Use of a Weight Loss Aid in a Population Exposed to Polybrominated Biphenyls (PBB)
Phase: PHASE4
Conditions: Polybrominated Biphenyl Poisoning
Sponsor: Emory University

Study Protocol 
 
Title: Use Of A Weight Loss Aid In A PopulaƟon Exposed To  
Polybrominated Biphenyl (Pbb) 
 
NCT Number: NCT03582722 
 
Protocol date: August 8, 2018 

USE OF A WEIGHT LOSS AID IN A POPULATION 
EXPOSED TO POLYBROMINATED BIPHENYL 
(PBB)
Principal Investigator: Michele Marcus, PhD, MPH 
Professor of Epidemiology, Rollins School of Public Health
Funded by: NIH-NIEHS
Version Number:  3.0
8 August 2018

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
1
EXTERNAL COLLABORATORS 
Jennifer Morse, MD, Medical Director, Mid-Michigan District Health Department. The Mid-Michigan 
District Health Department does not have an IRB and a reliance agreement has been executed.
ABSTRACT
Millions of people living in Michigan were exposed to brominated flame retardants (Polybrominated 
biphenyls or PBB) as a result of the largest agricultural disaster in US history. Over the past six years, 
Emory researchers have tested nearly 900 Michigan residents and determined that 60% still had PBB in 
their bodies from that disaster. PBB is stored in body fat and we have been asked by community members 
if weight loss might reduce their body burdens of PBB and other lipophilic chemicals. In an effort to 
understand how PBB and other persistent organic pollutants (POPs) are eliminated, we have proposed 
(and funding has been approved for) a randomized trial of Orlistat vs. placebo. The Notice of Award will 
be issued when we receive IRB approval for the trial.
Orlistat is an over-the-counter product approved by the FDA for weight loss and works by increasing 
excretion of fat into the stool. Since PBB is stored in body fat, we hypothesized that Orlistat may reduce 
the body burden of PBB and other POPs. The proposed study is a randomized, placebo-controlled trial of 
Orlistat (at the dose available over-the-counter) plus diet and exercise for 6 months in a population with 
elevated PBB levels. Participants will be healthy overweight adults and Orlistat will be taken as directed 
for the approved indication (weight loss). We will follow all FDA-approved eligibility criteria and not 
enroll anyone with contra-indications to taking the drug. In addition, we will screen individuals for liver, 
kidney, or thyroid abnormalities, excluding anyone with abnormal values. We will repeat clinical 
laboratory tests at the conclusion of the trial (at 6 months). The primary outcome is weight loss and the 
secondary outcomes are blood levels of PBBs and other POPs. Sixty individuals will be included in each 
arm, with the aim of fifty participants completing 6 months of participation in each arm (100 total).

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
2
PROTOCOL SUMMARY
Screening 1
 
 
Screening 2
Enrollment
Intermediate 
study tasks 
Month 3 
Month 6
Post Participation
Complete online health, dietary, and physical activity questionnaires 
Screen potential participants based on already collected data.  
Participant:  Take intervention 3 times/day and 1 multivitamin daily; 
follow diet and exercise instructions.
Research team:  Telephone calls to encourage/facilitate adherence & record 
possible adverse events. The frequency of these calls will depend on 
participant needs and preferences. They will range in frequency from 
once/week to once/month
Repeat blood collection for clinical lab tests (analyzed immediately) and 
POPs analyses
Laboratory analyses for 
POPs; Statistical Analyses 
Orlistat + 
Multivitamin
       N = 60
 Placebo + 
Multivitamin 
N = 60
Repeat blood collection for POPs analyses.
Randomize 120 eligible individuals
Obtain informed consent; screen for exclusionary health conditions; 
Collect blood for clinical lab screening and POPs analyses. 
Figure 1: Schema

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
3
INTRODUCTION & BACKGROUND
In 1973, the Michigan Chemical Company accidentally shipped FireMaster, a brominated flame retardant 
mixture in place of a nutritional supplement for livestock feed. This introduced polybrominated biphenyls 
(PBB) into the Michigan food chain, ultimately exposing millions of Michigan residents, and resulted in 
one of the largest chemical exposure incidents in US history. To evaluate long-term health effects of 
exposure, the Michigan PBB Research Registry was established in 1976. The Registry is a 
multigenerational cohort with over 7,000 individuals ever enrolled, and includes those exposed during the 
contamination incident as well as subsequent generations, as PBB can be transferred from mother to child 
in the womb and through breastfeeding. Health-related research has been ongoing with this cohort for 
almost forty years and evidence to date of adverse health outcomes associated with PBB exposure 
includes increased risk of breast cancer, lymphoma, earlier age at menarche, increased miscarriages and 
lower estrogen levels among females, and more urogenital problems among males. Increased risks of 
thyroid dysfunction have also been found among men and women. 
PBB is a Persistent Organic Pollutant (POP). POPs are characterized by a very long half-life and storage 
in adipose (fat) tissue. Approximately 60% of 867 Registry participants recently tested still have elevated 
blood levels of PBB (above the 95%ile of NHANES, random sample of the US population) in their blood. 
PBB Research Registry participants have repeatedly asked whether weight loss could reduce their body 
burdens of PBB and if there was a way to speed elimination of PBBs. Orlistat is a reversible inhibitor of 
gastric and pancreatic lipases (enzymes that break down dietary fats for absorption in the intestines), thus 
inhibiting absorption of dietary fats by approximately 30% [1] and increasing excretion of fat into feces 
[2]. Orlistat was approved by FDA in 2007 as an over-the-counter aid to weight loss for overweight 
individuals. Although the weight loss attributed to Orlistat (compared to diet and exercise alone), is 
modest, the loss of body fat is much greater with Orlistat than diet and exercise alone. 
We hypothesized that weight loss due to Orlistat, because it preferentially results in loss of adipose tissue, 
may also reduce blood levels of PBB and other POPs. There is biologic evidence that supports this 
hypothesis [3] and in a pilot study using a rodent model [4], Orlistat was shown to safely reduce body 
burden of lipophilic chemicals. In addition, the study suggested that the rate of toxicant elimination 
increases with a higher dose of Orlistat. A recent review of detoxification regimens noted the absence of 
randomized controlled trials and the need for such trials [5]. We proposed such a randomized controlled 
trial of Orlistat to provide some evidence of whether weight loss due to Orlistat may also reduce serum 
levels of POPs in a highly exposed community. The study was approved for funding by NIH/NIEHS.
OBJECTIVES

The primary objective is to determine if the use of Orlistat results in weight loss that is 
accompanied by a reduction in the body burdens of PBB and other POPs. 

The primary endpoint is the change in weight and BMI in the Orlistat group compared to the 
placebo. 

The secondary endpoint is the change in serum concentrations of PBBs, PCBs, DDE, and PBDE 
in the Orlistat group compared to placebo.

