Fecal Microbiota Transplantation for the Treatment of Obesity
Phase: PHASE1
Conditions: Obesity
Sponsor: Brigham and Women's Hospital

 
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Fecal Microbiota Transplantation for the Treatment of Obesity: 
An Investigation of the microbial contribution to pathogenesis of 
disease 
 
 
NCT: 02741518 
 
 
 
Version date: 5/16/2018 
 
 
 
 
 
 
 
 
 
 

 
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Fecal Microbiota Transplantation for the Treatment of Obesity: An Investigation of the 
microbial contribution to pathogenesis of disease 
Version Date: 05/16/2018 
 
I. 
BACKGROUND AND SIGNIFICANCE: 
Obesity is a major health burden affecting over one third of Americans and is associated with 
chronic diseases such as diabetes mellitus, cardiovascular disease, nonalcoholic fatty liver 
disease (NAFLD) and cancer 1-3. Pharmacologic options and lifestyle modifications, including 
caloric restriction, exercise, and behavioral modifications have provided only modest weight loss 
benefit 4,5. Surgery, while shown to result in significant weight loss and resolution of co-morbid 
metabolic illness, is invasive and accompanied by significant morbidity and mortality risk 6. There 
is an urgent need to develop novel treatment strategies targeting the underlying pathology 
leading to obesity and obesity-related diseases. 
Associations between the gut microbiota and obesity have been identified. Germ-free mice are 
protected from diet –induced obesity, insulin resistance, and NAFLD when fed western-type 
diets 7. Additionally, both obese humans and mice have been found to have an altered gut flora 
composition compared to lean counterparts 8; specifically, a decrease in the 
Bacteroidetes/Firmicutes ratio 9,10.  
Potential mechanisms of bacteria mediated weight gain/loss have been linked to short-chain 
fatty acids (SFCAs), which are a known byproduct of intestinal bacteria and are used as an 
energy source by colonic epithelial cells. Carbohydrates are fermented to SCFAs such as acetate, 
propionate, and butyrate by colonic bacteria, specifically Clostridial clusters IV and XIVa, 
including Eubacterium, Roseburia, Faecalibacterium, and Coprococcus 11. Additionally, SCFAs 
modulate the release of gut hormones from enteroendocrine cells such as glucagon-like peptide 
1 (GLP-1), through binding of SCFAs to the G-protein-coupled receptors GPR41 and GPR43 12-14. 
The main mechanism of action of GLP-1 is to increase glucose-mediated insulin release, delaying 
gastric emptying, and inhibiting glucagon release. GLP-1 agonists have been shown to promote 
satiety 15, leading to weight loss. GLP-1 is secreted within minutes of food intake by L-cells, 
located in the distal ileum and colon. Oral (but not IV) glucose administration causes GLP-1 
secretion 16. Additionally, GLP-1 readily crosses the blood brain barrier where it is thought to 
regulate ingestive behavior in the hypothalamus, which subsequently has direct effects on 
gastric emptying and resultant satiety 15. GLP-1 is secreted 15 to 30 minutes after food intake 
and is there measured at multiple time points post-prandial 17. Additionally, GLP-1 has been 
shown to increase following other weight loss interventions such as gastric bypass, with 
significant changes seen as early as 6 weeks 17.   
This connection has led to attempts at manipulations of the gut microbiome in order to 
modulate this process 18. In a recent trial, obese diabetic patients received a fecal microbiota 
transplantation (FMT) from either lean donors or autologous stool 19. Those in the treatment 
group were noted to have improved peripheral and hepatic insulin sensitivity. FMT involves the 
transfer of donor stool to a recipient. It has become widely accepted as a treatment for 
recurrent Clostridium difficile infection (CDI), with a cumulative cure rate of >90% and minimal 
adverse events 20. These preliminary studies suggest that FMT using lean donor stool may be 

 
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used to treat obesity and its sequela. We hypothesize that for obese patients, induction and 
maintenance FMT utilizing lean donor stool will correct a dysbiosis that has led to a decrease 
in circulating GLP-1 which acts as a surrogate marker for weight loss.  
 
II. 
SPECIFIC AIMS  
Specific Aim 1: Assess the safety of FMT in patients with obesity.  
Hypothesis: Induction FMT followed by weekly maintenance capsule FMT will be safe and well 
tolerated by obese patients.  
Specific Aim 2: Assess GLP-1 as a therapeutic biomarker for clinical response to fecal microbiota 
transplantation  
Hypothesis: Fecal Microbiota Transplantation will lead to an increase in SCFA which will lead to 
an increase in the metabolic regulator GLP-1.  
Specific Aim 3: Determine the impact of fecal microbiota transplantation on the intestinal 
microbiome of patients with obesity via 16s ribosomal RNA sequencing.  
Hypothesis: Fecal microbiota transplantation will result in a sustained repopulation of the 
patient’s microbiome that corresponds to the bacteria from the donor stool.  
 
III. 
Methods and Study Design  
This is a randomized controlled pilot study to assess the safety and to measure the 
microbiological and clinical impacts of FMT in patients with obesity. We will continue to 
prospectively enroll and screen adult patients until 20 patients have completed all study visits. 
We anticipate total enrollment to be 50 patients to account for screen fails and dropouts. 
Eligible patients are those who are obese (BMI of 35 kg/m^2 or greater). Patients will be 
randomized 1:1 to receive FMT or placebo. The participants will receive either an FMT from a 
lean healthy donor using 30 induction FMT capsules or placebo capsules. The participants will 
continue to receive a monthly maintenance dose of 12 FMT oral capsules or placebo at week 4 
and week 8. Serum for hormone levels will be collected at baseline, weeks 1, 4, 6, 8 and 12. 
Stool for microbial assessment will be collected at baseline and weeks 1, 4, 6, 8, 12, 26, and 52. 
A Food Frequency Questionnaire will be taken by the patient at week 0. Donor Stool will be 
obtained from OpenBiome. OpenBiome is a nonprofit 501(c)(3) organization that provides 
hospitals with screened, filtered, and frozen material ready for clinical use (See Attachments for 
OpenBiome Quality and Safety Program as well as donor screening examples).  
Primary Safety Endpoint:  
Safety Endpoints: Number and nature of adverse events at week 1, 6, 12 and 26.  
 
Primary Clinical Endpoint: 
The primary clinical end point is an increase in the AUC for GLP-1 after a mixed meal test from 
baseline and 12. 
 
Secondary Endpoints: 

 
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• 
Microbial Endpoints: Recipients fecal microbial diversity at week 6 and 12 compared to 
baseline  
• 
Clinical Endpoints: Decrease in BMI and waste circumference at week 6 and 12 compared 
to baseline.  
 
 
Trial Treatment:  
The treatment for this trial will be administration of an induction dose of 30 FMT capsules ingested 
orally. Treatment will occur after screening. 
 
Subsequent FMT administration will be maintenance capsules of frozen FMT material ingested 
orally every 4 weeks (weeks 4 and 8). All ingestions will be undertaken in the clinic under 
supervision. A follow-up phone call will be undertaken 4 hours after each ingestion visit to screen 
for adverse events. At 48 hours and 24 hours prior to and the day of each capsule dose (regardless 
of group) the patient will take a single dose of 20mg of omeprazole. 
 
Dosage Form 
1. Initial dose - filtered solution of donor stool in 30 gelatin capsules at Day 0 (16500µl total 
). 
2. Maintenance dose – twelve capsules of fecal material taken every 4 weeks (550µl of fecal 
material in each size 00 gelatin capsule)  
 
Dosing Regimen 
Single induction dose of 30 capsules (16500µl)  
Monthly dose of 12 capsules of fecal material (total 6600µl of fecal material at week 4 and week 
8) 
 
Capsule preparations are delivered to clinical investigators in double containment shipping 
vessels packed with dry ice, as with non-encapsulated placebo preparations. Packaging is 
labeled with the same information included on non-encapsulated preparations, with the 
addition of a clause instructing clinicians to administer the material to patients within 90 
minutes of removal from frozen storage. Patient instructions listed in Appendix 6.  
 
Packaging 
Encapsulated fecal material in freezer safe bottles will be stored in Styrofoam boxes from the 
Microbiome Health Research Institute at Massachusetts Institute of Technology, as described in 
their Drug Master File (15543). 
 
 
The Placebo Treatment: 
Those in the placebo arm will undergo procedures as in the active arm. They will be given 30 
placebo capsules at time of induction (Day 0) and this will be followed by 12 placebo capsules each 
month.  
 

 
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Placebo Oral Capsules 
Placebo capsules are prepared to support randomized, placebo-controlled studies of FMT. These 
capsules are prepared according to the specifications described below and utilized in studies as 
indicated by the study IND. 
1. An autoclaved solution consisting of 80% cocoa butter, 20% glycerol and brown food 
coloring, without the addition of human stool, is used as a placebo control. 
2. The autoclaved placebo solution is transferred to a reservoir. 
3. Capsules are generated as outlined in 6-9 of section V above. 
4. Each capsule is visually inspected for integrity and contamination of the outer surface.  
Capsules passing inspection are placed into an HDPE plastic bottle for immediate storage at -
80ºC. 
5. Placebos are quarantined until they have passed bioburden testing, as outlined in section XII 
below. 
6. Doses are transferred into the final pharmaceutical bottle packaging. The dosage size 
depends upon the requirements of an individual clinical trial’s specifications. Clinical trial 
specifications vary with the trial protocol, objectives, and the indication being targeted.  
 
 
Labeling 
See Drug Master File (15543). 
 
