TRIPLE-A PILOT: Actively Intercepting ADT-Induced Metabolic Aberrations in Newly Diagnosed Prostate Cancer
Phase: NA
Conditions: Localized Prostate Carcinoma, Prostate Adenocarcinoma
Sponsor: Fred Hutchinson Cancer Center

 
 
Official Title 
TRIPLE-A PILOT: Actively intercepting ADT-induced 
metabolic aberrations in newly diagnosed prostate cancer 
NCT Number 
NCT04870515 
Document Type 
Protocol and Statistical Analysis Plan 
Document Date 
4/3/2024 
 
 

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Clinical Research Protocol 
TRIPLE-A PILOT: Actively intercepting ADT-induced metabolic aberrations in newly diagnosed prostate 
cancer 
RG Number: 
1121348 
Version Number: 
5b 
Version Date: 
May 06, 2022 
Development Phase: 
NA 
Indication 
Androgen Deprivation Therapy + RT, prostate cancer 
Study sites 
Fred Hutchinson Cancer Center 
Veterans Affairs Puget Sound Health Care System 
University of Washington 
Funding Organization: 
National Cancer Institute, SPORE Pilot P50 CA097186-18 
Principal Investigators: 
Marian L. Neuhouser, PhD (FHCRC) 
Jonathan Wright, MD (VAPSHCS) 
 
 
 
Fred Hutch IRB
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TABLE OF CONTENTS 
1 
BACKGROUND 
5 
2 
STUDY DESIGN 
5 
2.1
STUDY OVERVIEW 
5 
3 
ELIGIBILITY CRITERIA 
6 
3.1
INCLUSION CRITERIA 
6 
3.2
EXCLUSION CRITERIA 
6 
4 
STUDY PROCEDURES 
6 
4.1
RECRUITMENT 
6 
4.2
ORIENTATION AND CONSENT 
7 
4.3
CLINIC VISIT 1 
7 
4.4
MID STUDY VISIT 
7 
4.5
CLINIC VISIT 2 
7 
4.6
CONSENTS 
7 
4.7
INTERVENTION 
8 
4.8
CONTROLS 
8 
4.9
COMPLIANCE 
8 
5 
DATA COLLECTION 
9 
5.1
OUTCOMES 
9 
5.1.1 BLOOD BIOMARKERS 
9 
5.1.2 BODY COMPOSITION AND ANTHROPOMETRICS 
9 
5.1.3 PATIENT REPORTED OUTCOMES 
9 
6 
POTENTIAL RISKS AND BENEFITS 
10 
6.1
POTENTIAL RISKS 
10 
6.2
PROTECTION AGAINST RISKS 
10 
6.3
  POTENTIAL BENEFITS 
11 
6.4
  COMPENSATION 
11 
6.5
ALTERNATIVES 
11 
7 
DATA ANALYSIS PLAN 
11 
7.1
SAMPLE SIZE 
11 
8 
DATA SAFETY MONITORING PLAN 
11 
8.1
ADVERSE EVENT REPORTING 
12 
8.2
PLAN FOR SAFETY REVIEW 
12 
8.3
PLAN FOR ANNUAL REPORTING 
12 
8.4
MONITORING FOR DATA INTEGRITY AND SAFETY 
12 
9 
REFERENCES 
13 
 
 
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Protocol Synopsis 
TITLE 
Triple-A Pilot Study 
SPONSOR 
P50 CA097186-18 
FUNDING 
ORGANIZATION 
National Cancer Institute  
NUMBER OF SITES 
2: Fred Hutchinson Cancer Center, Veterans Affairs Puget Sound Healthcare 
System 
RATIONALE 
National Guidelines specify that one treatment option for newly diagnosed 
intermediate and high-risk prostate cancer patients is external beam radiation 
therapy (RT) plus 6-24 months of concomitant androgen deprivation therapy 
(ADT). This standard of care combination therapy demonstrates significant 
survival benefits. ADT effectively slows the growth of prostate cancer cells, 
thereby enhancing the therapeutic effectiveness of RT. Despite the clinical gains, 
ADT leads to an array of side effects including insulin resistance, dyslipidemia, 
weight gain, increased visceral fat mass coupled with increased muscle 
wasting/sarcopenia, and quality of life deterioration. These metabolic and 
physiologic changes begin rapidly within the first few months of ADT use and 
place patients at increased risk of new co-morbidities such as diabetes, 
cerebrovascular disease, coronary artery disease, venous thromboembolism and 
sudden cardiac death. Identifying translational approaches to attenuate these 
ADT metabolic aberrations have not been rigorously tested, leaving a gap in 
determining patient treatment options. This proposal pilot tests a comprehensive 
nutrition and physical activity intervention initiated concurrently with RT+ADT in 
newly diagnosed intermediate and high-risk prostate cancer patients to determine 
whether the intervention intercepts the abrupt metabolic and physiologic changes 
caused by ADT.  
STUDY DESIGN 
This is a pilot randomized controlled trial to investigate the effects of a 6-month 
nutrition and physical activity intervention on blood measures of lipids and insulin 
resistance, and anthropometry, body composition, and patient reported outcomes 
in newly diagnosed intermediate and high-risk prostate cancer patients 
undergoing RT+ADT. 
PRIMARY OBJECTIVE 
The study has the following primary specific aims: 
1. Examine intervention effects on ADT-induced insulin resistance measured 
by HOMA-IR; 
2. Examine intervention effects on ADT-induced changes in anthropometry 
and body composition;  
SECONDARY 
OBJECTIVES 
Exploratory aims: 
1. Explore intervention effects on blood lipids (triglycerides and total, HDL- 
and LDL-cholesterol) and hemoglobin A1c; 
2. Explore intervention effects on patient reported outcomes. 
3. Explore intervention effects on the gut microbiome 
NUMBER OF 
SUBJECTS 
20 
SUBJECT SELECTION 
CRITERIA:  
Inclusion Criteria 
 