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
4
STUDY DESIGN & METHODS
Study Overview
Title:
Use of a Weight Loss Aid in a population exposed to PBBs.
Study Description:
Orlistat is an over-the-counter weight-loss aid that preferentially reduces 
body fat compared to diet and exercise alone. Our primary outcome is 
weight loss. Our secondary outcome is the change in concentration of 
chemicals that are stored in body fat (POPs). We hypothesize that the 
Orlistat group will lose more weight than the placebo group and because 
Orlistat preferentially reduces fat, that the weight loss in the Orlistat group 
will be accompanied by a reduction in serum levels of fat-soluble chemicals 
(POPs). Eligible individuals (using stricter criteria than recommended by 
FDA), will be randomized to Orlistat or placebo taken 3x daily with food. 
Both groups will receive multivitamins and a program of diet and exercise 
for six months. 
Objectives:
To explore whether weight loss associated with Orlistat has a secondary 
effect of reducing blood levels of PBB and other POPs 
Endpoints:
Primary Endpoint: Weight loss 
Secondary Endpoint: Change in serum concentrations of PBBs, PCBs, 
DDE, and PBDE.
Study Population:
We will conduct this study among individuals exposed to polybrominated 
biphenyls (PBB) as the result of an industrial accident. We estimate we will 
need to enroll approximately 120 individuals into the trial to have 100 
complete the 6-month trial duration. Healthy men and women, aged ≥18 
with a BMI ≥ 25 and at high risk for a PBB level ≥ 1 part-per-billion or a 
recently measured PBB level ≥ 1 part-per-billion will be screened for 
additional health-related eligibility criteria. We will NOT enroll individuals 
with contra-indications for Orlistat and will have more stringent inclusion 
criteria than recommended by the FDA for Orlistat.
Description of 
Sites/Facilities 
Enrolling Participants:
Participants will be enrolled by telephone from Emory University or 
enrolled in-person by Emory staff in Michigan.
Description of Study 
Intervention:
Random assignment to Orlistat at the over-the-counter dose (60 mg capsule, 
up to three times daily with fat-containing meals) or placebo capsule. Diet 
and exercise plus a daily multivitamin will also be recommended and 
monitored for both groups. 
Study Duration:
Approximately three years.
Participant Duration:
Six months

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
5
Study Design Overview: A randomized, double-blind, placebo-controlled 6-month trial will be 
conducted among selected participants from the PBB Registry. Signed informed consent will be obtained, 
in person or online, after discussion with study staff and an opportunity to ask questions. Potential 
participants will be screened for eligibility by self-report of health information and clinical laboratory 
tests. Study participants will be randomized into one of two groups: the Orlistat (intervention) group or 
the control (placebo) group. Both groups will be prescribed the same diet and exercise regimen. 
STUDY CALENDAR
Screening
Time (months) ± 2 weeks
Procedures
1
2
Enroll
ment
3
6
Review previously collected data for provisional 
eligibility
X
Informed Consent
X
Telephone screen for additional eligibility 
criteria 
X
Online comprehensive health questionnaire 
(CHQ) or update of previous health 
questionnaire 
X
Blood draw for clinical function blood tests 
(liver, kidney, thyroid); review for eligibility and 
return results to individuals
X
X
Anthropometry (weight, height, waist 
circumference)
X
X
X
Blood draw for serum POPs concentrations
X
X
X
Analyses of serum POPs concentrations 
(baseline, 3 mo., 6 mo.)
After all samples collected 
Randomization
X
Dietary Assessments 
X
X
X
Physical activity assessments
X
X
X
Pill count to check adherence
Months 3, 6
Compensation
$40
$60
Initiate a weekly telephone call – to answer 
questions, encourage adherence and determine 
any adverse events or new health problems – 
then reduce frequency of calls depending on each 
patient’s needs and preference. 
Months 1 -6
Medication dispensed (Orlistat or placebo)
Enrollment: 3 mo. supply
Month 3: 3 mo. supply
Multivitamins dispensed (200ct)
X
Post-study follow-up telephone calls
One week and one month 
after completion 
Figure 2: Schedule of Activities

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
6
Anthropometry measurements (weight, height, waist circumference) will be obtained at enrollment and 
serum levels of PBB, PCB, DDT/DDE and PBDE (POPs) will be measured at enrollment, at 3 months 
and at 6 months (all chemical analyses will be done at the conclusion of the trial). We will determine if 
body weight and serum concentrations of POPs have changed over time in each group. Subgroup analyses 
by amount of weight loss, enrollment PBB concentration, and gender will be undertaken as well. Data 
will be analyzed to see if the Orlistat group experiences greater weight loss than placebo and secondarily, 
whether the Orlistat group experiences a greater reduction in serum POPs over the course of the trial. 
Intervention: Orlistat is the active ingredient while the inactive ingredients include microcrystalline 
cellulose, povidone, sodium lauryl sulfate, and xylitol. Store at 20-25 C (68-77F.) FDA has approved a 
60mg dose 3x daily with meals for over-the-counter sale.  This is the lowest dose available of Orlistat. 
Higher doses require a prescription. The dosage will not change during the course of the trial (6 months 
for each participant). Upon enrollment we will dispense a three-month supply of Orlistat or placebo. At 
the end of month three they will receive a three-month supply. 
Alli (trade name) or Orlistat is a weight loss aid for overweight adults, 18 years and older. It is 
recommended that Alli be accompanied by a reduced-calorie and low-fat diet and exercise program until 
weight loss goal is reached. Most weight loss occurs in the first 6 months, hence the 6-month duration of 
the trial. Participants will be instructed to take 1 capsule (60mg) with each meal containing fat, and not to 
take more than 3 capsules daily. These are the FDA-approved instructions provided in over-the-counter 
Alli. Orlistat may decrease absorption of fat soluble vitamins and thus a multivitamin will be provided for 
all participants to be taken once a day, at bedtime. 
Study Procedures: Individuals will undergo two levels of screening before randomization (see details in 
section “9. Participant Selection” below). Briefly, we will identify those likely to be eligible using 
information they provided to the PBB Research Registry previously. This includes age ≥ 18, BMI ≥ 25 
likely PBB serum level ≥ 1 part-per-billion, indicated from recent PBB level data or as a part of a high-
risk sub-group, and no contra-indicated medical conditions such as, have type 1 diabetes, had an organ 
transplant, are pregnant or lactating, current use of weight-loss medications, oral steroids, Coumadin, 
warfarin or Cyclosporine, have a diagnosed problem absorbing food, or have an eating disorder, a history 
of bariatric surgery, pancreatitis, kidney stones, a gall bladder disorder or a serious chronic disease (e.g. 
uncontrolled diabetes, congestive heart failure, chronic kidney disease) or allergies to any ingredients of 
the Orlistat OTC capsules. Ingredients including Orlistat, microcrystalline cellulose, povidone, sodium 
lauryl sulfate, and xylitol. Those who are provisionally eligible will be interviewed over the telephone to 
update those characteristics. Informed consent will be obtained in person or online. The participant will be 
asked to get a blood sample drawn at a local health department or medical facility for additional screening 
for liver, kidney, and thyroid levels. Additional blood will be collected for later chemical analyses. They 
will also be weighed and measured. Their clinical test results and medical history will be reviewed by Dr. 
Jennifer Morse to determine final eligibility. Anyone with abnormal clinical test results will be ineligible. 
Randomization: Dr. Amita Manatunga, Professor of Biostatistics at RSPH will perform the 
randomization.  Because background characteristics may affect PBB elimination rates, assignments to the 
study groups (Orlistat or placebo), will be stratified by gender and BMI and a randomization plan will be 
generated using a pseudo-random-number generator with randomly permuted blocks. This method serves 
to balance the group assignments over the course of the study and to ensure that the desired number of 

