anti-insulin receptor 
(1:100; Santa Cruz Biotechnology), rabbit anti-phospho-insulin receptor (1:50; Abcam), rabbit anti-AKT, rabbit 
anti-phospho-AKT (1:50; Cell Signaling) or rabbit or mouse control IgG at the same concentration, washed and 
incubated with biotinylated secondary antibody (1:100; Santa Cruz Biotechnology), developed using the 
Vectastain ABC kit (Vector Laboratories Inc.) and stable DAB (Vector Laboratories), counterstained with 
hematoxylin, dehydrated, and mounted with Permount (Fisher).  All staining will be performed in Dr. Plymate’s 
laboratory.  A research pathologist will score the staining and be blinded to intervention arm.  Blind duplicates 
(5%) will be included. IHC staining intensity for each tissue section will be determined as follows: 0=no 
staining, 1=faint/present staining, 2=strong/intense staining. The percentage of staining cells is then estimated 
and a composite score calculated by multiplying mean intensity score and percent cells stained positively, and 
then dividing by number of cores taken.    
 
Pathologic Features. Pathologic findings will be recorded from the baseline and post-intervention biopsies, 
including Gleason grade, number of cores taken (12 core biopsy is standard); number of cores with cancer, 
and the percentage of each core involved with cancer.  Adverse pathology on surveillance biopsy will be 
indicated by any of the following:  a ≥ 1pt increase in Gleason grade, an increase to > 50% of any one core 
involved with cancer, and/or an increase in the number of cores involved with cancer. 
 
Intervention Sustainability. Participants will return to the clinic 6 months after the active intervention ends to 
assess whether they have continued to follow the lifestyle intervention on a long term basis. Additional 
measures of blood glucose, weight and quality of life will be assessed. 
 
Quality of Life Outcomes. 
Memorial Anxiety Scale for Prostate Cancer (MAX-PC). The MAX-PC will measure anxiety related to PCa. 

 
PALS Protocol V10 
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MAX-PC contains subscales that assess general PCa anxiety, anxiety regarding PSA level, and fear of PCa 
recurrence.  
 
EQ-5D-5L. The EQ-5D-5L is a generic QOL instrument. It is extensively validated and includes domains of 
mobility, self-care, activity level, pain/discomfort, and anxiety/depression.118 EQ-5D-5L responses can be used 
to calculate health state utilities for health economic analyses. 
 
Expanded Prostate Cancer Index (EPIC) Short Form. The EPIC will measures urinary and sexual function and 
bother.116 EPIC survey results are transformed into summary scores scaled from 0-100, with a higher score 
indicating better QOL.   
 
8 RISK / BENEFIT ASSESSMENT 
Potential Risks  
1. Participants may experience a little discomfort or have a temporary bruise from having blood drawn.  
Occasionally a participant may feel lightheaded or feel faint when having blood drawn.   
2. There is a small risk of medical problems occurring during or after exercise testing.  
3. The major risks of participating in this monitored program include fatigue, muscle soreness, and 
possible joint or skeletal injury or other unspecified medical events.  
4. Some participants may feel that coming to clinic visits (including the nutrition and physical activity 
curriculum training sessions) may be inconvenient and/or burdensome. 
5. Some participants may feel that the quality of life questionnaires about sexual and urinary function are 
embarrassing. 
6. . Other potential risks are associated with the collection of personally identifiable and health information 
from the subjects, and the potential for (a) psychological harm if the subject learns they have a disease 
or medical condition they were previously unaware of; and (b) a financial and/or employment risk, as a 
breach of confidential information could make it harder for the subject to find health insurance, life 
insurance, or employment. 
 