IV. 
STUDY PROCEDURES 
An outline of the study timeline and measurements is shown in Appendix 1 
 
Overview. This is a randomized controlled pilot study to assess the safety of FMT in obese 
patients. Additionally, the study will measure the microbiological and clinical impacts of FMT in 
patients with obesity. We will continue to prospectively enroll adult who are obese (BMI of 35 
kg/m^2 or greater) after providing written informed consent until 20 have completed all study 
visits. We anticipate total enrollment to be 50 patients to account for screen fails and dropouts. 
The study participants will be randomized 1:1 to either the treatment arm or the placebo arm. 
The treatment arm will receive an FMT induction followed by monthly (weeks 4 and 8) 
maintenance oral capsules for 12 weeks. The placebo group will receive placebo capsules   at 
the time of their induction followed by monthly intake of oral placebo capsules for 12 weeks. 
The participants will not receive dietary instruction and will be asked to continue with their 
regular diet. Information about their dietary habits will be collected at each study visit. Donor 
Stool and placebo material will be obtained from OpenBiome. OpenBiome, with whom we have 
previously collaborated with, is a nonprofit 501(c)(3) organization that provides hospitals with 
screened, filtered, and frozen material ready for clinical use. 
 
A. Recipient Procedures 
Week -2: Screening – potential subjects will undergo the following screening procedures one to 
two weeks prior to FMT to determine if they meet the recipient selection criteria; 

 
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1. Repeat of Medical record review to confirm diagnosis and treatment history if questions 
remain after initial screen. This will include either review of partner’s available data or data 
provided from home provider (When applicable) 
2. Symptom assessment (Symptom Diary Card) and physical exam by study physician  
3. Anthropometric measurements: BMI, Iliac measurements, waist-to-hip ratio 
4. Baseline blood work to assess for sequela of obesity: insulin, LFTs, CBC, and HgA1C and fasting 
serum lipids and blood glucose  
5. Stool sample to exclude current infections (bacterial culture, ova & parasites, Clostridum 
difficule toxin) and a sample for high-throughput 16S rRNA sequencing and metabolomics.  
6. Urine Pregnancy Test for females of child-bearing age: Women of child-bearing potential will 
be counseled by study clinicians that those randomized to the treatment arm will be requested 
to avoid pregnancy by hormonal or barrier methods from randomization for 4 months (duration 
of FMT therapy and one month lag afterwards). 
7. Diet recall and question about specific dietary restrictions or preferences. The patients will be 
asked to maintain their standard diets throughout the study. 
8. Baseline levels of ghrelin, Leptin, PYY and adiponectin will be measured 
9. A mixed meal tolerance test will also be performed. GLP-1, leptin and PYY measurements will 
be taken at time 0, 15, 30, 45, and 60 minutes.  
10. Pre FMT screening labs including HIV, Hepatitis B and C and Syphillis 
11. Serum will also be collected for metabolomic profiling  
12: Test swallow of an empty capsule  
13. Indirect Calorimetry – see Appendix 7 
14. Patients will be sent home with 9 doses of a proton pump inhibitor to be taken 48 hours 24 
hours prior to and the day of each capsule administration ( 3 times total). 
 
Week 0: (Treatment and Control Arms): Randomization: Eligible patients will be randomized 1:1 
according to a computer-generated randomization list. The randomization will be held centrally 
at the Brigham and Women’s Hospital Research Pharmacy. The treatment location will be 
masked to the patient and investigators performing data analysis. The health care worker 
administering FMT or placebo will not be aware of the treatment being administered. Treatment 
will be administered based on the result of randomization.  
• 
Food Frequency Questionnaire 
• 
Stool transplant (or Placebo) via capsule induction  
• 
A proton pump inhibitor will be taken daily at 48 hours and 24 hours prior to and day of 
capsule consumption.   
 
Week 1: (Treatment and Control Arms): Follow up and adverse event screening. Additionally: 
• 
BMI, Iliac measurements, hip to waist ratio 
• 
Indirect Calorimetry  
• 
Stool for microbiome analysis and metabolomics 
• 
CBC, LFTs, FBG, HgA1C, lipids, glucose, metabolomics 
• 
diet recall 
• 
Symptom Diary Card and Adverse Event screening 
Weeks 2-12: (Treatment and Control Arms) 

 
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Symptom diary Cards will be filled out weekly for adverse event monitoring 
 
Week 4, 8 (Treatment and Control Arms): Monitored Capsule Consumption and Follow-up study 
visits for assessment of:  
• 
Ingestion of 12 FMT capsules or inactive placebo. 
• 
A proton pump inhibitor will be taken daily for the 48 hours 24 hours prior to and day of 
capsule consumption.   
• 
BMI, Iliac measurements, hip to waist ratio 
• 
Stool for microbiome analysis and metabolomics 
• 
CBC, LFTs, FBG, HgA1C, lipids, glucose, metabolomics 
• 
diet recall 
• 
Symptom diary Card and Adverse Event screening 
Weeks 6, 12 : Follow-up study visits for assessment of:  
• 
BMI, Iliac measurements, hip to waist ratio 
• 
Stool for microbiome analysis and metabolomics 
• 
CBC, LFTs, FBG, HgA1C, lipids, glucose, metabolomics, ghrelin and leptin, PYY and 
adiponectin 
• 
Mixed meal tolerance test followed by serum for GLP-1, Leptin and  PYY at time 0, 15, 30, 
45, and 60 
• 
diet recall 
• 
Indirect Calorimetry  
• 
Symptom Diary Card and Adverse Event screening 
Week 26 and 52:  
• 
Safety assessment and Symptom Diary Cards via phone interview by a physician to screen for 
adverse events. 
• 
Stool sample for microbiome analysis to be mailed in 
• 
Ask for the patients current weight 
 
Stool collection instructions are outlined in Appendix 2. 
Patient obligations in the study will end at week 52 however the patient’s medical record may 
be followed prospectively for evaluation of weight loss and weight loss surrogates as well as 
metabolic parameters done for clinical care through year 5 post-enrollment as needed. This may 
include review of partner’s available records or records from home provider. (when applicable)  
 
Stopping Criteria 
Adverse events will be specifically monitored at week 1, 4, 6, 8, 12, 26, and 52 after FMT by direct 
patient interviews, or by reporting from clinical sites of adverse events at any time in-between. A 
data safety and monitoring board (DSMB, Appendix 5) will review all patient data to ensure optimal 
patient safety and precautions for subjects with obesity treated with FMT. A severity grade for 
adverse events (Appendix 6) and subject symptom diary cards will be used (Appendix 7). The DSMB 
will meet a minimum of 2 times: after treatment of the first 10 subjects, and after treatment of all 
20 subjects. Study will be stopped under the following circumstances; 

 
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Any unexpected serious adverse events occur that the DSMB determines as at least possibly 
related to FMT or detection of new pathogenic intestinal infection in stool samples in any 
patient treated.  
 
Any subject who develops a serious adverse event that is judge to be probably, possibly, or definitely 
related to FMT therapy will receive no further FMT treatment. They will remain in the trial only for 
adverse event follow-up.  
 
Accountability Procedures for the Investigational Product 
The location, volume and number of all FMT donor solutions will be maintained in a log by the 
research team. The principal investigator will be responsible for accurate record and tracking of all 
FMT solutions. Logging of FMT solution used for administration will be performed using a two-
person process. 
  
Data to be Recorded Directly on the CRFs 
Data will be obtained from patients directly, and their electronic health record as follows; 
Demographics , age, gender, co-morbidities, medication use, and laboratory values.  
 
Donor Procedures (OpenBiome): 
Prior to enrollment, donors (age >18), receive informed consent with oversight from MIT’s IRB 
and COUHES. Donors are interviewed by a healthcare professional to determine whether they 
meet the following:  
Clinical Exclusion criteria: 
1. Infectious risk factors: 
a. Known HIV, Hepatitis B or C infections or exposure within previous 12 months 
b. High risk sexual behaviors 
c. Use of illicit drugs 
d. Tattoo or body piercing within previous 6 months 
e. Incarceration or history of incarceration 
f. Known current communicable disease 
g. Risk factors for variant Creutzfeldt-Jakob disease 
h. Travel within previous 3 months to countries where risk of infectious diarrhea is 
elevated 
2. Gastrointestinal and systemic comorbidities: 
a. History of IBD, irritable bowel syndrome, chronic constipation or chronic diarrhea 
b. History of gastrointestinal malignancy or known polyposis 
c. Antibiotic use within the previous 3 months 
d. Immunosuppressive state or use of immunosuppressive medications 
e. History of major gastrointestinal surgery (e.g., gastric bypass) 
f. Metabolic syndrome ; history of NAFLD, hypertension, dyslipidemia, CAD, CHF 
g. Systemic autoimmunity, e.g., multiple sclerosis, connective tissue disease 
h. Atopic diseases including asthma and eczema, eosinophilic disorders of the 
gastrointestinal tract 
i. Chronic pain syndromes, e.g., chronic fatigue syndrome, fibromyalgia 
j. Specifically for this study: BMI < 23; waist circumference < 35 inches for women, < 40 
inches for  men; fat mass < 20%; FBG <95 mg/dL; HbA1C<5.7; LDL < 100 mg/dL; TG<100 
mg/dL; HDL> 60 mg/dL; ALT < 20 U/L for women, < 30 U/L for men. 