Inclusion Criteria: 
1. Males aged 40or older with newly diagnosed D’Amico risk category 
intermediate or high-risk prostate cancer; 
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2. Primary treatment is external beam radiation therapy with androgen 
deprivation therapy [Zoladex, Lupron, Degarelix, and other luteinizing
hormone-releasing hormone (LHRH)-directed therapies]; 
3. Physically able to undertake an exercise program. 
SUBJECT SELECTION 
CRITERIA:  
Exclusion Criteria 
Exclusion Criteria: 
1. Advanced, metastatic disease;  
2. Planning to join a commercial/structured diet change or fitness program;  
3. Have significant pre-existing T2D (poor glycemic control while on medication, 
Hemoglobin A1c ≥10) or significant pre-existing CVD (myocardial infarction 
or stroke within prior six months); 
4. Physician confirmed cognitive impairment or alcohol/narcotic abuse; 
DURATION OF 
SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
Subjects will participate in the study for 6 months. 
The total duration of the study is expected to be 1.5 years 
PRIMARY ENPOINTS 
 
Primary Aim 1: Compare intervention effect HOMA-IR levels relative to baseline 
in intervention and control participants.  
Primary Aim 2: Compare intervention effect on weight, waist circumference, fat 
mass and lean mass relative to baseline in intervention and control participants. 
SECONDARY 
ENDPOINTS 
Exploratory Aims.  We will explore the intervention effect on blood lipids and 
HbA1c, and whether the intervention induces patient reported outcomes (PROs)- 
specifically quality of life and fatigue differences between the intervention and 
control arms  
STATISTICS 
Primary Analysis Plan 
Linear regression models will test the intervention effects on ADT-induced
changes in HOMA-IR (Aim 1), body composition (Aim 2) and metabolic 
biomarkers, PRO measures and gut microbiome (Exploratory aims). Separate 
models will be fit for each outcome measure, with an indicator variable for study 
arm (intervention/control) and adjustment for the respective baseline metabolic 
biomarker, body composition or PRO measure. Further adjustment for 
biomarkers that may have shared biology (i.e., total and LDL cholesterol) and for 
medication use that could affect biomarker concentrations will be considered. We 
expect most potential confounding variables will be evenly distributed between 
arms at randomization, but this assumption will be checked prior to analysis.  
Analyses will follow an intent-to-treat approach.  
Rationale for Number 
of Subjects 
We have set a sample size of 10 in each of the intervention and control arms for 
this pilot study, which will provide preliminary data to support an R01. 
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1.
BACKGROUND 
Prostate cancer represents 19% of all new cancers in men with an age-adjusted incidence rate of 
109/100,000.1 Many prostate cancers are low risk, localized tumors where the 5-year relative survival rate is 
99% even without treatment.1 However, at least a third of prostate cancers present at diagnosis as 
intermediate to high-risk disease and a 2018 report noted a recent increase in incidence of these more 
aggressive tumors.2,3 The National Comprehensive Cancer Network (NCCN)4 Guidelines, the American 
Urological Association (AUA), the American Society for Radiation Oncology (ASTRO) and the Society of 
Urologic Oncology (SUO) all specify that these patients should 
receive curative-intent, multimodal treatment consisting of 
radiation therapy (RT) + at least six months of ADT.5-8 The 
RT+ADT combination therapy gives clinically important 
improvements in biochemical-free survival and disease-free 
survival over RT alone.9,10 
ADT effectively slows the growth of prostate cancer cells, 
thereby enhancing therapeutic effectiveness of RT.4,5,11 Despite 
clinical gains, ADT induces rapid shifts in metabolic health 
including dyslipidemia, insulin resistance, and shifts in body 
composition favoring fat mass deposition and lean mass loss.12-
28 Further, many patients report quality of life deterioration, 
particularly from increased fatigue and loss of vitality.29-32 These 
ADT metabolic changes occur rapidly, within 2-3 months of 
starting ADT33 and persist even after cessation of ADT.34,35 
Table 1 summarizes these consistently observed changes from observational studies and meta analyses.12,15-
17,19,30,36-40 Nearly all patients, even those with pre-ADT healthy weight and blood profiles, will experience some 
of these shifts, demonstrating a need for intervention.   
Our overall research and clinical goals are to intercept or prevent the constellation of dyslipidemia, insulin 
resistance, weight gain and body composition shifts in these patients. These conditions are harder to treat than 
prevent since the body quickly becomes refractory to weight loss after a large gain has occurred. A small 
number of RCTs tested resistance or strength exercise during ADT and yielded modest improvements in 
overall muscle mass, fitness, quality of life and fatigue.41-44 However, most have been small, pilot studies45 and 
a lack of rigor may have contributed to inconsistent findings. No large trials have tested physical activity 
together with a dietary pattern (e.g., the DASH diet) shown to decrease cardiovascular disease and its 
antecedent risk factors that commonly develops in these patients. The AUA acknowledges the ADT-induced 
adverse effects but there are no proactive prevention guidelines and early intervention is not part of standard of 
care clinical protocols for patients on ADT.46 This represents an important gap that we will address first in this 
pilot followed by a fully powered RCT in an R01. 
The study has the following primary specific aims: 
1. Examine intervention effects on ADT-induced insulin resistance measured by HOMA-IR; 
2. Examine intervention effects on ADT-induced changes in anthropometry (weight and waist 
circumference) and body composition (fat and lean mass). 
Exploratory aims: 
1. To explore intervention effects on blood lipids (total, HDL- and LDL-cholesterol) and HbA1c; 
2. To explore intervention effects on patient reported outcomes; 
3. To explore intervention effects on gut microbiome. 
 