8.1 Protection Against Risks  
In the event that this research activity results in an injury, medical treatment will be available, including first aid, 
emergency treatment and follow up care, as needed.   All procedures involving blood collection, DXA, exercise 
testing and anthropometry will be done at the FHCRC Prevention Center Clinic.  Trained staff will be available 
to assist should a medical emergency occur.  An MD licensed in Washington State is the Prevention Center 
Director. Participants will be informed in the written consent form that payment for any such treatment must be 
provided by the individual and/or the individual’s insurance company.   
1. Blood draws are associated with certain physical risks such as bruising, fainting, or phlebitis. We will 
minimize these risks by making sure that all blood draws will be conducted by well-trained phlebotomists 
at the FHCRC Prevention Center. Subjects will be asked before the blood draw if they have experienced 
problems with blood draws in the past, and will be offered an opportunity to lie down during the procedure 
if they wish. In our experience, blood draws performed in this manner are well tolerated, and any side 
effects are minimal. Participants should be able to tolerate the loss of 10-20 cc of blood without negative 
health consequences.  
2. We will screen participants so that only participants with no known heart conditions will be tested.  
Persons with a serious heart condition will not be eligible for this study.  Participants may feel tired 
during or after the exercise test.  Recovery generally occurs within 30 minutes.  Participants will be 
continuously monitored and the test will be stopped at any time the participant asks (an emergency 
stop mechanism is available for subjects to use).  A technician with Advanced Cardiac Life Support 
(ACLS) certification will be present at all times.  In persons with an underlying heart condition, there is a 
slight (less than 1 chance in 1,000) risk of having a sudden heart attack and an even slighter (less than 
2 chances in 10,000) risk of sudden death. 
3. The risks associated with the exercise intervention will be reduced by proper warm-up/cool-down 
periods, instruction from a trained exercise specialist at a slow-paced progression which will be 
determined by the participants’ current fitness level and careful monitoring by an exercise specialist.  
The exercise specialists will teach participants techniques to minimize joint or muscle injury.  The risk of 
medical adverse events is greatly reduced by having all participants complete and pass an exercise 
test prior to entering the program. 

 
PALS Protocol V10 
18 
 
4. We will make every effort to schedule participants to come to the FHCRC at times that are convenient 
for them. This includes all sessions with the study dietitian and exercise specialist. 
5. Participants may choose to not answer any questions that make them feel uncomfortable or 
embarrassed. 
6. To minimize the risk of breach of confidentiality s, we will make sure that all health information and 
records are labeled with a study identification number and initials. Personally identifiable information will 
be kept physically separate from any health information, and only one computer file will link the study 
identification number to the personally identifiable information such as name, address, telephone 
number, or e-mail address. Only the PI, study coordinator and study staff will have access to this 
password-protected file. 
7. In the extremely rare and unexpected event of an emergency while subjects are attending to the Fred 
Hutch Prevention Center, a staff member and study staff will be on hand at all times throughout the visit 
to call for help as needed, and a physician will be on call. For complications arising among subjects that 
have left clinical facilities, subjects will be provided with the telephone numbers of the PI and the study 
coordinator, and will be encouraged to call with any problems at any time. Participants will be encouraged 
to call 911 in case a life-threatening emergency occurs; such an event is unlikely, and it would be 
extremely unlikely to be related to the study procedures. 
 
8.2 Potential Benefits 
Participants will be paid $100 upon completion of the study to help compensate for time and travel.   
 
Participants will receive small study-branded gifts during the study in appreciation of their participation in the 
study.  Below is the plan for distribution of these items: 
 
 
Intervention  
Control 
PALS squeeze apple and gel pack Clinic visit 1 
Clinic visit 4 
PALS hat 
Clinic visit 3 
Clinic visit 4 
 
The data generated from this proposed research study will provide essential information for the scientific 
community involved in making recommendations for optimal diet and physical activity regimens for men with 
prostate cancer undergoing active surveillance.  This is an important area of research because if lifestyle 
factors can be shown to improve measures of glucose control, energy balance and subsequent health of 
prostate cancer patients, then it will have far reaching implications for the thousands of men undergoing active 
surveillance – hopefully demonstrating that lifestyle changes can prevent more invasive and life-altering 
procedures (i.e. radical prostatectomy). Thus, with minimal risk to study participants, we will generate data that 
will be beneficial to men with localized prostate cancer.   
 
 
Overall, using this proposed study design, we have attempted to minimize any potential risks to study 
participants, whilst maximizing the amount of important scientific data that can be generated and ultimately 
shared with the scientific community and the general public.  
 
8.3 Medical Monitoring 
Jonathan Wright should be contacted directly at these numbers to report medical concerns or questions 
regarding safety. 
Phone: 206-579-8922 
Pager : 206-340-5071   
 
9 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
 
9.1 Early Discontinuation of Study Treatment  
A subject may be discontinued from study treatment at any time if the subject, the investigator, or the 
Investigator feels that it is not in the subject’s best interest to continue.  The following is a list of possible 
reasons for early discontinuation of study treatment: 
• 
Participant decision 
• 
Adverse event  
• 
Protocol violation  
• 
Death 

 
PALS Protocol V10 
19 
 
If a subject is discontinued from treatment due to a related adverse event, the subject will be followed and 
treated by the Investigator until the abnormal parameter or symptom has resolved or stabilized.   
 