 
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Donor Testing 
Prospective donors that do not meet any of the exclusion criteria outlined above will then be 
subjected to a battery of serological and stool-based assays to determine whether common 
infectious agents are present. All tests will be outsourced to third party . 
Laboratory Improvement Amendments (CLIA) certified testing facilities. As a condition for 
participation in this program, donors are required to submit written authorization for the 
disclosure of the results of these tests to the Microbiome Health Research Institute, in 
compliance with the Health Insurance Portability and Accountability Act (HIPAA). We will redact 
all personal identifying information from each report when we receive it. We will share copies of 
these raw diagnostic reports with our clinical partners. In the event that material from multiple 
donors is provided in a single shipment, results will be provided for all samples along with a file 
indicating which samples correspond to which donor screens. Documentation will be provided 
for the battery of tests prior to enrollment of a donor and for tests performed at the end of the 
collection window. Positive results for any of the following assays will be treated as exclusion 
criteria for all materials. 
 
Serologic testing: 
a. HIV antibody, type 1 and 2 
b. Hepatitis A (IgM) 
c. Hepatitis B panel (HBsAg & HBc [IgM]) 
d. Hepatitis C (HCV antibody) 
e. Treponema pallidum screening cascade (EIA with reflex to RPR) 
f. Liver function panel 
g. Complete blood count 
h. C-reactive protein assay 
i. HTLV 1 and 2 antibodies 
h. measurement of FBG, HgA1C, ALT, lipid profile if not done previously. 
 
Stool testing: 
a. EIA assay for Clostridium difficile toxins A and B 
b. Culture-based assays for common enteric pathogens (including Salmonella, Shigella, E. coli, 
Campylobacter and Vibrio) 
c. Fecal Giardia antigen EIA 
d. Fecal Cryptosporidium antigen EIA 
e. Ova and parasites exam 
f. Tri-chrome stain for Isospora 
g. Cyclospora smear test 
h. H. pylori EIA 
f. measurement of SCFA and 16S rRNA microbiome interrogation 
 
Collection Window and Donor Monitoring 
Donors that meet the above criteria are enrolled to provide material for FMT. Donor material is 
collected for up to 60 days following the initial screening. During this collection window donors 
must not violate any of the risk factors identified in Part A above. During a collection window, all 
material is quarantined until the donor has passed a second battery of serological and stool 
tests as described in Part B above. Material will be released for clinical use only after the donor 
has successfully completed both sets of assays (before and after the collection window). 

 
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In the event that a donor is recruited to provide additional material beyond an initial 60-day 
collection window, additional testing will be performed at 60 day intervals. Repeat donors that 
have not been tested within 60 days will be treated as new donors subject to the same 
screenings described in Parts A and B above. This ensures that all donors (even long-term 
participants) are subject to regular health evaluation. 
In the event that the donor passes a loose stool or has other symptoms of disease, donors will 
immediately meet with a healthcare professional to evaluate their continued suitability for 
participation in our program. If the clinician determines that the donor is not healthy, the donor 
will be un-enrolled from the program. In the event of such a diagnosis, all material contributed 
during the preceding collection window will be destroyed. In addition to this qualitative 
exclusion by clinician’s discretion, we will also treat three or more loose stools passed in a 24-
hour period as an absolute exclusion criterion, and all material from the affected donor’s 
collection window will be destroyed, regardless of clinical evaluation. Although less frequent 
passage of loose stool is not medically indicated as a disease and is common among healthy 
individuals, in the interests of caution we will also destroy material collected near any loose 
stool movement. All material collected from within 48 hours of two loose stools will be 
destroyed. All material collected from within 24 hours of a single loose stool will similarly be 
destroyed. 
 
Production and Process Controls 
1. The donor deposits stool in a commode, seals the lid, and places the collection container in a 
plastic bag to serve as secondary containment. Donors receive training to ensure that samples 
are not contaminated during the collection process. 
2. After passage, the sealed sample collection container is immediately transferred from the 
donor to a qualified technician to process the sample. 
3. Samples are transferred to a UV-sterilized biosafety hood as quickly as possible, not to exceed 
60 minutes from the time of collection. 
4. Within the biosafety hood, the stool is transferred to a sterile filter bag. The filter bag fits 
around the collection commode entirely, so there is no risk of material escaping during this 
transfer process. All stool material is added to the same side of the membrane in the filter bag. 
5. An autoclaved dilutant consisting of 12.5% glycerol and a normal saline buffer (0.90% w/v 
NaCl in water) is added to the filter bag. 
6. The sample solution sealed inside the filter bag is then introduced to a homogenizer blender 
for 60 seconds to mix the materials. 
7. Samples are then aliquoted into sterile bottles using sterile, disposable serological pipettes. 
8. The bottles are then capped, sealed and frozen immediately at -80°C. Any samples not fully 
processed and frozen within 120 minutes of passage will be destroyed. 
9. Samples are sealed with a tamper evident shrink band as an additional level of containment 
and to ensure samples are not contaminated or tampered with during storage and distribution. 
10. Samples will be delivered to clinicians on dry ice, in double-containment vessels, with 
temperature indicators to ensure that samples have not thawed during transportation. 
11. Production of stool capsules and placebo 
12. Preparation of inactive slurry 
 
V. 
Subject Selection and Withdrawal.  

 
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Donors: OpenBiome donors are rigorously assessed and monitored. 
1. Donor candidates are screened with comprehensive evaluation of medical histories, 
behavioral risks, and current health status. 
2. Laboratory Screening: Donor candidates are screened for 20 stool and serological tests 
at a CLIA-certified laboratory. Less than 20% of those screened become qualified donors 
3. Continuous Requalification: Qualified donors are under medical monitoring through the 
entire donation window and are fully rescreened every 60 days 
4. Quarantine Procedure: Prior to release, donated material is quarantined for 60 days in 
between two full panel screens at a CLIA certified laboratory. After passing a first 
battery of tests, a donor may donate specimens for a 60-day window. All material made 
from these specimens is held in quarantine until a second battery of tests is 
administered. The material from this 60-day window is release only if and when the 
donor passes this second battery of tests. 
5. Additional metabolic criteria for donors: The donor used for this study must 
additionally meet the following inclusion criteria: 
a. BMI <21 kg/m2 or total body fat % < 20% 
b. HDL > 60  mg/dL for women; > 50 for men; LDL< 100 mg/dL; TG< 100 mg/dL 
c. FBG < 95 mg/dL 
d.  waist circumference for  men < 40 inches; women <35 inches 
e. ALT < 20 U/L for women; < 30 U/L for men. 
 
Patients: 
Patient enrollment will be done via two methods: 
1. Patient initiated  communication with investigator via the clinicaltrials.gov website. (This may 
be E-mail or phone calls depending on patient preference)   
2. Referral of appropriate patients from the GI or Primary Care clinic at Brigham and Women’s 
Hospital (BWH. All study procedures will take place at Brigham and Women’s Hospital.  
 
Selection of subjects. Obese (BMI 35 kg/m^2 or greater) subjects who meet the inclusion 
criteria will be enrolled in the trial, after providing written informed consent. The study 
participants will be randomized 1:1 to either the treatment arm or the placebo arm. The 
treatment arm will receive an FMT capsule induction followed by monthly maintenance oral 
capsules for 12 weeks. The placebo group will receive placebo capsules at the time of their 
induction followed by monthly intake of oral placebo capsules for 12 weeks. The participants 
will not receive dietary instruction and will be asked to continue with their regular diet. 
Information about their dietary habits will be collected. 
 
Inclusion criteria: 
1. Age 18 years or older 
2. Obesity defined as a BMI of 35 kg/m^2 or greater  
 
Exclusion criteria: 
1. Triglycerides > 500 mg/dL 

 
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2. Use of antibiotics <8 weeks prior to participation 
3. Use of probiotics <4 weeks prior to participation 
4. Alcohol use of greater than 20g/daily or suspicion of alcohol abuse and dependence 
5. Substance abuse, current 
6. LFTS greater then 3x the ULN 
7. Cirrhosis. 
8. DM type 2 that is insulin dependent,  treated with GLP1-agonists, or poorly controlled on oral 
medications (HbA1C > 10%) 
9. Use of any weight loss medication or participation in a weight loss study or program such as 
Weight Watchers in the past 3 months 
10. History of recent weight change (weight loss or weight gain in the two months preceding 
trial enrollment). This is defined as a gain or loss of 10 or more pounds in the preceding 2 
months. 
11. Patients who are pregnant or breastfeeding 
12. Patients who are unable to give informed consent 
13. Patients who have previously undergone FMT  
14. Patients who have a confirmed active malignancy or cancer 
15. Patients who are immunocompromised including HIV infection. 
16. Participation in a clinical trial in the preceding 30 days or simultaneously during this trial  
17. Previous gastric or small intestinal surgery that alters gut anatomy such as fundoplication, 
gastric resection, gastric bypass, small bowel resection, and ileocectomy 
18. Other comorbidities including: systemic lupus, inflammatory bowel disease, or Chronic 
kidney disease as defined by a GFR <60mL/min/1.73m2 44 or rheumatoid arthritis 
19. History of rheumatic heart disease, endocarditis, or valvular disease due to risk of 
bacteremia from colonoscopy 
20. Any condition, based on clinical judgment that may make study participation unsafe 
21. History of severe food allergies (e.g. anaphylaxis or anaphylactoid reaction) 
22. Use of immune modulators including methotrexate, mycophenolate mofetil, tacrolimus, 
cyclosporine, thalidomide, Interleukin-10, or Interleukin-11 or prednisone within the past 2 
months 
23. Treatment with infliximab, adalimumab, certolizumab, natalizumab, vedolizumab or 
thalidomide within the prior 2 months 
24. Congenital or acquired immunodeficiencies 
25. Patients with allergies to ingredients Generally Recognized As Safe (GRAS): glycerol, sodium 
chloride, hypromellose, gellan gum, titanium dioxide, cocoa butter 
26. Dysphagia: oropharyngeal, esophageal, functional, neuromuscular (e.g. stroke, multiple 
sclerosis, ALS) 
27. History of aspiration 
28. History of severe gastroparesis 
 