2.
STUDY DESIGN 
2.1 Overview 
This is a pilot randomized controlled trial to investigate the effects of a 6-month nutrition and physical activity 
intervention on blood measures of lipids and insulin resistance, and anthropometry, body composition, and 
patient reported outcomes in n=20 newly diagnosed intermediate and high-risk prostate cancer patients 
Table 1. Expected changes in blood biomarker 
and body composition measures due to initiation 
of ADT 
Measure 
% change from 
ADT initiation 
Blood biomarkers 
HbA1c, % 
 + 1.3 - 4.7% 
HOMA-IR 
+11.6% 
Total cholesterol, mg/dl 
+ 0 - 9.0% 
LDL cholesterol, mg/dl 
+0 - 7.3% 
HDL cholesterol, mg/dl 
+7.6 - 11.3% 
Triglycerides, mg/dl 
+13.3 - 36.0% 
Body composition markers 
Weight, kg 
+1.8 - 2.4% 
Waist circumference, cm 
+1.4 - 3.9% 
Total fat mass, kg 
+11.0 - 12.0% 
Total lean mass, kg 
-2.5 - (-3.6)% 
 
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undergoing RT+ADT. Patients will be randomized to either:  
1. Diet and physical activity intervention (modified DASH diet and aerobic activity and resistance training); 
or  
2. Control (oral and written information based on general U.S. dietary and physical activity guidelines). 
We will recruit and enroll patients from the 
VAPSHCS and UW prostate cancer clinics. 
The study design is a six-month single blind, 
parallel-arm, randomized clinical trial with 
equal numbers in the intervention (n=10) and 
control (n=10) arms (Figure 1). Study 
activities in Figure 1 take place at both the 
Fred Hutch Prevention Center and at the 
VAPSHCS. The intervention will be delivered 
by 10 in-person or virtual sessions with a 
Registered Dietitian, and on the same day, 
individual sessions with an Exercise 
Physiologist plus optional drop-in exercise 
sessions. We have already established procedures for safe participant contact and procedures during COVID-
19. Data collection includes self-reported lifestyle habits (diet, physical activity), objective measures of 
anthropometry/body composition (height, weight, waist circumference, dual x-ray absorptiometry (DXA)), 
biologic (blood biomarkers) and Patient Reported Outcomes (Health-Related Quality of Life and fatigue).  
3. 
ELIGIBILITY CRITERIA 
Subjects with a diagnosis of intermediate or high risk localized prostate cancer who meet all of the inclusion 
and none of the exclusion criteria will be eligible for participation in this study.  All races/ethnicities are eligible 
to participate.   
3.1 Inclusion Criteria 
1. Age ≥ 40 years; 
2. Histologically confirmed adenocarcinoma of the prostate, (D’Amico risk category intermediate or high
risk, localized or locoregional);  
3. Primary treatment is RT + ADT [Zoladex, Lupron, Degarelix, and other luteinizing hormone-releasing 
hormone (LHRH)-directed therapies] with standard RT dose and fractionation (anti-androgen 
monotherapy will not be allowed); 
4. Physically able to undertake an exercise program 
 