9.2 Withdrawal of Subjects from the Study 
All subjects are free to withdraw from participation at any time, for any reason, specified or unspecified, and 
without prejudice.  This may include subjects who withdraw from study treatment early and who decline to 
continue to come in for remaining follow-up visits or it may include subjects who completed treatment and 
decline to come in for remaining follow up visits.   
 
Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals.  The reason 
for the subject’s withdrawal from the study will be specified in the subject’s source documents.  Subjects who 
withdraw from the study should be encouraged to come in for a final visit.  
 
9.3 Replacement of Subjects 
Subjects who withdraw from the study will not be replaced.   
 
10 DATA SAFETY MONITORING 
Monitoring for data integrity and safety will be the responsibility of the investigators, the FHCRC Institutional 
Review Board, and a study Data and Safety Monitoring Committee, which will be established prior to recruiting 
any participants. The following will be included in the monitoring plan for the DSMC: safety of participants and 
volunteers, reporting of adverse events, validity and integrity of the data, enrollment rate relative to 
expectation, retention of participants and adherence to protocol, and data completeness.  
 
10.1 Adverse Event Reporting 
Adverse events for this study are expected to be very minimal since the diet and physical activity intervention 
activities have been safely used in many precious intervention studies without incident. Despite the low risk for 
adverse events, all study staff and investigators will carefully monitor and document any adverse events, which 
could include the following: bruising or fainting during the blood draws, injury from using the exercise 
equipment in the PHS Exercise Laboratory, injury from exercise at home (such as a fall) or a medical event 
during the treadmill test. All such adverse events will be reported to the Principal Investigator within 24 hours. 
Adverse event reporting to the IRO will occur within the required period of time depending on the nature and 
severity of the event. 
 
10.2 Data Safety Monitoring Committee 
The initial meeting of the DSMC will have primary focus on a review of the proposed study protocol and 
determination of stopping rules. Due to the low-risk nature of the intervention study, we expect the DSMC to 
review study progress each year. Informal rather than formal interim analyses will be performed, since the 
primary endpoints will not be determined until the end of the study. For each DSMC meeting, statistical reports 
will be prepared four weeks in advance. Tabulations of the distributions of the important variables will be 
inspected to detect outlying values. After the file has been thoroughly checked, tables and graphs of the data 
will be made and compared with the previous report. This check will identify major changes in the data that 
might be indicative of computational or processing errors. Tables will include data presented by study arm. 
These reports will include adverse events and participant drop-outs. The report will be mailed to members of 
the DSMC two weeks prior to the meeting. 
 
11 STATISTICAL METHODS AND CONSIDERATIONS 
Primary Aim 1. The primary analysis will compare change in fasting glucose level relative to baseline between 
the intervention and control arms. Global assessment of intervention effects will be evaluated using a two-
sided t-test or Wilcoxon rank sum test if normality of the measurement is questionable (as determined by QQ-
normal plots). Further analysis will quantify effects of patient age, BMI and other body composition measures 
on change in fasting glucose using linear regression. Differential effects between intervention and control arms 
will be quantified using interaction terms. All analyses will compare effects based on intention-to-treat.  

 
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Primary Aim 2.  Additional analyses will compare changes in levels of C-peptide, insulin, IGF-1, IGF-BP3, and 
adiponectin relative to baseline measurements between the intervention and control arms. As in Aim 1, we will 
compare global and subgroup effects based on intention-to-treat analyses.  
 
Primary Aim 3. We will test whether the change in expression of IR, IGF-1R, and AKT on prostate cancer 
epithelial cells from follow-up surveillance biopsy (6 months post-randomization) relative to ‘baseline’ (biopsy 
~6 months prior to randomization, see Fig. 3) differs between intervention and control arms. Global 
assessment of intervention effects will be evaluated using a two-sided t-test (or Wilcoxon rank sum test). 
Linear regression will be used to assess associations of IR, IGF-1R, and AKT expression with systemic 
measures of glycemic control at 6 months.  Exploratory analyses will also evaluate associations between 
adverse pathology, biomarkers of glycemic control and IR/IGF-1R/AKT expression.  
 
Primary Aim 4. We will test whether PCa patients randomized to the intervention arm are able to sustain the 
beneficial changes in weight and glucose regulation an additional 6 months after the active intervention. We 
will follow the DPP research group characterization of sustained weight loss as maintenance of a 7% reduction 
in weight17 and sustained glucose regulation as maintenance within 5% of 6-month levels. Because not all 
participants will achieve 7% weight loss at 6 months, we will look in the subset of participants who did and did 
not achieve this goal both separately and combined.  A one-sample test of proportions will be used to 
determine whether the proportion of participants that are able to sustain lifestyle changes differs from zero.   
 