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
7
participants will be allocated to each of the study groups at any time point during the randomization 
period.  Permuted block sizes will not be disclosed to the blinded study personnel to minimize the 
likelihood of their being able to predict the next randomization assignment in the series. These 
assignments will be stored in a backend database table that will be password protected with restricted 
access to designated study personnel. Dr. Michael Collins, Director of the Healthway Compounding 
Pharmacy will also have access to the participant assignments in order to dispense the appropriate 
capsules. 
After random assignment, the first installment of study supplies will be sent to participants (multivitamins 
for all participants and three-month supply of Orlistat or placebo, according to participant’s study group 
assignment) and instructions for dietary modification and exercise recommendations. Study participants 
must familiarize themselves with the material before beginning their regimen. Intervention will arrive 
ready in pill-form for the participant to ingest.
The study intervention and control product will be prescribed by Jennifer Morse, MD and provided by 
Healthway Compounding Pharmacy in Michigan by Michael E. Collins, R.Ph, by mail to participants’ 
homes.
Jennifer Morse, MD, is Medical Director for three local public health departments covering a 19-county 
area in Central and Northern Michigan, which covers the area the most highly exposed participants live. 
She is trained and Board Certified in Family Medicine and Board Certified in Obesity Medicine. She has 
experience prescribing and monitoring Orlistat in clinical practice and will be the prescribing physician 
for the clinical trial. 
Michael E. Collins R.Ph., FIACP is Director of Healthway Compounding Pharmacy in central Michigan 
where many of the most highly exposed participants live. He was selected as the Professional 
Compounding Centers of America 2015 Pharmacist of the year and has many years of experience 
dispensing medications as part of randomized clinical trials. Healthway Compounding Pharmacy was the 
first pharmacy in Michigan to be accredited by the National PCAB (Pharmacy Compounding 
Accreditation Board). 
Participants will be contacted upon expected receipt of study materials. Contact will be established 
weekly, then reduced as the study proceeds. The frequency of contact will depend on the individual 
needs/preferences of each participant until the conclusion of the trial at 6 months. Adherence will be 
monitored by these telephone calls and intervals of compensation. All participants will be asked to report 
pill counts to measure adherence at 3 and 6-month time points. Participants will also be asked at each 
study phone call whether they are experiencing any adverse symptoms potentially related to the 
medication or other aspects of the study. 
Weight Management Intervention: The weight management intervention, dietary assessments, and 
physical activity assessments will be supervised by Terry Hartman, PhD, MPH, RD, Professor of 
Epidemiology. Prior to relocating to Emory in 2013, Dr. Hartman was Professor of Nutrition and Director 
of the Diet Assessment Center at The Pennsylvania State University.  As a nutrition epidemiologist and a 
registered dietitian, she has approximately 20 years of experience exploring associations between 

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
8
nutritional exposures and chronic disease outcomes and has designed and collaborated on multi-
disciplinary trials of diet, exercise and other interventions to improve health.
Participants in both arms will follow the same study schedule with approximately equal contact time. Any 
contacts (e.g., in person, phone, e-mail) with the study staff will be logged to assess total contact time. We 
will provide weight loss and management guidance and support primarily via telephone interactions and 
online resources focusing on dietary and physical activity weight loss and management strategies. 
Participant interactions will begin weekly then adjusted based on participant needs and preferences. This 
plan allows the participants to implement strategies to gradually alter their food intake to promote weight 
loss and maintenance. Weight loss and management strategies for both study arms will be consistent with 
the Orlistat recommendations of limiting overall fat intake to 30% of daily energy with energy intake 
altered to lose 1-2 lbs. /wk. 
Participants in both arms will receive nutrition and activity information emphasizing weight loss 
management including instruction on reading food labels, determining appropriate portion sizes, lowering 
overall dietary fat content, replacing higher energy dense foods with intakes of satiating, low energy 
dense foods like fruits, vegetables and whole grains, and increasing physical activity. We will encourage 
intake of foods high in soluble fiber (e.g., legumes, oats, barley, flax, nuts, selected fruits (oranges, 
apricots, apples, pears) and vegetables. In addition, information will be provided on managing energy 
intake when snacking, dining out, when traveling, and on special occasions. We will encourage 
light/moderate physical activity (e.g., walking). All information will be provided as behaviorally-based 
strategies similar to those used in the Diabetes Prevention Program (DPP) [6] and Look Action for Health 
in Diabetes (AHEAD) [7] lifestyle intervention programs [8, 9] which used Social Cognitive Theory 
(SCT) to guide their interventions [10]. According to SCT, self-efficacy, goal setting and outcome 
expectations are the three predominant factors thought to influence behavior changes. For example, phone 
contacts will include skill-building activities to increase self-efficacy. Journaling (e.g., food intake, 
physical activity) and weekly at-home weigh-ins will be used both to monitor individual progress and 
promote adherence to the intervention. During the final few months, participants will be contacted 
monthly by the study staff either by phone, email, or text (depending on individual needs) to continue to 
reinforce and encourage healthy weight management practices.
Intervention Training and Quality Control  
Study staff delivering the intervention will participate in approximately eight hours of training initially 
with additional training as needed over the course of the study. The training, developed by Dr. Hartman, 
will include the purpose of the project and will review procedures and materials for use during the study. 
The PhD student will practice using materials and communicating with others during training. In addition, 
we will cover confidentiality, listening skills, strategies for coaching (but not directing) and sensitivity to 
cultural, ethnic, and related issues. During the intervention after obtaining the participants’ permission, 
Dr. Hartman will patch-in on a random sample of 5% of interactions to assure protocol fidelity and to 
provide comments to increase the effectiveness of the intervention.
Outcome measures 
1. Anthropometric measures / Body composition

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
9
Body weight, height and waist circumference (WC) will be measured using procedures based on the most 
recent NHANES Anthropometry Procedures Manual [11] at the local health department or medical 
facility at the time of the screening blood draw, 3 month and 6 month blood draws. Briefly, participants 
will have their weight measured in light clothing without shoes on a regularly calibrated digital scale. 
Height will be measured using a well-mounted stadiometer. Waist circumference will be assessed in 
duplicate with a measured tape placed horizontally just above the iliac crest, after completion of a 
respiratory cycle. When available, we will also measure body composition (% body fat measured by bio-
impedance scale). We will compare the initial measurements to the 3-month and 6-month weight 
measurements.   
2. Blood measures
Blood samples will be collected at screening and repeated at 3 and 6 months. 
Screening blood samples will be used to determine eligibility but will also be processed and stored for 
analysis of PBB, PCB, DDT/DDE, and PBDE concentrations with the participants’ other study time 
points. Blood samples will be aliquoted into smaller vials and frozen at -70°C and stored for analysis at 
the completion of the study. 
POPs laboratory methods: Samples will be analyzed under the direction the Emory University 
HERCULES Integrated Health Sciences Core. Dean Jones, PhD directs this core. All chemicals will be 
analyzed using state-of-the-art laboratory methods after all samples are collected. This will minimize 
batch-to-batch variability and maximize our ability to detect changes in these chemicals over the course of 
the trial. 
Samples for individual participants will be delivered to the laboratory in random order for analyses and 
blind quality control samples and duplicates will be included. 
3. Diet Assessment
Assessment of dietary intake will be conducted under the supervision of Dr. Terry Hartman, PhD, MPH 
RD. 24-hour (24-hr) recalls are regarded as the best methodology to measure short-term changes in food 
intake because they provide high-quality and relatively unbiased dietary data [12]. Subjects will be asked 
by a trained study staff member to recall their food and beverage intake during the previous 24 hour 
period, approximately midnight to midnight of the preceding day. During the week prior to 
randomization, two telephone 24-hour recall interviews will be conducted, one during a weekday and one 
on a weekend. This process will be repeated again at the 3- and 6-month assessments. At month 3, 
participants will receive only one call to recount their diet, rather than two. All diet recalls will be 
collected, processed, and analyzed using the most recent version of the Automated Self-administered 24-
hour Recall an interactive web-based system that prompts for food description details and automatically 
codes and calculates nutrient intakes using a database (USDA Food and Nutrient Database for Dietary 
Studies – FNDDS). The ASA24 system was developed and validated by researchers at the National 
Cancer Institute for direct use by respondents. However, if the participant prefers we will use it as an 
interviewer-administered tool (we have done this successfully in another study)[13]. The system includes 
a tracking system to monitor study progress but does not collect any identifying data about respondents to 
protect confidentiality. It provides values for total energy, nutrients and nutrient ratios, foods and food 
groups, and can be used to calculate the USDA Health Eating Index (HEI) to assess diet quality. Nutrient 