3.2 Exclusion Criteria 
1. Advanced, metastatic disease;  
2. Planning to join a commercial/structured diet change or fitness program;  
3. Have significant pre-existing T2D (poor glycemic control while on medication, defined as Hemoglobin 
A1c of ≥10 within the prior 12 months) or significant pre-existing CVD (myocardial infarction or stroke 
within prior six months); 
4. Physician confirmed cognitive impairment or alcohol/narcotic abuse; 
4.
STUDY PROCEDURES  
4.1 
Recruitment  
UW:  Clinic study staff will identify potential eligible participants from the UW urology clinic. Clinic study staff 
will pre-screen men to determine medical eligibility as listed in section 3. Recruitment efforts will be targeted 
towards medically eligible men living in the greater Seattle area. All of our recruitment messages and 
brochures will outline the parameters of the project and will stress the time commitment necessary in order to 
participate.  Clinic study staff will approach eligible prospective participants during a clinic visit to tell them 
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about the study.  Interested men will be asked to sign consent (Triple-A Consent for Contact UW_V1) to allow 
their contact information to be sent to Fred Hutch for final eligibility screening and scheduling. Fred Hutch study 
staff will contact potential participants by phone to provide additional information about the study, answer 
question and confirm eligibility (Triple-A ScreeningScript_V1).  Interested participants will be scheduled for 
Clinic Visit 1 and asked to provide verbal consent to complete pre-visit 1 study activities (Triple-
A_VerbalConsentScriptPreStudy_V1). Clinic Visit 1 will be scheduled to occur at Fred Hutch approximately 4 
weeks of the first scheduled ADT dose. Once consented, participants will be mailed instructions to prepare for 
Clinic Visit 1 (Triple-A CV1 instructions, Triple-A Stool collection), a stool collection kit, Serving Size Booklet 
(Serving Size Booklet) and Food Record (Food Record) to complete prior to Clinic Visit 1.  
VAPSHCS:  Clinic study staff will identify potential eligible participants from the VA urology clinic. Clinic study 
staff will pre-screen men to determine medical eligibility as listed in section 3. Recruitment efforts will be 
targeted towards medically eligible men living in the greater Seattle area. Given the high proportion of minority 
patients at the VAPSHCS, we will make every effort to recruit eligible minority patients into the study. All of our 
recruitment messages and brochures will outline the parameters of the project and will stress the time 
commitment necessary in order to participate.  Clinic study staff will approach eligible prospective participants 
either during a clinic visit or by phone to tell them about the study and confirm their eligibility.  Interested men 
will be scheduled for Clinic visit 1 and study staff will ask potential participants to provide verbal consent to 
complete pre-visit 1 study activities. Clinic visit 1 will be scheduled to occur at the VA within approximately 4 
weeks of the first scheduled ADT dose.  Once consented, participants will be provided (or mailed) instructions 
to prepare for Clinic Visit 1, a stool collection kit, Serving Size Booklet and Food Record to complete prior to 
Clinic Visit 1. 
4.2 
Clinic Visit 1 
UW (at Fred Hutch):  Fred Hutch study staff will review study procedures and confirm interest in participating 
in the study.  Participant will be given the opportunity to ask questions and interested participants will sign the 
UW study consent and HIPAA(Triple-A UW consent; Triple-A HIPAA). Study staff will collect the participants’ 
completed 4-day food record and stool sample (completed at home in preparation for Clinic Visit 1), measure 
height, weight and waist circumference, and collect fasting blood. In addition, participants will complete 
questionnaires on demographics/lifestyle characteristics (Triple-A demographic questionnaire), physical activity 
(Triple-A PA questionnaire) and quality of life/fatigue (Triple-A QOL questionnaire). Clinic staff will conduct a 
DXA scan and participants will be randomly assigned (via computerized program located within the Triple-A 
REDCap database) to either the intervention or control arm. After Clinic Visit 1 procedures are complete, 
participants randomized to the control arm will receive general healthy lifestyle instruction (Triple-A Control 
lifestyle instruction), while participants assigned to the intervention arm will receive an overview of the 
intervention goals (Triple-A Nutrition Intervention overview) and be scheduled for the first intervention session. 
VAPSHCS (at VAPSHCS): VA study staff will review study procedures and confirm interest in participating in 
the study.  Participant will be given the opportunity to ask questions and interested participants will sign the VA 
study consent and HIPAA. Study staff will collect the participants’ completed 4-day food record and stool 
sample (completed at home in preparation for Clinic Visit 1), measure height, weight and waist circumference, 
and collect fasting blood. In addition, participants will complete questionnaires on demographics/lifestyle 
characteristics, physical activity and quality of life/fatigue. Clinic staff will conduct a DXA scan and participants 
will be randomly assigned (via a computerized program) to either the intervention or control arm. To randomize 
participants, study staff will use a computerized program located within the Triple-A REDCap database.   
After Clinic Visit 1 procedures are complete, participants randomized to the control arm will receive general 
healthy lifestyle instruction. This instruction will be provided via teleconference by the Fred Hutch study 
nutritionist.  Participants assigned to the intervention arm will receive an overview of the intervention goals 
(Triple-A Nutrition Intervention_Orientation) and be scheduled for the first intervention session (which will occur 
at Fred Hutch). If requested, a participant may receive a copy of their DEXA scan results.   
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4.3 
Mid-Study Questionnaire (both sites) 
At the mid-point of study (month 3), participants will be asked to complete the quality of life/fatigue 
questionnaire (Triple A QOL questionnaire).  This questionnaire can be completed remotely via a web-survey 
link, on paper (via mail) or in person (if the study mid-point coincides with the participants’ second treatment 
visit or a nutrition intervention visit)..  
4.4 
Clinic Visit 2  
UW (at Fred Hutch): Clinic Visit 2 will occur at the end of the study, 6 months after Clinic Visit 1. In preparation 
for Clinic Visit 2, participants will be mailed (or given) the end of study Food Record (Food Record, Serving 
size booklet), stool collection kit, and instructions (Triple-A CV2 instructions, Triple-A Stool collection) to 
prepare for the visit.  Participants will be asked to complete the Food Record and collect a small amount of 
stool, and bring both to Clinic Visit 2. At Clinic Visit 2, study staff will measure weight and waist circumference, 
conduct a DXA scan and collect fasting blood. Participants will complete the final questionnaires on physical 
activity and quality of life (Triple-A QOL questionnaire, Triple-A PA questionnaire), and will complete an End of 
Study questionnaire (Triple-A Exit Survey).  Participants assigned to the control arm will also be given a copy 
all of the intervention materials and the study dietitian will review the materials. 
VAPSHCS (at VAPSHCS): Clinic Visit 2 will occur at the end of the study, 6 months after Clinic Visit 1. In 
preparation for Clinic Visit 2, participants will be mailed (or given) the end of study Food Record, stool 