For patients outside of the Partner’s system, medical diagnoses that are identified by the patient 
and relevant to inclusion and exclusion will be confirmed with their treating physician  

 
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Subject Withdrawal Criteria: Patients – patients will be withdrawn under the following 
circumstances: 
1. Patient withdraws their consent for follow-up visits or contacts. 
2. Patient is unable to successfully perform capsule test swallow. 
3. These above patients will only be followed-up for week 2 adverse event screening, as they 
will not have received FMT. These subjects will be replaced, as they will not be considered 
“treated” 
 
VI. 
SUBJECT ENROLLMENT 
Recruitment Procedures:  
BWH gastroenterologists and Primary Care Physicians, including attending physicians and 
fellows, will be informed of the study’s aims and inclusion criteria. These doctors who have 
firsthand knowledge of the patient's medical history must give approval for his/her patient to be 
contacted for research purposes and will inform the principal investigator of patients who meet 
the study criteria and who may be good candidates for the study. The referring physician will 
introduce the study to the potential patient and request the patient’s permission to be 
approached by study staff.   
After the treating physician has described the research study to the patient and has given 
permission to be contacted, a member of the study staff will be available for any follow-up 
questions. Investigators and study coordinators will reinforce with any potential subjects that 
participation is voluntary, that they do not have to participate, and the decision not to 
participate will not affect their care now or in the future. The patient will be given a copy of the 
informed consent, and encouraged to discuss the study with family, friends, their PCP, and/or 
others. Study staff will follow up to see if there are any questions or concerns that have not 
been addressed. These follow-up contacts will reoccur until the patient has either (a) been 
enrolled or (b) turned down participation in the study. 
To minimize the “undue influence” that the principal investigator may have on study subjects, 
Dr. Allegretti’s patients (whom she feels are eligible) will be initially approached by another 
physician or nurse practitioner in the practice about the study. Subjects will be approached by a 
study staff member (investigators, research assistant or coordinators) when they have given 
their permission to be contacted. They will be given both oral information about the study and 
they will have the opportunity to ask questions of the study staff at the time of recruitment. 
Patients will also have an opportunity to discuss participation with their primary physicians, 
including Dr. Allegretti, as well once they have received all study information.  
We will not utilize advertisement material or other informational materials for patients beyond 
the consent form. Patients will be given as much time as they need to decide.  They will be given 
a copy of the consent form to take home, read, and consider, and they will be encouraged to 
discuss participation with family members and health care providers.  

 
14
The consent form will be signed that day or at a future visit to the clinic. Once signed, the 
subject will undergo further screening to determine eligibility. No study related procedures will 
be performed until the informed consent form has been signed. 
If they decide to participate, both study and controls will be asked to maintain their standard 
diet. 
If patients reach out to us via the provided E-mail or phone number located at the 
clinicaltrials.gov website, we will pre-screen them using questions from the provided E-
mail/phone script. If the patient’s responses do not indicate any exclusion criteria being met, 
then we will contact their primary care provider via email or phone call (with patient 
permission) to confirm medical diagnosis. Once patient’s medical and treatment history are 
thoroughly vetted with the primary care physician, we will ask the physician to further discuss 
the study with the patient to minimize “undue influence” and ensure appropriateness for 
participation. When we are given the approval of the physician to enroll the patient in the study, 
we will then schedule the standard screening visit to re-review medical history (inclusion and 
exclusion criteria) and perform informed consent. (See below)  If the patient has no medical 
problems and has no treating physician due to lack of medical problems, the patient will be 
eligible to come in for a screening visit.  
Consent Procedures:  
The treating physician will introduce the study to the potential patient and request the patient’s 
permission to be approached by study staff.  With the treating physician’s permission, either a 
physician investigator or study coordinator will describe the research study in detail, including 
participation and risks and alternative courses of treatment, and answer any questions or 
concerns that the patient may have.  Patients will be given as much time as they need to 
consider participation before signing the consent form.   
 
In order to avoid coercion, study staff will reinforce that participation is voluntary and that their 
decision will not affect the medical care that they receive now or in the future.  If patients seek 
more time to consider participation, they will be given a copy of the consent form and 
encouraged to discuss the study with family, friends, PCP, or others.  Study staff will follow-up to 
see if any questions or concerns have not been addressed. A physician investigator will obtain 
informed consent signatures.   
 
VII. 
Assessment of Safety 
Patient safety monitoring schedule - although there have been no reported serious adverse events 
associated with fecal microbiota transplantation (FMT) in patients with recurrent refractory 
Clostridium difficile, we will have a special data safety and monitoring board (DSMB) to ensure 
optimal patient safety and precautions for subjects with obesity treated with FMT. Adverse events 
will be specifically monitored at 1,  4, 6, 8, and 12, weeks after FMT by direct patient interviews, or 
by reporting from clinical sites of adverse events at any time in-between.  Adverse events will also 
be assessed via telephone calls at weeks 26 and 52. The DSMB will meet a minimum of 2 times: 
after treatment of the first 10 subjects, and after treatment of all 20 subjects. A copy of the DSMB 
charter is located in Appendix 3.  
 

 
15
For this trial, an adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation patient administered a biologic product; such an occurrence does not 
necessarily have to have a causal relationship with this treatment. An AE can be any unfavorable 
and unintended sign, symptom, or disease temporally associated with the use of a medicinal 
product whether or not considered related to the medicinal product. A serious adverse event (SAE) 
is defined as any untoward medical occurrence that results in death, is life threatening, requires 
hospitalization or prolongation of existing hospitalization, results in persistent or significant 
disability/incapacity, is a congenital anomaly/birth defect, is an important medical event that may 
not be immediately life threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes previously mentioned. 
Adverse events will be determined by a toxicity grading scale (Appendix 4). 
 
Patients will be asked to document their symptoms using the symptom diary card  
(Appendix 5) as a memory aide. Subjects will be asked to complete a symptom diary card at 
baseline, prior to FMT, and on the day of treatment to assess their baseline. They will then be asked 
to complete a symptom diary card each day for 1 week post-FMT and then once a week thereafter 
for 12 weeks and then during follow-up at weeks 26 and 52. The symptom diary card will help the 
patient monitor and keep track of adverse events and will be reviewed by the Principal Investigator.   
 
In addition the DSMB may convene additional meetings if necessary to ensure the ongoing 
monitoring and safety of the subjects treated with FMT. The internal DSMB will include the 
following individuals: Dr. Walter Chan ( BWH Gastroenterology, Chair),  
Dr. Marvin Ryou (Gastroenterology – BWH) and Dr. Andrew Courtwright ( Pulmonology/Ethics-
BWH). All events will be reported directly to the DSMB and the Institutional Review Board (IRB) in 
accordance with Harvard University policy: Investigators will promptly report to the IRB all 
unanticipated problems involving risks to human subjects or others under Title 21 of the Code of 
Federal Regulations (21 CFR) part 56 (Institutional Review Boards), part 312 (Investigational New 
Drug Application), and part 812 (Investigational Device Exemptions).Harvard Medical School policy 
is consistent with guidance set forth by the Office for Human Research Protections (OHRP) 
(presented January 15, 2007) http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm and the FDA 
(presented January 14, 2009)  
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126572.pdf when 
determining what related events require review by the Institutional Review Board. Any serious AEs 
also will be evaluated by the DSMB for review and determination of whether the trial should 
continue. 
 
All subjects will be followed for an additional six months following the end of their treatment.   
Subjects that did not experience a AEs or SAEs will receive a telephone call to monitor their current 
symptoms and quality of life.  For subjects that did experience a AE or SAE that was found to be 
connected to the FMT treatment, we ask that they return to our medical center for an exam with 
their gastroenterologist. All treatment and outcome of AEs will be documented on the CRF and 
summarized in the CSR. All AEs will be followed to resolution or stabilization by the study physician. 
 
VIII. 
Biostatistical Analysis:  
This is an exploratory study as relatively little is known about the microbiome of patients with 
obesity. Thus, the main objective of our study is to assess the safety of FMT in obese patients. 
Secondarily we will be able to characterize variability in the microbiome of obese patients to aid 

 
16
in estimating effect sizes for designing larger studies powered to detect associations between 
microbiome data and GLP-1 levels and possible weight loss/BMI. 
 
IX. 
Risks and Discomforts:  
Fecal Microbial Therapy: 
 
Known Risks of FMT 
• 
Altered bowel pattern (diarrhea, constipation) 
• 
Cramping 
• 
Belching 
 
Potential Risks of FMT 
• 
Transmission of pathogenic bacteria, viruses, fungi 
• 
Transmission of allergens 
• 
Alteration in intestinal metabolism 
 
Privacy and Confidentiality:  
This study involves the collection of personal health information.  Accidental release of personal 
health information is a risk of participation in this study.  Measures will be taken to protect the 
confidentiality of all subjects’ information.  These measures include keeping all information 
collected about the subjects’ confidential, keeping information in locked rooms, and having 
physicians who are directly involved with a subject’s clinical care involved in the study. 
Venipuncture: Risks of having blood drawn include pain, bruising, or infection.   
 
Pregnancy: The risks to fetuses and women who are pregnant are unknown.  
 