Secondary Aim 1.  We will test whether the change in HRQOL, namely urinary and sexual QOL and bother, 
relative to baseline, differs between the intervention and control arms. Intervention effects will be evaluated 
using a two-sided t-test, and models will be adjusted for age, SES, marital status, and baseline BMI.  The 
minimally important difference for the HRQOL instruments will be a mean difference of at least 5 points. 
 
Secondary Aim 2. We will use a two-sample 
test of proportions to determine whether the 
proportion of participants with adverse 
pathology (Gleason upgrading, increase in 
number of positive cores, cores>50% positive) 
on follow-up surveillance biopsy differs 
between intervention and control arms.  
 
11.1 Sample Size and Randomization 
Our power calculations give the minimally 
detectable intervention effects for endpoints in 
Primary Specific Aims, setting two-sided alpha 
error at 5% and power at 80%. We have set a 
sample size of 100 in each of the intervention 
and control arms, based both on our overall 
evaluation of minimum detectable differences 
across the range of study endpoints and on a 
reasonable estimate of the number of men we can recruit. The sample size allows for a drop-out rate of 5%, 
and power calculations assume correlations of 0.70 between baseline and follow-up measures.   
  Table 4 gives the minimally detectable differences between treatment arms for serum and tissue biomarkers 
of glucose regulation.  We have used a variety of data sources to complete these tables, attempting whenever 
possible to use data generated from human studies. For serum biomarkers of glucose regulation, we use data 
from our own pilot study and the PCPT,133, 134 and for tissue expression of IR/IGF-R1 and AKT we use data 
from Cox et al.15 The minimum detectable intervention effects range from 5.3% for serum glucose to 33.1% for 
insulin. Previous studies have shown that dietary change can induce the following intervention effects: 7% for 
fasting glucose, 40% for insulin and 2.2 % for adiponectin.135 37 Our pilot study based on the DPP 
demonstrated an intervention effect of ↑9.7% for IGFBP3, ↓38% for insulin and ↓14% for C- peptide. Based on 
these observations, we will have good power to detect changes in all serum biomarkers of glucose regulation, 
consistent with those seen in other human intervention studies. 
   For expression of IR, IGF-1R and AKT on surveillance prostate biopsies, the minimum detectable 
intervention effects are 29.2%, 46.3% and 26.5%, respectively. Previous experimental studies in animals have 

 
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shown the following results: a low-fat/low-carbohydrate diet can reduce expression of IR; low-fat, or caloric 
restriction diets can reduce expression of IGF-1R by 40%; and low-fat and/or low-carbohydrate and no 
carbohydrate diets reduce expression of AKT by up to 60%.7, 59-61 Based on these observations, we have very 
good power to detect changes in IR, IGF-1R and AKT expression on epithelial cells from PCa biopsies. 
 
Table 5 indicates the minimal detectable 
differences in change, and the power to 
detect a 5-point change between arms for 
each QOL tool. For most HRQOL 
assessments, we have good power to 
detect the designated minimally important 
differences (5-points) in QOL scores.  
Analyses of the association between the 
intervention and adverse pathology are 
exploratory in nature; thus, power is 
limited for this endpoint.  Based on our clinical experience, approximately 25% of patients have ‘adverse 
pathology’ on their follow-up biopsy.  Given the sample size in this study, we will be able to detect a 15% 
difference between intervention and control arms in the proportion of participants with adverse pathology on 
follow-up biopsy. 
 
12 DATA COLLECTION, RETENTION AND CLINICAL MONITORING 
 
12.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents designed to record all 
observations and other pertinent data for each subject who signs consent or treated with the study intervention 
or enrolled in the study.   
 
Study personnel will enter data from source documents corresponding to a subject’s visit into the protocol-
specific electronic study forms OR study database when the information corresponding to that visit is available.  
Subjects will not be identified by name in the study database or on any study documents to be collected, but 
will be identified by a site number, subject number and initials. 
 
The study staff is responsible for all information collected on subjects enrolled in this study.  All data collected 
during the course of this study must be reviewed and verified for completeness and accuracy by the study 
staff.  A copy of the CRF will remain in the study’s files at the completion of the study. 
 