collection kit, and instructions to prepare for the visit.  Participants will be asked to complete the Food Record 
and bring it to Clinic Visit 2. At Clinic Visit 2, study staff will measure weight and waist circumference, conduct a 
DXA scan and collect fasting blood. Participants will complete the final questionnaires on physical activity and 
quality of life (Triple-A QOL questionnaire, Triple-A PA questionnaire).  Finally, participants assigned to the
control arm will be given a copy all of the intervention materials and the study dietitian will be scheduled for a 
brief teleconference with the study dietitian to review the materials. 
If requested, a participant may receive a copy of their DEXA scan results. 
4.5 
Consents 
Waiver of HIPAA authorization.  A waiver of HIPAA authorization will be obtained to allow the UW urology clinic 
study staff to pre-screen patients for eligibility.  A waiver of HIPAA authorization will also be obtained from the 
VAPSHCS obtained to allow the VA urology clinic study staff to pre-screen patients for eligibility.  
Triple-A Consent for contact UW. Potential participants recruited from the UW will be asked to sign a 
consent for contact to allow their contact information to allow their personal contact information to be sent to 
the Fred Hutch for recruitment into this study. [No comparable consent is needed for VA participants, since the 
clinic visits occur at the VA].  
Triple-A_VerbalConsentScriptPreStudy:  Prior to the first study clinic visit, participants will be asked to 
provide verbal consent to complete pre-visit 1 study activities.  
Triple-A UW Consent. At Clinic Visit 1,potential participants recruited from UW  will be asked to sign the main 
study consent to participate in the intervention trial. 
A comparable consent will be created for VA patients, which will cover the study activities that take place at 
the VA.  VA participants who are assigned to the diet and exercise intervention will complete those study 
activities at Fred Hutch, and will be asked to sign a separate consent (see below) to cover these activities. 
Triple-A VA_Intervention Consent.  VA participants assigned to the intervention arm will complete an 
additional consent to participate in the intervention (diet and exercise instruction) activities that occur at Fred 
Hutch.  
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4.6 
Intervention 
Intervention arm participants will attend 10 sessions with a registered dietitian over six-months to receive 
instruction on a modified-Dietary Approaches to Stop Hypertension (DASH) diet.  In addition, participants will 
attend two one-on-one sessions with an exercise physiologist to receive instruction on aerobic physical activity 
and strength/resistance training.  Participants will also be offered the opportunity to complete up to 21 
additional supervised exercise sessions at either the Fred Hutch Prevention Center (PC) or VA Clinical 
Research Unit (CRU). The following materials will be used to provide Intervention instruction to participants in 
the Intervention arm:  Triple-A Nutrition Intervention; Triple-A PA Intervention; Triple-A Supplemental 
Nutrition_V1; Triple-A Supplemental PA_V1. 
Diet.   
One-on-one diet instruction will be provided by the Fred Hutch study dietitian. This instruction will occur either 
in person at the Fred Hutch PC or, if necessary, via teleconference.  The dietary goals are to adopt and 
maintain a modified DASH eating pattern. The DASH feeding trial was designed to test whether the provided 
diet would lower blood pressure and serum lipids.47 The trial diet was high in fruits and vegetables, whole 
grains, and low in sodium.47  The preponderance of evidence supports that a DASH eating pattern or a 
modified-DASH, lowers inflammation, promotes healthy weight and body composition,48 and reduces T2D and 
CVD- both common complications that accompany ADT use.48,49  
The Triple A Pilot intervention has modified DASH to: 1) limit saturated fat to 7% of total energy. This will be 
accomplished via substitution with PUFA-rich plant oils; 2) restrict added sugars as DASH made no specific 
recommendation about added sugars (only sweetened beverages were reduced in DASH); 3) specify that > 
75% of grains should be whole grain and 4) advise lean protein with plentiful essential amino acids (especially 
branched chain amino acids, BCAAs) and to spread the protein intake throughout the day.50 The protein 
component is based on BCAAs’ well-known role in muscle protein synthesis and to help alleviate the muscle 
loss that accompanies ADT use. Additionally, skeletal muscle synthesis is more efficient when amino acid 
intake is spread throughout the day, particularly in older individuals.50 Sample menus will be provided across a 
range of estimated daily kcal (e.g., 2000, 2200). Information on the participant’s body weight, age and usual 
physical activity level will be used to calculate an individualized caloric need for weight maintenance for each. 
This calorie level will be explained to each participant as incorporated into the DASH curriculum and will be 
updated to accommodate changes to the participant activity level and/or weight as the study progresses. The 
modified-DASH diet can be adapted to participant food preferences, dietary restrictions, cultural values (e.g. 
Kosher, Halal) and cost.51  
Physical Activity. The physical activity goals are to increase daily moderate to vigorous aerobic activity to at 
least 150 minutes/week; and to engage in strength/resistance training at least three times per week. One-on-
one physical activity instruction will be provided by an exercise physiologist at the Fred Hutch PC. In-person 
training is critical to properly demonstrate safe resistance training and to receive an aerobic prescription 
suitable for each participant. Learning specific aerobic and resistance exercises will be coupled with behavioral 
skills instruction in setting and adhering to goals, making active choices, introducing variety and tools for 
motivation. Study staff have experience working with cancer patients in active treatment. If at any time, 
participants experience undue fatigue or other treatment-related symptoms, the exercise regimen will be 
altered as needed. In addition, participants may complete up to 21 supervised (but not one-on-one) exercise 
sessions at the Fred Hutch PC. Alternatively, the supervised exercise sessions can be completed at the VA 
Clinical Research Unit (CRU), which is a comparable exercise facility. At each exercise session, study staff will 
weigh the participant, and participants will record their activities completed (Exercise Training Record within 
the Triple-A Supplemental PA) 
4.7 
Controls.   
Written information (Triple-A Controls) 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 maintenance. 
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4.8 
Compliance.  
Compliance to dietary and physical activity goals will be evaluated by weight, which will be measured at each 
session, check-ins with the study dietitian and exercise physiologist, and self-monitoring through diet (Triple-A
diet daily log within the Triple-A Nutrition Intervention) and physical activity tracking (Triple-A PA daily log 
within the Triple-A PA Intervention). Formal compliance will be assessed by the 4-day food record (Food 
Record) and exercise questionnaire (Triple-A PA questionnaire). 
5. 
DATA COLLECTION  
This study involves a total of two participant visits.Study visits will occur at baseline and at the end of study (6-
months), where participants will undergo assessments of anthropometrics, collection of fasting blood and 
completion of study questionnaires.  At the mid-study timepoint (month 3) participants will complete 
questionnaires remotely. 
  