X. 
Potential Benefits:  
Subjects may not receive any benefits from taking part in this study. However this research and 
the results of this study may benefit others in the future.  
 
The potential benefits include:  
• Restoration of fecal diversity 
• Increase in GLP-1 hormones 
• Weight loss  
 
As this is a pilot study, it is difficult to quantify the expected benefits.  
 
XI. 
Monitoring and Quality Assurance:  

 
17
The Principal Investigator, Dr. Jessica Allegretti, will assure the validity and integrity of the data 
and adherence to the IRB-approved protocol.   
Study staff will review completed CRF’s before each visit to ensure completeness of previous 
entries.  Entries that need clarification will be reviewed by the PI, and the subject and/or 
treating gastroenterologist will be consulted if needed.   
 
 
 
 
 
 
 
 
 
 
Appendix 1:  
 
 
 
 
 
FMT capsule 
induction and 
Randomization 
Ingested every 
month 
Week 4  
Week 8 

 
18
 
Appendix 2. 
Stool collection Instructions 
Important note about sample collection and shipping: 
Collect and ship your stool samples by FedEx according to the Samples Collections Schedule that 
your research coordinator explained to you. Please ship within 24 hours of collection. Please 
contact your research coordinator, Madeline Carrellas (617)732-9223 if you have any 
questions.  
This kit contains the supplies needed for 1 stool sample collection and 1 return shipment.  
 
Part 1 — Preparation for one collection 
1. Each kit contains the following stool 
collection materials (see photo): 
- 1 Blue Bowl + Seat to collect your stool 
- 1 Tube with a screw cap top (a Para-Pak vial). 
This tube has a built-in spoon for scooping and 
contains a liquid that is a preservative solution 
- 1 Pair of gloves for hygienic collection 
- 1 Plastic dropper [optional use] 
2. Wash your hands with soap and water, then 
rinse. 
3. Urinate into toilet BEFORE stool collection. 
 
Part 2 — Collection Seat Placement  
1. Lift toilet seat. 
2. Place Blue Bowl and Seat at the back of the toilet bowl for 
collection. 
3. Lower toilet seat and ensure stability of the blue collection bowl. 
4. Deposit stool directly into the blue collection bowl.   
**DO NOT urinate into the blue stool collection bowl**. 
 

 
19
Part 3 — Collecting the Stool Sample  
1. Unscrew and remove the lid of the clean collection 
tube provided. 
2. Using the spoon attached to the lid, scoop one pea-
sized amount of your stool into the tube. Please DO NOT 
provide more stool than the pea-sized amount 
requested.  
For liquid stool the plastic dropper can be used.  Please 
provide ONE dropper full of material. 
3. Close and tighten the lid firmly.  
4. Shake the closed tube by inverting it a few times to 
completely immerse the stool sample in the liquid, and 
then tap the bottom of the closed tube on a table top to ensure that the sample is at the bottom 
of the tube.  
5. Dispose of the blue bowl, the seat, and the gloves in the trash. Wash your hands with soap 
and water. 
 
 

 
20
Stool shipping Instructions 
Part 4 — Labeling, Packaging and Shipping the Specimen  
1. Each kit contains the following shipping materials:  
- FedEx – UN3373 pack with pre-filled shipping label 
- An easy fold return shipper (cardboard box) 
- A small plastic bag with biohazard symbol 
- A strip of absorbent material (gray tissue) 
2. Please record the date and the time of the collection ONLY as 
previously explained to you by your research coordinator. DO NOT 
record your name or any personal information. To protect your 
privacy, this has been replaced with a patient barcode. 
3. Place the tube inside the small plastic bag with biohazard symbol 
on it. Please keep the absorbent material (gray tissue) inside this 
plastic bag.  
4. Seal the plastic bag by removing the 
white tab and exposing the adhesive. Firmly 
press flap to completely seal the bag. Place 
this plastic bag, with the vial inside, in the 
small cardboard box and close the box. 
5. Place the cardboard box inside the plastic 
pre-labeled FedEx UN3373 pak.  
6. Follow the instructions below to either schedule a FedEx pickup 
or to drop off the package. 
 
 
 
 

 
21
FedEx Shipping Instructions:  
Biological Samples 
 
 
 
 
 
Instruction for pick-up schedule (preferred option):  
1) Call 1-800-GO-FEDEX (1-800-463-3339) to schedule a home pickup within 24 hours of 
collection.  
2) Your call will be answered by an automated system and will give you several options. Follow 
the options and verbally state “schedule a pick up”.  
3) The system will ask you to enter or verbalize your 9 digit account number. The FedEx account 
number is 686124762. 
4) When asked if you want an express or ground delivery, please state “express”.  
5) Depending on what time of day you call, the system may ask if you the package is ready for 
pick up now. Please respond “NO” if it is to be picked up the next day. If it needs to be picked up 
that day, please respond “YES”.  
6) You will be asked for your zip code followed by the number of packages, and if any of them 
are over 150 pounds – give the zip code of your home address and state that you have 1 
package that does not weigh over 150 pounds.  
7) You will be required to provide the address where the package will be picked up.  
8) The system will then confirm the pickup time and location. After confirming the pickup is 
scheduled properly, the system will hang up.  
9) At any time during the call you may be directed to a customer service representative to 
confirm the details of your pick up.  
 
Instruction for drop-off (alternative option): 
1) Call 1-800-GO-FEDEX (1-800-463-3339) to determine the appropriate FedEx dropbox location. 
2) Verify with FedEx that the FedEx location of your choice can accept UN3373 pack and drop 
the package off within 24 hours of collection.  
 
 
If you have any questions about the stool collection procedures, please do not hesitate to 
contact your research coordinator at 617-732-9223 
 
Thank you for your participation in this study!  
 
 
 
 
 
 
 
 
 
 
 

 
22
 
In-clinic Stool collection Instructions 
 
Each stool collection kit contains: 
- 1 Blue Bowl + Seat to collect your stool. 
- 2 Tubes with a screw cap top (called Para-Pak vial). These tubes have a built-in 
spoon for scooping: 
1 empty tube, without any liquid (marked by blue dot stickers) 
1 tube containing a preservative solution (no sticker) 
- 1 Pair of gloves 
 
Part 1 - Collection Seat Placement  
1. Lift toilet seat. 
2. Place Blue Bowl and Seat at the back of the toilet bowl for collection. 
3. Lower toilet seat and ensure stability of the blue collection bowl. 
4. Deposit stool directly into the blue collection bowl.   
**DO NOT urinate into the blue stool collection bowl**. 
 
Part 2 - Collecting the Stool Samples  
1. Collection tube with blue dot sticker (no liquid) 
a. Unscrew and remove the lid of the clean collection tube with blue 
dot sticker. 
b. Using the spoon attached to the lid, scoop one pea-sized amount of 
your stool into the empty tube. Please DO NOT provide more stool than the 
pea-sized requested.  
c. Close and tighten the lid firmly.  
2. Collection tube with preservative solution 
a. Unscrew and remove the lid of the other collection tube (without 
blue sticker).  
b. Using the spoon attached to the lid, scoop one pea-sized amount of 
your stool into the empty tube. Please DO NOT provide more stool than the pea-sized 
requested.  
c. Close and tighten the lid firmly.  
 
d. Shake the closed tube by inverting it a few times to completely immerse the stool  
sample in the liquid, and then tap the bottom of the closed tube on a table top to ensure that 
the sample is at the bottom of the tube. 
3. Dispose of the bowl, the seat, and the gloves in the trash. Wash your hands with soap and 
water.  
4. Return both your collection tubes to the research coordinator. 
 

 
23
Appendix 3. 
Charter, Data and Safety Monitoring Board for  
Fecal Microbiota Transplantation for the Treatment of Obesity: An Investigation of the microbial 
contribution to pathogenesis of disease 
 
 
January 2016 
 
1. Introduction 
This Charter is for the Data and Safety Monitoring Board (DSMB) for the study “Fecal Microbiota 
Transplantation for the Treatment of Obesity: An Investigation of the microbial contribution 
to pathogenesis of disease.” 
 
 The DSMB will consist of a team of clinical researchers who are unaffiliated with this project.  
These individuals will not be investigators in this study and will be experienced in conducting 
and interpreting clinical trials; they will review the efficacy and safety endpoints at the below 
stated time points. There will be 3 members on the DSMB consisting of at least two 
gastroenterologists and one Ethics specialist.  The members of the DSMB are: 
 
Dr. Walter Chan (Gastroenterology – BWH, Chair)  
Dr. Marvin Ryou (Gastroenterology – BWH) 
Dr. Andrew Courtwright (Pulmonary/Ethics-BWH) 
 
The Charter is intended to be a living document.  The DSMB may wish to review it at regular 
intervals to determine whether any changes in procedure are needed.  
 
2. Responsibilities of the DSMB 
 
The DSMB is responsible for safeguarding the interests of study participants, assessing the 
safety and efficacy of study procedures, and for monitoring the overall conduct of the study.   
 
The DSMB is an independent group advisory and is required to provide recommendations about 
starting, continuing, and stopping the study.  In addition, the DSMB is asked to make 
recommendations, as appropriate, to the about: 
• 
Selection, recruitment, and retention of participants 
• 
Adherence to protocol requirements 
• 
Completeness, quality, and analysis of measurements  
• 
Amendments to the study protocol and consent forms 
• 
Participant safety 
• 
Notification of and referral for abnormal findings  
 
 
3.  Scheduling, Timing, and Organization of Meetings 
Data and Safety Monitoring Meetings 
The DSMB will meet a minimum of 2 times: after treatment of the first 10 subjects, and after 
treatment of all 20 subjects. In addition the DSMB may convene additional meetings if necessary 

 
24
to ensure the ongoing monitoring and safety of the subjects treated with FMT. Any serious AEs 
also will be evaluated by the DSMB for review and determination of whether the trial should 
continue. An example of the DSMB meeting minutes are at the end of this document. The study 
will not proceed at each of these time points until the DSMB gives approval to continue.  
 