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
10
data can be reported in a variety of formats and exported to a file for statistical analysis. Of particular 
interest in this study are dietary intake of total energy, macronutrients and selected food groups (e.g., 
fruits, vegetables, high-fat snacks). A potential limitation is inaccurate reporting of dietary intake; 
however, Dr. Hartman has extensive experience in the collection of dietary data and in maximizing the 
accuracy of this process. 
4. Physical activity 
We will assess recent usual physical activity and inactivity using the validated form of the Women’s 
Health Initiative Physical Activity Questionnaire (WHI-PAQ) [14, 15] which assesses physical activity 
for men as well as women, across several domains (leisure, domestic and yard, work and transportation-
related activities) and when scored can provide both continuous and categorical indicators of overall 
activity. This will be measured at enrollment, 3, and 6 month intervals.
Blinding: Due to their roles in assignment of participants to Orlistat or Placebo groups, and dispensing 
the appropriate medications, Dr. Amita Manatunga and Michael Collins, R.Ph and will not be blinded. All 
other study staff will be blinded to patient medication assignment to ensure no bias occurs in patient data 
collection and reporting. This will be maintained through the secure database given access only to those 
unblinded. All other laboratory and study staff, including the PI will remain blinded. Dr. Jennifer Morse 
will be notified of adverse effects reported and will be unblinded whenever necessary for patient safety.  
More information is provided in the Data Safety Monitoring Plan. 
Risks to Human Subjects
a. Potential risks:
Potential risks associated with the use of Orlistat include:

Headache

Oily rectal discharge

Urgent need to have a bowel movement

Inability to control bowel movements

Oxalate kidney stones/oxalate kidney damage

Pancreatitis

Liver injury or failure 
Most of these risks are not serious with the exception of the last three, kidney, pancreas or liver injury. 
We have minimized the likelihood of these serious risks by screening potential participants for a history 
of kidney, liver or pancreatic abnormalities and blood tests for kidney, thyroid and liver function. These 
clinical screening tests are an ADDITIONAL LAYER OF PROTECTION against risk.  They are not 
required nor recommended before initiating treatment with Orlistat.  In addition, we will ask about 
symptoms of kidney, pancreatic or liver injury during each telephone contact. Participants will be 
instructed to consult their health care professional if they are experiencing symptoms of liver, pancreatic, 
or kidney injury possibly associated with the use of Orlistat. Symptoms of liver injury include loss of 
appetite, itchy skin, yellowing of the skin or the white part of the eyes, amber colored urine, light-colored 

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
11
bowel movements (stools), or pain in the upper right portion of the stomach. , Signs and symptoms of 
pancreatitis include right upper abdominal pain, nausea, vomiting, and loss of appetite.  Symptoms of 
kidney problems include swelling, especially of the legs and feet, little or no urine output, frequent or 
painful urination, blood in the urine, loss of appetite, nausea, vomiting, or severe pain in the back, belly, 
or groin. These serious risks are also very rare. In 2010 FDA reported 13 cases of liver failure (12 of them 
with the prescription dose of Orlistat which is twice the over-the-counter dose). 
https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213038.htm
Because of this report, we will repeat liver and kidney function tests again at the conclusion of the study 
(at 6 months), to determine if any decline in liver or kidney function occurred during the trial. 

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
12
Potential risks associated with blood draws include:

Syncope or lightheadedness

Hematoma

Arterial puncture
Adequacy of Protection Against Risks
a. Recruitment and informed Consent
Individuals eligible for the study will be recruited from among those who have participated in PBB 
observational research. All Registry members that meet the provisional eligibility criteria will be 
contacted and informed about the trial by mail and telephone. The call will include detailed information 
about the trial procedures and potential risks of participating. If the individual indicates interest in 
participating, verbal consent will be obtained and the participant will be instructed to sign the online 
consent form. 
b. Protections Against Risk
All study participant data will be organized and maintained by an assigned study ID number. The results 
will be published only in aggregate form. All identifying information will be kept in locked cabinets and 
secure computer files and will only be used by select study personnel for purposes of contacting cohort 
members, data cleaning and analysis when necessary. Identifying information in electronic form will be 
kept on a password protected research drive in a folder that is only accessible to the study personnel who 
need this information. RSPH aligns with the National Institute of Standards and Technology (NIST) 
special publications (800 series) for identifying, assessing, and managing information security risk within 
a technology environment. Drawing on federal and industry best practices, RSPH has implemented a 
series of multi-layered security controls to protect the integrity, reliability, and confidentiality of data.
Additional protections 

Venipuncture will be conducted by trained phlebotomists. 

Study participants will report their health status weekly in the first few months and then monthly 
to the research team via phone. Additionally, participants will be informed to contact the research 
team in the case of changes in medical status or occurrence of side effects. In the case that a 
participant experiences a change in medical status or side effects Dr. Jennifer Morse, Co-
Investigator will be make recommendations regarding continuation in the trial and physician 
follow-up.

Since Orlistat may interfere with absorbance of fat-soluble vitamins, all study participants will 
receive a multivitamin dietary supplement to take daily during the study period. 

Liver function, thyroid function, and creatinine levels (for kidney function) will be measured prior 
to enrollment to ensure that the participant is healthy enough to partake in the study. These 
requirements go beyond the OTC recommendations to provide additional protection.
Potential Benefits of the Proposed Research to Human Subjects and Others

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
13
The risks associated with participation in the PBB Registry and the proposed study include that associated 
with venipuncture, the use of Orlistat at the over the counter approved dose, and the collection of PHI. 
These risks, along with the proposed protections are reasonable in comparison to the anticipated benefit to 
individual human subjects, their community and others in similar situations.
Potential Benefits: All participants will be overweight and are likely to lose weight as a consequence 
of the diet and exercise regimen regardless of whether they are assigned to the Orlistat or placebo 
interventions. The benefits of weight loss in overweight adults is well-documented. Registry members 
have shown a high degree of interest in continued health monitoring, as reflected in the most recent 
study’s high participation rate and large number of study-related inquiries. Study findings are also of 
potential direct benefit to individual participants as knowledge of individual exposure levels can help 
health care providers understand health risks of their patients and provide appropriate screening and 
healthcare based on this information. Individuals with high PBB levels may be at increased risk of thyroid 
dysfunction, breast cancer and other cancers. Relevant findings from investigations have been, and will 
continue to be, conveyed in lay terms to individuals and to the community through various methods of 
communication. These findings will also benefit members of other similarly exposed communities.
The potential knowledge to be gained from the proposed study include understanding the disposition of 
PBB and other POPs in the body, understanding how the body eliminates such chemicals and to 
understand the relationship between weight loss and blood levels of POPs. The findings could directly 
benefit the affected community, similarly exposed populations, and public policy. Our community 
partners strongly support this study and submitted letters of support to NIH with our application for 
funding (we can provide these upon request).
DISPOSITION OF COLLECTED DATA
After data is collected, analyzed and recorded it will be archived using a secure database, used for all 
Michigan PBB Research Registry participants. Data collected will be used for future research on this 
cohort. Biological samples remaining after study-specific analyses will be banked in the PBB 
biorepository for further research. More information about this is provided in the confidentiality section. 
COMMUNITY PARTICIPATION
This community-driven, community-partnered study was developed in direct response to concerns 
expressed by PBB Registry members at community meetings held across the state between 2010 - 2015. 
The community meetings were held to share previous PBB research findings with the community and to 
learn their continuing concerns. Members representing three community partners contributed to the 
development of the research proposal and design: the Mid-Michigan District Health Department, Pine 
River Superfund Citizen Task Force, and the PBB Citizens Advisory Board. Two representatives from 
each of these partner groups meet monthly with the PBB research team to discuss study progress and 
address study concerns. Partners contribute to study design, outreach, data and specimen collection 
logistics, development and testing of study materials, logistics for community meetings and partner 
meetings, and development of educational materials. Individual results (anthropometric measures, blood 
measures, diet assessments, and physical activity assessments) will be shared individually with each 
research participant either by email or by mail. Overall study findings will be shared with both individual 