Twelve-hour fasting blood. Fasting blood samples will be collected at baseline and 6 months at the Fred Hutch.  
Vacutainers will be labeled with participants’ study ID and date, processed within 1 hour of collection and
stored at -80ºC.   
Stool sample. Stool samples will be collected by participants at home prior to the clinic visits at baseline and 6 
months. Vacutainers will be labeled with participants’ study ID and date, stored within 1 hour of receipt at -
80ºC.   
Questionnaires:  
Food Record. All participants will complete a 4-day food record at baseline and 6 months.  
Triple-A PA questionnaire. Physical activity will be assessed at baseline and 6 months with a self-
administered administered physical activity questionnaire, the Community Healthy Activities Model 
Program for Seniors Physical Activity Questionnaire for Older Adults (CHAMPS),52 which assesses a 
variety of physical activities that are meaningful and appropriate for older adults.  For participants 
assigned to the intervention arm, resistance and aerobic activities will also be documented during 
supervised exercise sessions. 
Triple-A lifestyle questionnaire. Race/ethnicity, education, smoking, alcohol use and family history of 
prostate cancer will be assessed at baseline only.  
 
Triple-A Exit survey.  Participants will be asked about their experience in the study, and for participants 
in the intervention arm – challenges they experienced with the intervention. 
5.1 
Outcomes 
5.1.1
Blood Biomarkers 
Blood markers of glucose, insulin, hemoglobin A1c, triglycerides and total, LDL- and HLD-cholesterol will be 
analyzed by the University of Minnesota Advanced Research and Diagnostics Laboratory.  Homeostatic model 
assessment of insulin resistance (HOMA-IR) will be computed from glucose and insulin concentrations. 
5.1.2
Body Composition and Anthropometrics 
Height will be measured at baseline only, and weight and waist (1” above umbilicus) circumferences will be
measured at baseline and 6 months.  Dual x-ray absorptiometry (DXA) using a GE Lunar DXA will be obtained 
to measure body fat and lean mass at baseline and 6 months. 
5.1.3
Patient Reported Outcomes. 
Triple-A QOL questionnaire.  Patient reported outcomes including quality of life and fatigue will be measured at 
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baseline, month 3 (mid-study) and at 6 months (end of study). This questionnaire will be based on the 
Expanded Prostate Cancer Index Composite (EPIC)-26 Short Form, including prostate and ADT-specific 
questions53 and the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scale, measuring 
fatigue.54  
5.1.4
Microbiome 
Stool DNA will be extracted from the stool samples. The gut microbial community will be 
characterized by sequencing the 16SRNA and comparing the readouts between the intervention and 
comparison groups. 
6. 
PARTICIPANT RISKS AND BENEFITS 
6.1 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. Participants in the intervention arm may experience fatigue, muscle soreness, and possible joint or 
skeletal injury, injury from exercise (such as a fall) or a medical event during exercise at home or in the 
VA Clinical Research Unit or the Fred Hutch Prevention Center. 
3. Participants in the intervention arm may experience 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. Other potential risks are associated with the collection of personally identifiable and health information 
from the subjects, and the potential for 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.  
6.2 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 and 
anthropometry will be done at the Fred Hutch 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 Fred Hutch 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 persons with significant cardiovascular disease that would preclude 
exercise, will be excluded from participation in this study.  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.   
 