Safety Reporting 
In accordance with applicable policies of the BWH/PHRC Institutional Review Board (IRB), the 
investigator-sponsor will report, to the IRB, any observed or volunteered Unanticipated Problem 
that is determined to be 1) unexpected); 2) related or at least possibly related to study 
participation; and 3) suggests that the research places subjects or others at a risk of unknown 
harm or addition/increased frequency of harms (including physical, psychological, economic, 
legal, or social harm) than was previously known or recognized. Unanticipated problems may be 
adverse events, protocol deviations, noncompliance or other types of problems, but MUST meet 
all of the criteria listed above. Unanticipated problem reports will be submitted to the IRB in 
accordance with the respective IRB procedures.  
Applicable unanticipated problems will be reported to the IRB as soon as possible and, 
in no event, later than 10 calendar days following the investigator-sponsor’s receipt of the 
respective information.  For Internal Fatal/Life-Threatening Unanticipated Problems, the PI 
should notify the IRB Chair by phone immediately and consider voluntarily halting subject 
enrollment. 
Follow-up information to reported adverse event will be submitted to the IRB as soon as 
the relevant information is available.  If the results of the investigator’s follow-up investigation 
show that an adverse event that was initially determined to not require reporting to the IRB 
does, in fact, meet the requirements for reporting; the investigator will report the unanticipated 
problem to the IRB as soon as possible, but in no event later than 10 calendar days, after the 
determination was made. 
 
 
4. Grading and Attribution Methods for Adverse Events 
 
 
Grading Scale 
0 
No adverse event or within normal limits 
1 
Mild adverse event – did not require treatment 
2 
Moderate adverse event – resolved with treatment 
3 
Severe adverse event – resulted in inability to carry on normal activities and 
required professional medical attention 
4 
Life threatening or disabling adverse event 
5 
Fatal adverse event 
 
Attribution Scale 
Definite: 
The adverse event is clearly related to the study drug 
Probable: 
The adverse event is likely related to the study drug 
Possible: 
The adverse event may be related to the study drug 
Unlikely:  
The adverse event is doubtfully related to the study drug 
Unrelated: 
The adverse event is clearly not related to the study drug 
 
 
Data and Safety Monitoring Meeting Minutes 

 
25
 
Date:  
 
Title of Protocol/IRB Number:  
 
Principal Investigator/Designee:   
 
Recommendations: 
 
□ Continue the trial without modification 
 
□ Accrual: 
□ Recommend study be closed because of slow accrual 
□ Continue to monitor study, but consider closure because of slow accrual 
 
□ Recommend study is amended/changed: 
□ For patient safety reasons 
□ Rate of adverse events 
□ Early stopping of inferior therapy 
□ To extend accrual because of an event rate slower than expected 
 
□ Other: _________________________________________________________ 
 
Signature/Principal Investigator or Designee:  
 
_______________________________________________ 
DSMB meetings will be held at the Brigham and Women’s Hospital. The purpose of the first 
meeting is to review and discuss this charter and process.  
 
  The DSMB also will review adverse event data, other safety data, quality and completeness of 
study data, and enrollment data at each meeting to ensure proper trial conduct.  At intervals, as 
noted above, the DSMB will also review formal interim analyses of the primary end point. 
 
 
5.  
Reports of DSMB Deliberations 
 
• 
Initial summary:  The Director or designee will review this summary and approve or 
disapprove the recommendation(s), or request additional information.  The 
recommendations will then be sent to the DCC, and the clinical investigators.   
 
• 
Action plan:  If the DSMB’s recommendations require significant changes or follow-up, 
the BWH IRB staff will prepare an action plan outlining the steps required to implement 
the recommendations. 
 
• 
Formal minutes:  The DSMB Chair is responsible within 30 days of the meeting or call to 
present minutes to the IRB.  These minutes are subject to FOIA requests and are 
prepared accordingly to summarize the key points of the discussion and debate, 
requests for additional information, response of the investigators to previous 

 
26
recommendations, and the recommendations from the current meeting.  These minutes 
will be reviewed by IRB staff, key study personnel before being forwarded to the DSMB 
Chair for final review and approval.  The DSMB Chair may sign the minutes or indicate 
approval electronically via email.  Then, the minutes are sent to the BWH IRB for 
approval. Subsequently, the minutes are sent back to the IRB and the relevant 
investigators, and included in the materials for the subsequent DSMB meeting to be 
approved by voice vote at that meeting.  Once they have been voted and approved by 
the Board, they are considered Final. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
27
Appendix 4. 
Toxicity Grading Scale for Adverse Events 
 
         
PARAMETER 
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical adverse 
event NOT 
identified 
elsewhere in this 
DAIDS AE Grading 
Table 
Symptoms causing 
no or minimal 
interference 
with usual 
social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
basic self-care 
functions OR Medical 
or operative 
intervention indicated 
to prevent permanent
SYSTEMIC 
Acute systemic
Localized urticaria
Localized urticaria
Generalized urticaria
Acute anaphylaxis OR
allergic reaction 
(wheals) with no 
medical 
intervention 
indicated 
medical intervention 
indicated OR Mild 
angioedema with 
no 
medical intervention 
i di
t d
OR Angioedema with 
medical 
intervention 
indicated OR 
Symptomatic mild 
b
h
Life-threatening 
bronchospasm OR 
laryngeal edema 
Chills 
Symptoms causing 
no or minimal 
interference 
with usual 
social &
Symptoms causing 
greater than 
minimal 
interference with 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Fatigue
Symptoms causing
Symptoms causing
Symptoms causing
Incapacitating fatigue/
Malaise 
or minimal 
interference with 
usual social & 
functional
greater than minimal 
interference with 
usual social & 
functional activities
inability to perform 
usual 
social & 
functional 
activities
malaise symptoms 
causing inability to 
perform basic self-
care functions
Fever (nonaxillary) 
37.7 – 38.6°C 
38.7 – 39.3°C 
39.4 – 40.5°C 
> 40.5°C 
Pain (indicate 
body site) 
DO NOT use for 
pain due to 
injection (See 
Injection Site 
Reactions: 
Injection site pain) 
See also
Pain causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Pain causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Pain causing inability 
to perform usual 
social & functional 
activities 
Disabling pain causing 
inability to perform 
basic self-care 
functions OR 
Hospitalization (other 
than emergency room 
visit) indicated 

 
28
PARAMETER 
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Unintentional 
weight loss 
NA 
5 – 9% loss in body 
weight from 
baseline 
10 – 19% loss in 
body weight from 
baseline 
≥ 20% loss in body 
weight from baseline 
OR Aggressive 
intervention indicated 
[e.g., tube feeding or 
total
INFECTION 
Infection (any 
other than HIV 
infection) 
Localized, no 
systemic 
antimicrobial 
treatment indicated 
AND Symptoms 
causing no or 
minimal 
Systemic 
antimicrobial 
treatment indicated 
OR Symptoms 
causing greater 
than 
minimal interference 
with usual social & 
f
i
l
i i i
Systemic 
antimicrobial 
treatment indicated 
AND Symptoms 
causing inability to 
perform usual 
social & functional 
activities OR 
Life-threatening 
consequences 
(e.g., septic shock) 
INJECTION SITE REACTIONS 
Injection site pain 
(pain without 
touching) Or 
Tenderness (pain 
when area is 
touched) 
Pain/tenderness 
causing no or 
minimal limitation 
of use of 
limb 
Pain/tenderness 
limiting use of limb 
OR Pain/tenderness 
causing greater than 
minimal 
interference with 
usual social &
Pain/tenderness 
causing inability to 
perform usual social 
& functional 
activities 
Pain/tenderness 
causing inability to 
perform basic self-
care function OR 
Hospitalization (other 
than emergency room 
visit) indicated for
Injection site reaction (localized) 
Adult > 18 years 
Erythema 
OR 
Induration 
of 5x5 cm – 9x9 cm 
(or 25 cm2 – 81cm2)
Erythema OR 
Induration OR 
Edema 
> 9 cm any diameter 
(or > 81 cm2)
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR
Necrosis 
(involving dermis 
and 
deeper 
tissue)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
29
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Pruritis associated 
with injection See 
also Skin: Pruritis 
(itching - no skin 
lesions)  
Itching localized to 
injection site AND 
Relieved 
spontaneously or 
with < 48 hours 
treatment  
Itching beyond the 
injection site but 
not generalized OR 
Itching localized to 
injection site 
requiring ≥ 48 
hours treatment  
Generalized itching 
causing inability to 
perform usual social 
& functional 
activities  
NA  
SKIN – DERMATOLOGICAL  
Alopecia  
Thinning 
detectable by 
study participant 
(or by caregiver for 
young children and 
disabled adults)  
Thinning or patchy 
hair loss detectable 
by health care 
provider  
Complete hair loss  
NA  
Cutaneous reaction 
– rash  
Localized macular 
rash  
Diffuse macular, 
maculopapular, or 
morbilliform rash 
OR Target lesions  
Diffuse macular, 
maculopapular, or 
morbilliform rash 
with vesicles or 
limited number of 
bullae OR Superficial 
ulcerations of 
mucous membrane 
limited to one site  
Extensive or 
generalized bullous 
lesions OR Stevens-
Johnson syndrome 
OR Ulceration of 
mucous membrane 
involving two or 
more distinct 
mucosal sites OR 
Toxic epidermal 
necrolysis (TEN)  
Hyperpigmentation  
Slight or localized  
Marked or 
generalized  
NA  
NA  
Hypopigmentation  
Slight or localized  
Marked or 
generalized  
NA  
NA  
Pruritis (itching – no 
skin lesions) (See 
also Injection Site 
Reactions: Pruritis 
associated with 
injection)  
Itching causing no 
or minimal 
interference with 
usual social & 
functional 
activities  
Itching causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Itching causing 
inability to perform 
usual social & 
functional activities  
NA  
CARDIOVASCULAR  
Cardiac arrhythmia 
(general) (By ECG 
or physical exam)  
Asymptomatic 
AND No 
intervention 
indicated  
Asymptomatic AND 
Non-urgent 
medical 
intervention 
indicated  
Symptomatic, non-
lifethreatening AND 
Non-urgent medical 
intervention 
indicated  
Life-threatening 
arrhythmia OR 
Urgent intervention 
indicated  
Cardiac-
ischemia/infarction  
NA  
NA  
Symptomatic 
ischemia (stable 
Unstable angina OR 
Acute myocar  