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
14
research participants in a mailing (or email), in scientific presentations and publications, via traditional 
and social media, and in-person at community meetings held across the state of Michigan.
PARTICIPANT SELECTION
Population: The Emory research team collected blood samples from nearly 900 individuals during the 
last few years, and the majority (approximately 60%) were above-background levels for PBB (NHANES 
95%ile). We have identified at least 140 individuals that have historically high PBB levels, recent 
measurements ≥1 part per billion (ppb) or identified to be part of a high-risk sub-group. During the next 
two years we expect to test an additional 500 individuals. Those who fit the above criteria will be 
screened for eligibility for the trial. We will enroll 20% more participants than our final target sample 
size.
Inclusion of Women and Minorities
Participants will be included without regard to sex/gender, race or ethnicity. Currently, the large majority 
of PBB Registry participants are Non-Hispanic Whites, with a relatively equal distribution of males and 
females. Individuals expected to be newly enrolled into the PBB Registry will also fall into this category. 
The lack of representation of diversity of racial or ethnic groups is directly related to the characteristics of 
the population in the state of Michigan. It is possible that individuals from other racial or ethnic categories 
will be included.
Justifications for Exclusion of Children
Children under the age of 18 will not be included in the clinical trial. Orlistat will be prescribed in 
coherence with over the counter indications and is not indicated for anyone under the age of 18.
 Recruitment and Informed Consent
Individuals eligible for the study will be recruited from among those who have participated in PBB 
observational research. All Registry members that meet the provisional eligibility criteria will be 
contacted and informed about the trial by mail and telephone. The call will include detailed information 
about the trial procedures and potential risks of participating. If the individual indicates interest in 
participating, verbal consent will be obtained and the participant will be directed to an online consent 
form and directed to their local health department for a blood draw for additional screening tests.  
Provisional Eligibility: Registry participants will be provisionally eligible if they have a current or recent 
(within the last five years) PBB level of ≥1ppb, or are a member of a sub-group likely to have high serum 
PBB (former chemical worker, family member of former chemical worker, lived on a farm with animals 
that were quarantined because of PBB exposure), are at least  18  years old; currently reside in Michigan; 
and able to participate in examinations and laboratory tests and to engage in moderate physical activity 
(e.g. walking). Participants will complete informed consent after a telephone discussion with study staff, 
complete a health history questionnaire online and have a blood sample drawn at a local health 
department or other medical health facility for determination of eligibility. The blood tests include a lipid 
panel, liver panel, thyroid function, and creatinine levels (for determination of kidney function). These 
tests will also be repeated at the conclusion of the 6 month-trial. Persons eligible for the trial will receive a 
follow-up telephone call from study staff to review the study protocol and answer questions. 

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
15
Participants will be EXCLUDED if they have any of the following: 
BMI≤25, abnormal liver function, abnormal creatinine levels, abnormal thyroid levels (TSH), have type 1 
diabetes , have had an organ transplant, are pregnant or lactating, current use of weight-loss medications, 
oral steroids, Coumadin, warfarin or Cyclosporine, have a diagnosed problem absorbing food, or have an 
eating disorder, a history of bariatric surgery, pancreatitis, kidney stones, a gall bladder disorder or a 
serious chronic disease (e.g. uncontrolled diabetes, congestive heart failure, chronic kidney disease) or 
allergies to any ingredients of the Orlistat OTC capsules. Ingredients of Orlistat include the active 
ingredient, Orlistat, and the inactive ingredients, microcrystalline cellulose, povidone, sodium lauryl 
sulfate, and xylitol. Participants will become ineligible at any point during the study if they begin a 
medical regimen involving any of the above medications. Participants with undiagnosed abdominal pain 
or diarrhea, Crohn’s disease, Ulcerative Colitis, Celiac Disease, treated diabetes or treated thyroid 
disorder, will only be eligible following consultation with their primary care provider. Any participant 
using levothyroxine will be instructed to take their dosage 4 hours before or after Orlistat in order to 
maintain eligibility. Because Orlistat may impede absorption of lipid-soluble vitamins, all participants 
will receive a daily multivitamin to be taken at bedtime. Due to an abundance of caution and a desire 
to minimize variance in response to Orlistat, these exclusion criteria are more conservative than 
FDA recommendations. 
We will NOT enroll any individuals with contra-indications for Orlistat as described by the FDA 
approved “Drug Facts”.
Participants will be informed of their clinical test results, if results are abnormal. Abnormal results will 
disqualify participants from the study. More information is provided in the DSMP. Persons eligible for the 
trial will receive a follow-up telephone call from study staff to review the study protocol and answer 
questions. 
Final determination of eligibility: Blood tests, along with health questionnaires will be reviewed by the 
study physician, Dr. Jennifer Morse, for final determination of eligibility. Individuals who do not meet the 
criteria for participation in this trial (screen failure) because of an abnormal lab result will not be re-
screened.
Participant Discontinuation or Withdrawal:
Participants are free to withdraw from participation in the study at any time upon request.
Discontinuation from Orlistat does not mean discontinuation from the study, and remaining study 
procedures should be completed as indicated by the study protocol.  If a clinically significant finding is 
identified (including, but not limited to changes from baseline) after enrollment, Dr. Jennifer Morse will 
determine if any change in participant management is needed. Any new clinically relevant finding will be 
reported as an adverse event (AE).
The data to be collected at the time of study intervention discontinuation will include the following:

Reason for discontinuing

Participant will be asked to complete all study procedures including 3 month and 6 month blood 
draws for POPs determination.
The PI may discontinue or withdraw a participant from the study for the following reasons:

Pregnancy

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
16

Significant study intervention non-compliance 

If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant

Disease progression which requires discontinuation of the study intervention

If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation

Participant unable to receive Orlistat
The reason for participant discontinuation or withdrawal from the study will be recorded on a Case Report 
Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive the 
study intervention may be replaced.  Subjects who sign the informed consent form, and are randomized 
and receive the study intervention, and subsequently withdraw, or are withdrawn or discontinued from the 
study, will not be replaced, unless the withdrawal rate exceeds that anticipated (approximately 20%)
A participant will be considered lost to follow-up if he or she is unable to be contacted by the study staff. 
The following actions will be taken if a participant fails to return for the required 3-month or 6-month 
blood draw. Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (telephone calls, emails and, if necessary, a certified letter to 
the participant’s last known mailing address or local equivalent methods). These contact attempts will be 
documented in the participant’s study file. Should the participant continue to be unreachable, he or she 
will be considered to have withdrawn from the study with a primary reason of lost to follow-up.
INFORMED CONSENT PROCESS
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Consent forms will be Institutional Review 
Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator or approved team members will explain the research study to the participant and answer any 
questions that may arise. A verbal explanation will be provided over the phone in terms suited to the 
participant’s comprehension of the purposes, procedures, and potential risks of the study and of their 
rights as research participants.  Participants will have the opportunity to carefully review the consent form 
and ask questions prior to signing. The participants will also have the opportunity to discuss the study 
with their family or surrogates or think about it prior to agreeing to participate. The participant will sign 
the informed consent document prior to any procedures being done specifically for the study. Participants 
will be informed that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. If the participant is unable to save an electronic copy of the consent form, one can be 
provided via mail. The informed consent process will be conducted and documented in the participant’s 
record, and the form signed electronically, before the participant undergoes any study-specific procedures. 
The rights and welfare of the participants will be protected. 
COMPENSATION
Attrition is a concern for any weight loss intervention; thus, we will use several methods to encourage 
retention of participants for the duration of the trial. At the beginning of the study we will have frequent 
telephone contact with participants (at least once/week) followed by reduced frequency as the study 