In the extremely rare and unexpected event of an emergency while participants 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, participants will be provided with the telephone numbers of the study PIs and 
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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. 
 
 
3. 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. 
 
4. To minimize the risk of breach of confidentiality, we will make sure that all health information and 
records are labeled with a study identification number only. 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.  
 
6.3 Benefits 
The data generated from this proposed research study will provide the data necessary to inform the final 
design, power, sample size and endpoints for a fully powered randomized controlled trial in newly diagnosed 
prostate cancer patients receiving RT + ADT. 
 
 
Our long-term research and clinical goals are to reduce the morbidity and mortality from prostate cancer. This 
pilot will provide much needed preliminary data to support an R01. We expect that the future R01 RCT results 
could lead to practice changing paradigms for newly diagnosed prostate cancer patients receiving radiation + 
ADT as primary curative-intent treatment. Demonstration that the intervention intercepts the abrupt metabolic 
and physiologic changes could be widely disseminated to allow more men to receive the most effective cancer 
therapy without compromising their overall health.  
6.4 
Compensation 
Participants will be paid $100 total (25$ at the baseline visit, and 75$ at the 6-month visit) to help compensate 
for time and travel.   
6.5 
Alternatives 
Alternatives to participating in this research study include not participating 
7. 
DATA ANALYSIS PLAN 
This pilot trial tests whether a nutrition and physical activity intervention initiated concurrently with RT+ADT will 
intercept ADT-induced metabolic and physiologic abnormalities compared to control. We expect clinically 
meaningful changes in the control arm and minimal to no changes in the intervention arm, as the primary 
intervention goal is prevention. To test the intervention effects for our aims, we will use this difference in 
differences approach, which accounts for expected temporal changes in the biomarkers and body composition 
measures in the control arm.55 
1. The effects of the intervention on ADT-induced changes in HOMA-IR will be evaluated using linear 
regression models with adjustment for the baseline biomarker.   
2. The effects of the intervention on ADT-induced changes in body weight and composition will be 
evaluated using linear regression models.  Separate models will be fit for each measure, with an 
indicator variable for study arm (intervention/control) and adjustment for the respective body 
composition measure.  
 