 
30
angina) OR Testing 
consistent with 
ischemia  
 
 
  
PARAMETER 
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
             GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Hemorrhage 
(significant 
acute blood 
loss) 
NA 
Symptomatic AND 
No transfusion 
indicated 
Symptomatic AND 
Transfusion of ≤ 2 
units packed RBCs 
(for children ≤ 10 
cc/kg) indicated
Life-threatening 
hypotension OR 
Transfusion of > 2 
units packed RBCs 
(for children > 10 
Hypertension 
Adult > 18 years 
(with repeat 
testing at same 
visit) 
140 – 159 
mmHg systolic 
OR 
90 – 99 
mmHg 
160 – 179 
mmHg systolic 
OR 
100 – 109 
mmHg diastolic 
≥ 180 mmHg systolic 
OR 
≥ 110 mmHg diastolic 
Life-threatening 
consequences (e.g., 
malignant 
hypertension) OR 
Hospitalization 
Hypotension 
NA 
Symptomatic, 
corrected with 
oral fluid 
replacement 
Symptomatic, IV 
fluids indicated 
Shock requiring use 
of vasopressors or 
mechanical 
assistance to 
maintain blood 
Pericardial effusion 
Asymptomatic, 
small 
effusion 
requiring 
no 
intervention 
Asymptomatic, 
moderate or 
larger effusion 
requiring no 
i t
ti
Effusion with non-life 
threatening 
physiologic 
consequences OR 
Eff
i
ith
Life-threatening 
consequences (e.g., 
tamponade) OR 
Urgent intervention 
i di
t d
Prolonged PR interval 
Adult > 18 years 
PR interval 
0.21 – 0.25 sec 
PR interval 
> 0.25 sec 
Type II 2nd degree 
AV block OR 
V
t i
l
Complete AV block 
 
  
PARAMETER 
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
           GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Prolonged QTc 
Adult > 18 years 
Asymptomatic, 
QTc interval 0.45 
– 0.47 sec OR 
Increase interval 
Asymptomatic, 
QTc interval 0.48 
– 0.49 sec OR 
Increase 
in 
Asymptomatic, QTc 
interval ≥ 0.50 sec 
OR Increase in 
interval 
Life-threatening 
consequences, e.g. 
Torsade de pointes or 
other associated 

 
31
Thrombosis/embolis
m 
NA 
Deep vein 
thrombosis AND No 
intervention 
indicated (e.g., 
anticoagulation, 
Deep vein 
thrombosis AND 
Intervention 
indicated (e.g., 
anticoagulation, 
Embolic event 
(e.g., pulmonary 
embolism, life-
threatening 
thrombus) 
Vasovagal episode 
(associated with a 
procedure of any
Present without 
loss of 
consciousness
Present with 
transient loss of 
consciousness
NA 
NA 
Ventricular 
dysfunction 
(congestive 
h
t f il
)
NA 
Asymptomatic 
diagnostic finding 
AND intervention 
i di
t d
New onset with 
symptoms OR 
Worsening 
t
ti
Life-threatening 
congestive heart 
failure 
GASTROINTESTINAL 
Anorexia 
Loss of appetite 
without 
decreased oral 
intake 
Loss of appetite 
associated with 
decreased oral 
intake without 
significant weight 
loss
Loss of appetite 
associated with 
significant weight 
loss 
Life-threatening 
consequences OR 
Aggressive 
intervention 
indicated [e.g., tube 
feeding or total
Comment: Please note that, while the grading scale provided for Unintentional Weight Loss may be used as a 
guideline when grading anorexia, this is not a requirement and should not be used as a substitute for clinical 
Ascites 
Asymptomatic 
Symptomatic AND 
Intervention 
indicated (e.g., 
diuretics or 
Symptomatic 
despite 
intervention 
Life-
threatening 
consequences 
 
 
 
PARAMETER 
 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Cholecystitis 
NA 
Symptomatic AND 
Medical 
intervention 
indicated
Radiologic, 
endoscopic, 
or 
operative 
intervention indicated
Life-threatening 
consequences 
(e.g., sepsis or 
perforation)
Constipation 
NA 
Persistent 
constipation 
requiring regular 
use 
of dietary 
modification
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences 
(e.g., obstruction) 
Diarrhea 
Adult > 18 years 
 
Transient or 
intermittent 
episodes of 
unformed stools 
OR Increase of ≤ 3 
Persistent episodes 
of unformed to 
watery stools OR 
Increase of 
4 – 6 stools over 
b
l
Bloody diarrhea OR 
Increase of ≥ 7 
stools per 24-hour 
period OR IV fluid 
replacement 
Life-threatening 
consequences 
(e.g., hypotensive 
shock) 

 
32
Dysphagia- 
Odynophagi
a 
Symptomatic but 
able to eat usual 
diet 
Symptoms causing 
altered dietary 
intake without 
di
l
Symptoms causing 
severely altered 
dietary intake with 
di
l i t
ti
Life-threatening 
reduction in oral 
intake 
Mucositis/stomatitis 
(clinical exam) 
Indicate site 
(e.g., larynx, 
oral) 
See Genitourinary for
Erythema of 
the mucosa 
Patchy 
pseudomembranes 
or ulcerations 
Confluent 
pseudomembranes 
or ulcerations OR 
Mucosal bleeding 
with minor trauma 
Tissue necrosis OR 
Diffuse 
spontaneous 
mucosal bleeding 
OR Life-threatening 
See also 
Dysphagia- 
Odynophagia and
Nausea 
Transient (< 24 
hours) or 
intermittent nausea 
with no or minimal 
interference with 
Persistent nausea 
resulting in 
decreased oral 
intake for 24 – 48 
hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours 
OR Aggressive 
h d
Life-threatening 
consequences 
(e.g., hypotensive 
shock) 
  
PARAMETER 
 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Pancreatitis 
NA 
Symptomatic AND 
Hospitalization not 
indicated (other 
th
Symptomatic AND 
Hospitalization 
indicated (other than 
Life-threatening 
consequences 
(e.g., circulatory 
f il
Proctitis (functional-
Rectal discomfort
Symptoms causing
Symptoms causing
Life-threatening
symptomatic) 
AND No intervention greater than minimal inability to perform 
l
consequences (e.g., 
Also see 
indicated 
interference with 
l
social & functional 
perforation) 
Mucositis/stomatitis 
social & functional 
activities OR Operative 
for clinical exam 
activities OR Medical 
intervention 
indicated 
intervention indicated 
Vomiting 
Transient or 
intermittent 
vomiting with no 
or minimal 
Frequent episodes 
of vomiting with no 
or mild 
dehydration 
Persistent vomiting 
resulting in 
orthostatic 
hypotension OR 
Life-threatening 
consequences 
(e.g., hypotensive 
shock) 
NEUROLOGIC 
Alteration in
Alteration causing no Alteration causing
Alteration causing
Behavior potentially
personality-behavior or minimal 
greater than minimal inability to perform 
harmful to self or 
or in mood (e.g., 
interference with 
interference with 
l
social & functional 
(e.g., suicidal and 
agitation, anxiety, 
usual social & 
social & functional 
activities 
homicidal ideation or 
depression, mania, 
functional activities 
activities 
attempt, acute 
psychosis) 
psychosis) OR Causing 
inability to perform 
basic self-care 
functions

 
33
Altered Mental 
Status 
For Dementia, see 
Cognitive and 
behavioral/attentio
nal disturbance 
(including dementia
Changes causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Mild lethargy or 
somnolence causing 
greater than 
minimal 
interference with 
usual social & 
functional activities
Confusion, memory 
impairment, lethargy, 
or somnolence 
causing inability to 
perform usual social 
& functional activities 
Delirium OR 
obtundation, OR coma 
Ataxia 
Asymptomatic 
ataxia detectable 
on exam OR 
Minimal ataxia 
causing no or 
minimal
Symptomatic 
ataxia causing 
greater than 
minimal 
interference with 
usual social &
Symptomatic ataxia 
causing inability to 
perform usual social 
& functional 
activities 
Disabling 
ataxia 
causing inability to 
perform basic self-
care functions 
   