12.2 Data Management Procedures 
For this proposal we will adhere to all federal requirements to submit relevant publications to PubMed Central. 
We will present results from this study at national and international scientific meetings. We will collaborate with 
other investigators, both within and external to FHCRC to share data and knowledge as required by the NIH. 
For outside investigators wishing to use the data generated from this study, we will supply de-identified data. 
These data will be available approximately 12 months after the close of the intervention and after the 
submission of the primary manuscripts from this study. The costs for data transfer, including generation of data 
dictionaries and other documentation will be the responsibility of the investigator requesting to use the data. 
We are cognizant of and completely support the need to share data and resources with other investigators to 
maximize the NIH investment and prevent duplication of efforts. We welcome collaborations with outside 
investigators and those wishing to collaborate and use data will be asked to contact Dr. Wright directly. 
 
12.3 Archival of Data 
Databases are maintained with nightly backups and security updates.   
 
12.4 Availability and Retention of Investigational Records 
The study staff must make study data accessible to the IRB upon request.  A file for each subject must be 
maintained that includes the signed Informed Consent, HIPAA Authorization and Assent Form and copies of all 
source documentation related to that subject.  The study staff must ensure the reliability and availability of 
source documents from which the information on the CRF was derived. 
Table 5. Power and MDD for QOL 
QOL  tool 
Baseline  
Mean (SD) 
Mean  
MDD 
Power to detect  
5-point 
difference  
in score 
MAX-PC 
14 (9)136 
4.0 
97%  
EQ-5D 
86 (15)137 
6.7 
63% 
EPIC-Urinary bother 
86 (14)138 
6.3 
69% 
EPIC-Sexual bother 
63 (23)139 
10.3 
32% 

 
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All study documents (e.g., patient files, signed informed consent forms, copies of CRFs, Essential Document 
and Study Reference Binders) must be kept secured.   
 
12.5 Monitoring 
Monitoring and/or auditing of this study will be performed by Fred Hutchinson Cancer Research Center 
according to the Institutional Data and Safety Monitoring Plan (DSMP).  
 
12.6 Subject Confidentiality 
In order to maintain subject confidentiality, only a subject number and subject initials will identify all study 
subjects on CRFs and other documentation submitted to the IRB. 
 
12.7 Protocol Amendments 
Any amendment to the protocol will be written by the Investigator. Protocol amendments cannot be 
implemented without prior written IRB approval except as necessary to eliminate immediate safety hazards to 
patients.  A protocol amendment intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, provided the IRB is notified within five working days. 
 
12.8 Institutional Review Boards  
The protocol and consent form will be reviewed and approved by the IRB prior to study initiation. Serious 
adverse events regardless of causality will be reported to the IRB in accordance with the standard operating 
procedures and policies of the IRB, and the Investigator will keep the IRB informed as to the progress of the 
study. The Investigator will obtain assurance of IRB/IEC compliance with regulations. 
 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol amendments, 
Investigator’s Brochure, consent forms, information concerning patient recruitment, payment or compensation 
procedures, or other pertinent information) will be submitted to the IRB/IEC. The IRB/IECs written 
unconditional approval of the study protocol and the informed consent form will be in the possession of the PI 
before the study is initiated.  This approval must refer to the study by exact protocol title and number and 
should identify the documents reviewed and the date of review. 
 
Protocol and/or informed consent modifications or changes may not be initiated without prior written IRB/IEC 
approval except when necessary to eliminate immediate hazards to the patients or when the change(s) 
involves only logistical or administrative aspects of the study.  Such modifications will be submitted to the 
IRB/IEC and written verification that the modification was submitted and subsequently approved should be 
obtained.   
 
The IRB/IEC must be informed of revisions to other documents originally submitted for review; serious and/or 
unexpected adverse experiences occurring during the study in accordance with the standard operating 
procedures and policies of the IRB; new information that may affect adversely the safety of the patients of the 
conduct of the study; an annual update and/or request for re-approval; and when the study has been 
completed. 
 
12.9 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US Code of 
Federal Regulations for Protection of Human Subjects  the Health Insurance Portability and Accountability Act 
(HIPAA, if applicable), and local regulations. 
 
A properly executed, written, informed consent will be obtained from each subject prior to entering the subject 
into the trial.  Information should be given in both oral and written form and subjects must be given ample 
opportunity to inquire about details of the study.  If appropriate and required by the local IRB/IEC, assent from 
the subject will also be obtained.  If a subject is unable to sign the informed consent form (ICF) and the HIPAA 
authorization, a legal representative may sign for the subject.   A copy of the signed consent form (and assent) 
will be given to the subject and the original will be maintained with the subject’s records. 
 
During the course of the study, if modifications are made to the consent form that impact the subject, the 
subject will be re-consented as described above.  

 
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12.10 Publications  
The publication or presentation of any study results shall comply with all applicable privacy laws, including, but 
not limited to, the Health Insurance Portability and Accountability Act of 1996.  
 
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