As exploratory aims, we will explore intervention effects on blood lipids HbA1c, patient reported outcomes 
and gut microbiome will be evaluated using linear regression models.  Separate models will be fit for each 
biomarker, with an indicator variable for study arm (intervention/control) and adjustment for the respective 
baseline biomarker. Further adjustment for biomarkers that may have shared biology (i.e. total and LDL 
cholesterol) and for medication use that could affect biomarker concentrations will be considered. 
We expect most potential confounding variables will be evenly distributed between arms at randomization, but 
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this assumption will be checked prior to analysis.  Analyses will follow an intent-to-treat approach; tests will be 
2-sided and statistical significance will be set at P<0.05. 
7.1 
Sample Size  
For this pilot trial with a fixed sample size of 20 participants total (10 per arm), we estimate that we will have 
80% power to detect a minimum detectable difference in differences in HOMA-IR (intervention effect) between 
intervention and control participants of 2.6 (HOMA-IR is unitless). Power calculations used R 
(package::function) stats::power.t.test for t-tests and assumed a standard deviation of 1.4, pre-post correlation 
of 0.5 and 2-sided α=5%.   
8. 
DATA SAFETY MONITORING PLAN 
Oversight for this study will be provided by the Principal Investigators, Drs. Marian Neuhouser and Jonathan 
Wright, with delegation of responsibilities to designated study personnel. Study PIs will ensue all entry criteria 
are met prior to the initiation of the protocol, and all study procedures and reporting of adverse events are 
performed according to the IRB-approved protocol.  
Institutional support of trial monitoring will be in accordance with the Fred Hutch/University of Washington 
Cancer Consortium Institutional Data and Safety Monitoring Plan. Under the provisions of this plan, Fred Hutch 
Clinical Research Support coordinates data and compliance monitoring conducted by consultants, contract 
research organizations, or Fred Hutch employees unaffiliated with the conduct of the study. Independent 
monitoring visits occur at specified intervals determined by the assessed risk level of the study and the findings 
of previous visits per the institutional DSMP. Study participants are prostate cancer patients undergoing ADT + 
RT, in whom the study intervention is non-therapeutic. The study is low risk, per the Consortium DSMP 
guidelines.  
8.1 
Adverse Event Reporting 
All adverse events related to the study procedures will be fully documented on the appropriate case report 
form(s) and entered in a study database. For each adverse event, the investigator will provide the onset, 
duration, intensity, treatment required, and outcome, including documentation of need for premature 
termination of any study procedures. Anticipated 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 previous 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 exercise in the PHS exercise Laboratory. Serious Adverse 
Events will be reported within 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. 
8.2 
Plan for safety review  
The PIs will perform a cumulative review of all adverse events and premature terminations review every 6 
months after study initiation.  
8.3 
Plan for annual reporting 
A summary of the investigation including all adverse events and how they were handled, enrollment, drop-outs 
and reason for discontinuation and any protocol modifications will be provided to the IRB on an annual basis.  
Annual Reports will contain:  
a. The number of adverse events and an explanation of how each event was handled  
b. The number of complaints and how each complaint was handled  
c. The number of subject withdrawals and an explanation of why the subject withdrew or was withdrawn  
d. The number of protocol deviations and how each was handled 
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8.4 
Monitoring for data integrity and safety  
Monitoring for data integrity and safety will be the responsibility of the investigators. Investigators will include 
the following in routine monitoring review: A) Validity and integrity of data: Data are checked for missing, 
unusual, or impossible values when they are entered into the study’s computer database. B) Enrollment rate
relative to expectation: Early lags in recruitment will be rectified with increased recruitment efforts so that 
recruitment will be completed on time. The investigators will monitor this closely to ensure full enrollment of 
appropriate participants. C) Retention of participants and adherence to protocol: The investigators will monitor 
retention and adherence to study protocol. Adherence to the intervention will be monitored via participant 
weight, nutrition and physical activity visits.  
 
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Protocol_V5b 
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Fred Hutch IRB
Approved
4/3/2024