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
17
progresses but no less than monthly. These frequent interactions with study participants should encourage 
retention. We will also contact participants (e-mail or text) to provide encouragement regularly (weekly in 
months 1-3; at least monthly, but more if needed in months 4-6). Compensation of $100 per participant 
will be offered to promote retention over the 6-month duration of the study. Participants will be 
compensated with $40 after the first 3 months of participation and an additional $60 after completion of 
the 6 months of the trial. 
STATISTICAL ANALYSIS
The statistical hypothesis of interest is whether a mean change in weight or serum levels of POPs is 
detected at six months from the baseline. H0:I-P=0 vs Ha: I-P>0, testing whether the mean change in 
weight or serum levels of POPs differs (mean change: , between the groups; I, intervention group; P, 
placebo group). The null hypothesis denotes no mean difference between the groups, and the one-sided 
alternative hypothesis denotes a difference between the groups, with the intervention group having a 
greater reduction in weight or serum levels of POPs over the course of the trial.
We plan to recruit and screen PBB registry participants, to enroll 120 participants into the trial. Our goal 
is to have 100 participants complete the 6-month trial duration. These estimates are based on the power 
analyses described here: 
Power Analysis: The primary objective is to determine if the use of Orlistat results in weight loss in this 
population. Previous studies have shown an average of 2 to 3 kg weight difference between the 
intervention and placebo groups [16]. Assumming a standard deviation for weight change of 5 kg, we 
would have adequate power (80%) to detect a 2-3 kg difference (=0.05; =0.5) in weight with a sample 
size of 50 in each group. Power analyses were performed in PASS 13 software [17]. 
The secondary endpoint is the change in serum concentrations of PBBs, PCBs, DDE, and PBDE at six 
months from the baseline. For the outcome of change in serum POP levels, we based our sample size 
estimations on the historical PBB data for PBB registry participants with at least 2 measurements within a 
year and the pilot data from Jandacek et al [18]. We estimate that the variance of the differences in PBB 
levels is expected to be between 0.1 and 0.2 log parts per billion (ppb) (2diff). We have used the pooled 
variances for our power calculations. From our historical data, we expect a 1% reduction in PBB levels 
due to the natural course of exposure. A sample size of 50 in each group, would provide at least 80% 
power to detect a mean change in log PBB levels of -0.1 and -0.2 log ppb with a significance level of 
=0.05. 
After accounting for 20% attrition (based on 18% in Jandacek), our goal is to recruit at least 60 
participants per group. The sample size projections are, in large part dependent on the estimated 
variances. Given the small sample sizes on which we have to estimate the anticipated variance, there is 
much uncertainty in the sample size needed. However, given the statistically significant findings of 
increased excretion of PCBs with only 14 individuals in each group consuming potato chips with artificial 
fat [18], we feel that 50 individuals in each group comparing Orlistat to placebo is reasonable based on all 
available preliminary data.

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
18
Data Management: Analysis variables will be captured from the study measures (anthropometric 
measures, blood levels, diet assessment, and physical activity assessment). Data will be collected and 
coded systematically, reviewed periodically for quality control, logical checks, data entry errors, missing 
or invalid values and logical inconsistencies among related questions will be checked. Plausibility of 
outliers will be examined.  All data related changes, including changes to respective datasets will be 
documented electronically. Analytic datasets will be created to address specific study aims. Data 
dictionaries will be created. All data files will be maintained on a password-protected network system. 
Original and back-up datasets are stored on a secured network server. 
Data exploration and will include the following: 1) determining whether the shapes of continuous 
distributions indicate that transformations are needed, 2) ensuring that the underlying assumptions of 
statistical analyses are satisfied (normality, linearity and homogeneity of variance), 3) identifying 
potential collinearity problems, 4) identifying potential outliers that require further investigation, and 5) 
exploring bivariate and unadjusted associations with the endpoints and reviewing potential confounding 
variables. These will be considered prior to constructing models to address our study hypothesis. 
Descriptive statistics will include means, medians, and percentiles as appropriate for each variable of 
interest. 
The health history questionnaire (already approved by IRB for the related study IRB# 45959) and an 
online version of the WHI-PAQ will be created using REDCap Software and available to participants 
through an online website. The Automated Self-Administered 24-Hour (ASA24) dietary assessment tool 
will be used to collect information on food consumption over the past 24 hours. Participants will complete 
the ASA24 at enrollment, 3 months and 6 months. If the participant prefers, the PhD student or authorized 
staff member will complete the assessments with the participant by telephone. Data from all 
questionnaires will be reviewed periodically for quality control, data entry errors, logical checks, and 
inconsistencies among related questions. Plausibility of outliers will be examined. All data related 
changes, including changes to the datasets will be documented electronically. Analytic datasets will be 
created to address specific study aims. Data dictionaries will be created. All data files will be maintained 
on a password-protected network system. Original and back-up datasets are stored on a secured network 
server.
Exploratory Analyses: Comparisons between the intervention and placebo groups will be conducted to 
assess the degree to which comparability of study groups was achieved. From the ASA24, we will 
calculate mean daily caloric, total fat, and carbohydrate intake. We will examine changes in these 
measures over the study period. From the WHI-PAQ, we will estimate physical activity intensity. 
Summary tables (descriptive statistics and/or frequency tables) will be provided for all baseline, follow-
up, clinical, and exposure data. We will examine longitudinal trends through graphical methods, such as 
individual profile plots and plots of mean POP levels over time, by group. These plots will be inspected to 
characterize the within and between subject variations across time.
Statistical Modeling: Data will be analyzed according to the intention to treat (ITT) principle. We will 
use a repeated measures approach and mixed-effects models [19] where the dependent variable is either 
body weight in kg or natural-log PBB levels and the primary predictors of interest are the group variable 
(placebo or intervention) and the measurement time treated as a continuous variable. 
The general random-intercept model notation is:

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
19
𝑌𝑖𝑗= (𝛽0 + 𝑏𝑖) + (𝛽1 + 𝛽2𝑋𝑖)𝑡𝑖𝑗+ 𝜀𝑖𝑗
where Yij denotes the weight in kg or the log-transformed serum PBB concentrations measured on 
participant 𝑖 at time 𝑡𝑖𝑗 where (𝑖= 1,2,…𝑛) for participants and (𝑗= 1,2,…𝑛) for measurements within a 
participant. 𝑋𝑖 is an indicator variable which takes the value zero for the placebo group and one for the 
intervention group. 𝛽0, represents the overall intercept (mean weight in kg or mean log PBB levels) at 
baseline, independent of group and 𝑏𝑖 is the random effect that represents the deviation from the 
population mean for participant 𝑖. This model assumes that the random effect 𝑏𝑖~𝑁(0,𝜎2
𝑏) and the error 
𝜀𝑖𝑗~𝑁(0,𝜎2) are independent. 𝛽1 and (𝛽1 + 𝛽2), represent the slopes (or elimination rates of PBB) for the 
placebo or the intervention group, respectively. The group-by-time interaction parameter (𝛽2𝑋𝑖∗𝑡𝑖𝑗) 
assesses if the mean change in weight or if the PBB elimination rates vary by group across time. Slopes 
that vary randomly among participants will also be considered and an appropriate covariance structure 
will be selected. 
Adjustment for relevant baseline variables and subgroup analyses will be performed to assess differences 
in weight change or PBB elimination rates by relevant covariates (such as age, gender, initial PBB level, 
or initial BMI). Since, physical activity reduces body weight and BMI, and increases metabolism, both 
may be associated with reducing PBB body burden. In multivariable models of serum PBB 
concentrations, we will consider adjusting for intensity of physical activity and change in BMI in order to 
measure the independent effect of Orlistat on reducing PBB levels. For the ASA24 measures, we will 
examine possible associations between changes in mean daily caloric, fat, and carbohydrate intake and 
serum PBB concentrations. Statistical analyses will be performed in SAS 9.4 software, and models will be 
fit with the Mixed procedure [19].
DATA & SAFETY MONITORING & REPORTING
Data Safety and Monitoring Plan
OVERSIGHT RESPONSIBILITIES
Oversight of the progress and safety of the trial will be provided by the Principal Investigator (PI), Dr. 
Michele Marcus, and co-investigators Drs. Terry Hartman, Amita Manatunga, and Jennifer Morse along 
with Ms. Metrecia Terrell, project data manager/biostatistician. Adverse events are not anticipated, but 
any occurring will be documented and reported according to Emory IRB policies and procedures. 
Cumulative adverse events and study progress summary will be communicated to the IRB at the time of 
continuing review 
MONITORING PROCEDURES
Dr. Marcus assures that informed consent is obtained prior to performing any research procedures, that all 
participants meet eligibility criteria, and that the study is conducted according to the IRB-approved 
research plan. Dr. Morse will also review individual (de-identified) records and laboratory tests to confirm 
eligibility. 
De-identified study data are accessible at all times for the PI and co-investigators to review. The PI and 
co-investigators review study conduct, including protocol deviations and dropouts, on a monthly basis. 
The PI and co-investigators review adverse events (AEs) individually in real-time and in aggregate on a 
monthly basis. The PI and co-investigators review serious adverse events (SAEs) in real-time. Liver 

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
20
function, thyroid function, and creatinine levels will be measured prior to enrollment to ensure that the 
participant is healthy enough to partake in the study. Participants with abnormal levels or functions will 
not be eligible to participate in the study and will be counseled to seek care from their primary care 
physician. Additionally, participants with chronic kidney disease (defined by a glomerular filtration rate 
below 60) or kidney stones or gall bladder disorder will be excluded. Participants will be excluded if they 
are pregnant or lactating, have a diagnosed problem absorbing food, have a history of pancreatitis, 
bariatric surgery, organ transplantation, a diagnosed eating disorder, or a serious chronic disease as 
identified by the study doctor. Use of weight-loss medications, Coumadin, warfarin, Cyclosporine, or oral 
steroids will also exclude participants from the study. Allergies to any ingredients of the Orlistat OTC 
capsules including the active ingredient, Orlistat, and the inactive ingredients, microcrystalline cellulose, 
povidone, and xylitol will result in exclusion from the study. Participants will become ineligible at any 
point during the study if they begin a medical regimen involving any of the above medications.  
Pancreatitis is a very rare side effect of Orlistat use. Due to the extreme rarity, no routine laboratory tests 
will be performed. Patients will be counseled about the signs and symptoms of pancreatitis and instructed 
to report any relevant symptoms to Emory study staff. Liver injury is a very rare possible side effect. We 
will minimize the risk of liver injury by screening individuals for abnormal liver function and counseling 
participants about the signs and symptoms of possible liver injury. 
The PI ensures that all protocol deviations, AEs, and SAEs are reported to NIEHS and IRB according to 
applicable regulatory requirements.
COLLECTION AND REPORTING OF SAEs AND AEs
For this study, the following standard AE definitions are used:
Adverse event: Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure, 
regardless of whether it is considered related to the medical treatment or procedure.
Serious Adverse Event:
Any AE that results in any of the following outcomes:
Death
Life-threatening event
Event requiring inpatient hospitalization 
Persistent or significant disability/incapacity
An important medical event based upon appropriate medical judgment of Dr. Morse
AEs are graded according to the following scale, based on their impact on the patient:
Mild:
An experience that is transient, and requires no special treatment or intervention. The experience 
does not generally interfere with usual daily activities. This includes transient laboratory test 
alterations.
Moderate:
An experience that is alleviated with simple therapeutic treatments. The experience impacts usual 
daily activities. Includes laboratory test alterations indicating injury, but without long-term risk.
Serious:

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
21
An experience that requires therapeutic intervention. The experience interrupts usual daily activities. 
If hospitalization (or prolongation of hospitalization) is required for treatment, it becomes a serious 
adverse event.
The study uses the following AE attribution scale to determine the likelihood that they are related to the 
study intervention:
Not related:
The AE is clearly not related to the study procedures (i.e., another cause of the event is most 
plausible and/or a clinically plausible temporal sequence is inconsistent with the onset of the event).
Possibly related:
An event that follows a reasonable temporal sequence from the initiation of study procedures, but 
that could readily have been produced by a number of other factors.
Related: 
The AE is clearly related to the study procedures. 
AEs are identified through self-report by participants via follow-up phone calls. At the beginning of the 
study we will have frequent telephone contact with participants (at least once/week) followed by reduced 
frequency as the study progresses but no less than monthly. Participants can request more frequent phone 
calls. Participants will be asked to contact the Emory study staff if additional adverse events occur or if 
they have any concerns or questions about the protocol.
All AEs are reported according to the Emory IRB AE reporting guidelines. 
MANAGEMENT OF RISKS TO SUBJECTS
AEs that may be associated with the use Orlistat include:

Headache

Oily rectal discharge

Urgent need to have a bowel movement

Being unable to control bowel movements

Oxalate kidney stones/oxalate kidney damage

Pancreatitis

Liver injury or failure 
AE Management
AEs are identified through self-report by participants via follow-up phone calls that occur weekly and 
then are adjusted based on patient’s needs and preferences. Participants can request more or less frequent 
phone calls. Participants will be asked to contact the Emory study staff if additional adverse events occur 
or if they have any concerns or questions about the protocol.
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE. 

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
22
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode.
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the training 
and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring 
while on study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during interviews of a study participant presenting for medical care, or upon review by a 
study monitor. 
If participants report gastrointestinal issues following Orlistat use, they will be counseled to reduce the fat 
content of their meals. If symptoms persist or more serious symptoms arise, participants will be told to 
discontinue the Orlistat regimen but continue with the diet and exercise plan.
The signs and symptoms of severe liver injury include loss of appetite, itchy skin, yellowing of the skin or 
the white part of the eyes, amber colored urine, light-colored bowel movements (stools), or pain in the 
upper right portion of the stomach.  People who experience these signs and symptoms should contact their 
healthcare professional immediately.
Signs and symptoms of pancreatitis include right upper abdominal pain, nausea, vomiting, and loss of 
appetite.  
Symptoms of kidney problems include swelling, especially of the legs and feet, little or no urine output, 
frequent or painful urination, blood in the urine, loss of appetite, nausea, vomiting, or severe pain in the 
back, belly, or groin
An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the study intervention. After review of reported 
symptoms and real-time communication with Dr. Morse, she will determine the appropriate action needed 
on a case-by-case basis. If contact with participant is necessary then Dr. Morse will learn the identity of 
the individual, their intervention group and contact information. She will contact the participant to discuss 
management. 
SAE REPORTING
SAEs that are unanticipated, and possibly related to the study intervention will be reported to the, IRB, 
and NIEHS in accordance with requirements. There are no expected SAEs associated with this trial.
PROCEDURES

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
23
Study personnel will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation. We will call participants one week and one month after the participant completes the study. 
Any of these findings detected from one or more of our study assessments found by our study personnel 
will then follow a chain-of-command in a notification scheme provided to study personnel at the 
beginning of the study. This chain-of-command will lead to the appropriate channels being notified of a 
possible event.
After each study telephone call, the staff member will inform the PI, Dr. Marcus of the occurrence of 
AE/SAEs since the last visit.  If a further input is necessary Dr. Marcus will request advice from study 
clinician, Dr. Morse. If, after review, there is a confirmation of an AE/SAE, Dr. Morse, will immediately 
report to the PI, Dr. Marcus any serious adverse event, whether or not considered study intervention 
related, including those listed in the protocol or and must include an assessment of whether there is a 
reasonable possibility that the study intervention caused the event. Dr. Morse will notify patients 
individually by phone of AEs and SAEs, and study-related results that are of concern and may need 
additional management by the patient’s health care provider. 
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information.  
DATA QUALITY AND MONITORING PLAN
The PI or study staff will review all data collected on an ongoing basis for data completeness and 
accuracy as well as protocol compliance. Dropout rates will be monitored but will not affect the study’s 
progress. All SAEs and aggregate AEs will be reviewed. 
Research staff will collect information on adherence to protocol through follow-up phone calls abiding by 
the aforementioned schedule. Adherence of participants will be evaluated by pill counts, completion of 
Automated Self-Administered 24-Hour Dietary Assessment and the Physical Activity Questionnaire 
surveys completed by all participants at enrollment, 3 months, and 6 months. The PI, co-investigators and 
study statistician, will review adherence and drop-outs on a regular basis (probably monthly depending on 
the rate of accrual of participants). 
Safety oversight will be under the direction of a Data and Safety Monitoring Plan (DSMP) composed of a 
procedure with input from the appropriate expertise, including Dr. Marcus, Dr. Hartman, and Dr. Morse. 
All deviations will be addressed in study documents. Protocol deviations will be sent to the Institutional 
Review Board (IRB). 
If a pregnancy is reported the patient will be discontinued from the study intervention effective 
immediately. 
UNANTICIPATED PROBLEMS
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria:

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
24
•
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied;
•
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and suggests that the research places participants or others at 
a greater risk of harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized.
The investigator will report unanticipated problems (UPs) to the Institutional Review Board (IRB). The 
UP report will include the following information:
•
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number;
•
A detailed description of the event, incident, experience, or outcome; 
•
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
•
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP.
CONFIDENTIALITY
PLAN FOR DATA MANAGEMENT AND CONFIDENTIALITY
Confidentiality of participants will be maintained throughout the trial. Only a study ID number will 
identify participant blood samples and other study data and not their personal identifiable information, 
such as a name. Any database used to store data from this study will be password protected. Electronic 
communication with outside collaborators will involve only unidentifiable information. All documents 
will be maintained electronically and only accessible to the study staff and investigators. AE reports and 
annual summaries will not include subject- or group-identifiable material. Each report will only include 
the identification code. Additionally, Emory has obtained a Certificate of Confidentiality from the 
National Institutes of Health to help protect participant privacy. There are no conflicts of interest among 
the co-investigators to report.
REFERENCES
1.
McClendon, K., D. Riche, and G. Ikponmousa Uwaifo, Orlistat: current status in clinical 
therapeutics. 2009. 8: p. 727-744.
2.
Zhi, J., et al., Retrospective population-based analysis of the dose-response (fecal fat 
excretion) relationship of orlistat in normal and obese volunteers. Clin Pharmacol Ther, 
1994. 56(1): p. 82-5.
3.
Jandacek, R.J. and S.J. Genuis, An assessment of the intestinal lumen as a site for 
intervention in reducing body burdens of organochlorine compounds. 
ScientificWorldJournal, 2013. 2013: p. 205621.

Weight loss aid in a population exposed to PBB 
Version 3.0
8 Aug 2018
25
4.
Jandacek, R. and P. Tso, Enterohepatic circulation of organochlorine compounds: a site 
for nutritional intervention. The Journal of Nutritional Biochemistry, 2007. 18(3): p. 163-
167.
5.
Klein, A.V. and H. Kiat, Detox diets for toxin elimination and weight management: a 
critical review of the evidence. J Hum Nutr Diet, 2015. 28(6): p. 675-86.
6.
Diabetes Prevention Program Research, G., The Diabetes Prevention Program (DPP): 
description of lifestyle intervention. Diabetes Care, 2002. 25(12): p. 2165-71.
7.
Look, A.R.G., et al., The Look AHEAD study: a description of the lifestyle intervention and 
the evidence supporting it. Obesity (Silver Spring), 2006. 14(5): p. 737-52.
8.
Mason, C., et al., Dietary weight loss and exercise effects on insulin resistance in 
postmenopausal women. Am J Prev Med, 2011. 41(4): p. 366-75.
9.
Foster-Schubert, K.E., et al., Effect of diet and exercise, alone or combined, on weight 
and body composition in overweight-to-obese postmenopausal women. Obesity (Silver 
Spring), 2012. 20(8): p. 1628-38.
10.
Bandura, A., Social cognitive theory of mass communication., in Media effects: Advances 
in theory and research, Z.D. Bryant J, Editor. 2002, Hillsdale, NJ: Erlbaum. p. 121-153.
11.
Centers for Disease Control and Prevention, National Health and Nutrition Examination 
Survey (NHANES) Anthropometry Procedures Manual. 2016: Atlanta, GA.
12.
Thompson, F. and A.F. Subar, Diet Assessment Methodology, in Nutrition in the 
Prevention and Treatment of Disease, A.M. Coulston, C.J. Boushey, and M.G. Feruzzi, 
Editors. 2013, Academic Press: New York, NY.
13.
Subar, A.F., et al., The Automated Self-Administered 24-hour dietary recall (ASA24): a 
resource for researchers, clinicians, and educators from the National Cancer Institute. J 
Acad Nutr Diet, 2012. 112(8): p. 1134-7.
14.
Langer, R.D., et al., The Women's Health Initiative Observational Study: baseline 
characteristics of participants and reliability of baseline measures. Ann Epidemiol, 2003. 
13(9 Suppl): p. S107-21.
15.
Okonkwo, O.C., et al., Physical activity attenuates age-related biomarker alterations in 
preclinical AD. Neurology, 2014. 83(19): p. 1753-60.
16.
Li, Z., et al., Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med, 2005. 
142(7): p. 532-46.
17.
PASS, PASS Software. 2002, NCSS Statistical Software: Kaysville, Utah.
18.
Jandacek, R.J., et al., Reduction of the body burden of PCBs and DDE by dietary 
intervention in a randomized trial. J Nutr Biochem, 2014. 25(4): p. 483-8.
19.
ed, S.S.f.W., SAS System for Windows. 9.4 ed. 2014, SAS Institute, Inc.: Cary, NC.