PARAMETER 
GRADE 1 
MILD 
GRADE 2  
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Cognitive and 
behavioral/attentio
nal disturbance 
(including dementia 
and 
attention 
deficit 
Disability causing 
no or minimal 
interference with 
usual social & 
functional 
activities OR 
Specialized
Disability causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Specialized
Disability causing 
inability to perform 
usual social & 
functional activities 
OR 
Specialized 
resources on a full
Disability causing 
inability to perform 
basic self-care 
functions OR 
Institutionalization 
indicated 
CNS ischemia 
(acute) 
NA 
NA 
Transient 
ischemic attack 
Cerebral vascular 
accident (CVA, 
stroke) with
Headache 
Symptoms causing 
no or minimal 
interference 
with usual 
social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
basic self-care 
functions OR 
Hospitalization 
indicated (other than 
emergency room 
visit) OR Headache 
Insomnia 
NA 
Difficulty sleeping 
causing greater 
than minimal 
interference with 
Difficulty sleeping 
causing inability to 
perform usual social 
& functional 
Disabling insomnia 
causing inability to 
perform basic self-
care functions 
Neuromuscul
ar weakness 
(including myopathy 
& 
neuropathy) 
Asymptomatic 
with decreased 
strength on exam 
OR Minimal 
muscle weakness 
causing no or 
minimal
Muscle weakness 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities
Muscle weakness 
causing inability to 
perform usual social 
& functional 
activities 
Disabling muscle 
weakness causing 
inability to perform 
basic self-care 
functions OR 
Respiratory muscle 
weakness impairing
 

 
34
  
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Neurosensory 
Asymptomatic with
Sensory alteration or Sensory alteration or
Disabling sensory
alteration (including sensory alteration on paresthesia causing 
paresthesia causing 
alteration or 
h
paresthesia and 
exam or minimal 
greater than minimal inability to perform 
causing inability to 
painful neuropathy) 
paresthesia causing 
no or minimal 
interference with 
usual social & 
functional
interference with 
usual 
social & 
functional 
activities 
social & functional 
activities 
perform basic self-care 
functions 
Seizure: (new onset)
NA
1 seizure
2 – 4 seizures
Seizures of any kind
– Adult ≥ 18 years 
which are prolonged, 
See also Seizure: 
repetitive (e.g., status 
(known pre-existing 
epilepticus), or difficult 
seizure disorder) 
to control (e.g., 
refractory epilepsy) 
Seizure: (known 
pre- existing 
seizure disorder) 
– Adult ≥ 18 years 
For worsening of 
existing epilepsy 
the grades should 
be based on an 
increase from 
NA 
Increased frequency 
of pre-existing 
seizures (non-
repetitive) without 
change in seizure 
character OR 
Infrequent break- 
through seizures 
while on stable 
Change in seizure 
character from 
baseline either in 
duration or quality 
(e.g., severity or 
focality) 
Seizures of any kind 
which are 
prolonged, 
repetitive (e.g., 
status epilepticus), 
or difficult to 
control (e.g., 
refractory epilepsy) 
Syncope (not 
associated with 
a procedure)
NA 
Present 
NA 
NA 
Vertigo 
Vertigo causing no 
or minimal 
interference with 
usual social & 
Vertigo causing 
greater than 
minimal 
interference with 
Vertigo causing 
inability to perform 
usual social 
& functional activities 
Disabling vertigo 
causing inability to 
perform basic self-
care functions 
                                                    

 
35
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
RESPIRATORY 
Bronchospasm 
(acute) 
FEV1 or peak 
flow reduced to 
70 – 80% 
FEV1 or peak flow 
50 – 69% 
FEV1 or peak flow 
25 – 49% 
Cyanosis OR FEV1 
or peak flow < 25% 
OR Intubation 
Dyspnea or respiratory distress 
Adult ≥ 18 years 
Dyspnea on 
exertion with no 
or minimal 
interference with 
Dyspnea on 
exertion causing 
greater than 
minimal 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional activities 
Respiratory failure 
with ventilatory 
support indicated 
MUSCULOSKELETAL 
Arthralgia 
See also Arthritis 
Joint pain causing 
no or minimal 
interference with 
usual social & 
Joint pain causing 
greater than 
minimal 
interference with 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-
care functions 
Arthritis 
See also Arthralgia 
Stiffness or joint 
swelling causing no 
or minimal 
interference with 
usual social & 
Stiffness or joint 
swelling causing 
greater than 
minimal 
interference with 
Stiffness or 
joint swelling 
causing 
inability to perform 
usual social & 
functional
Disabling joint 
stiffness or swelling 
causing inability to 
perform basic self-
care functions 
Bone Mineral Loss 
Adult ≥ 18 years 
BMD t-score 
-2.5 to -1.0 
BMD t-score < -2.5 
Pathological 
fracture (including 
loss of vertebral
Pathologic fracture 
causing life-
threatening
Myalgia 
(non-injection site) 
Muscle pain 
causing no or 
minimal 
interference with 
Muscle pain causing 
greater than 
minimal 
interference with 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle 
pain causing inability 
to perform basic 
self-care functions 
 
 
 
 
 
 
 
 
 
 
 
 

 
36
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Osteonecrosis 
NA 
Asymptomatic with 
radiographic 
findings AND No 
operative 
Symptomatic bone 
pain with 
radiographic findings 
OR Operative 
Disabling bone pain 
with radiographic 
findings causing 
inability to perform 
GENITOURINARY 
Cervicitis
Symptoms causing
Symptoms causing
Symptoms causing
Symptoms causing
(symptoms) 
or minimal 
greater than minimal inability to perform 
l
inability to perform 
b
(For use in studies 
interference with 
interference with 
l
social & functional 
self-care functions 
evaluating topical 
usual social & 
social & functional 
activities 
study agents) 
functional activities 
activities 
For other cervicitis see 
Infection: Infection 
(any other than HIV 
infection) 
Cervicitis
Minimal cervical
Moderate cervical
Severe cervical
Epithelial disruption
(clinical exam) 
abnormalities on 
abnormalities on 
abnormalities on 
> 75% total surface 
(For use in studies 
examination 
examination 
examination 
(
th
evaluating topical 
(erythema, 
(erythema, 
mucopurulent 
study agents) 
mucopurulent 
mucopurulent 
discharge, or friability) 
For other cervicitis 
see 
Infection: Infection 
(any other than HIV
discharge, or 
friability) 
OR 
Epithelial 
disruption 
25% f t t l
discharge, or 
friability) 
OR Epithelial 
disruption of 25 – 
49% 
t t l
f
OR Epithelial 
disruption 
50 – 75% total surface 
Inter-menstrual
Spotting observed by Inter-menstrual
Inter-menstrual
Hemorrhage with life-
bleeding (IMB) 
participant OR 
bleeding not greater greater in duration or 
threatening 
h
Minimal blood 
duration or amount 
amount than usual 
OR Operative 
observed during 
than usual menstrual menstrual cycle 
intervention indicated 
clinical or 
l
cycle 
examination 
Urinary tract
NA
Signs or symptoms of Signs or symptoms of
Obstruction causing
obstruction (e.g., 
urinary tract 
urinary tract 
b
threatening 
stone) 
obstruction without 
hydronephrosis 
or renal 
dysfunction
with hydronephrosis 
or 
renal dysfunction 
consequences 
 
 
 
 
 
 
 
 
 
  

 
37
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Vulvovaginitis 
(symptoms) 
(Use in studies 
evaluating 
topical study 
agents) 
For other 
vulvovaginitis see 
Symptoms causing 
no or minimal 
interference 
with usual 
social & 
functional activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
basic self-care 
functions 
Vulvovaginitis 
(clinical exam) 
(Use in studies 
evaluating 
topical study 
agents) 
For other 
vulvovaginitis see 
Minimal vaginal 
abnormalities on 
examination OR 
Epithelial 
disruption 
< 25% of total 
surface 
Moderate vaginal 
abnormalities on 
examination OR 
Epithelial disruption 
of 
25 - 49% total surface
Severe vaginal 
abnormalities on 
examination OR 
Epithelial 
disruption 
50 - 75% total surface 
Vaginal perforation 
OR Epithelial 
disruption 
> 75% total surface 
OCULAR/VISUAL 
Uveitis 
Asymptomatic 
but detectable on 
exam
Symptomatic 
anterior uveitis OR 
Medical
Posterior or pan-
uveitis OR Operative 
intervention
Disabling visual loss 
in affected eye(s) 
Visual changes (from Visual changes
Visual changes
Visual changes causing Disabling visual loss in
baseline) 
causing no or 
minimal 
interference with 
usual social & 
causing greater than 
minimal 
interference with 
usual social &
inability to perform 
usual 
social & 
functional 
activities
affected eye(s) 
ENDOCRINE/METABOLIC 
Abnormal fat
Detectable by study
Detectable on
Disfiguring OR Obvious NA
accumulation 
participant (or by 
exam by health care 
changes on casual 
(e.g., back of neck, 
caregiver for young 
provider 
visual inspection 
breasts, abdomen) 
children and 
disabled 
d lt )
Diabetes mellitus 
NA 
New onset without 
need to initiate 
medication OR 
Modification of 
current medications 
New onset with 
initiation of 
medication indicated 
OR Diabetes 
uncontrolled despite 
Life-threatening 
consequences 
(e.g., ketoacidosis, 
hyperosmolar 
non- ketotic 
 
 
 
  

 
38
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Gynecomastia 
Detectable by 
study participant 
or caregiver (for 
young children and 
Detectable on 
physical exam by 
health care provider 
Disfiguring OR 
Obvious on casual 
visual inspection 
NA 
Hyperthyroidism 
Asymptomatic 
Symptomatic 
causing greater than 
minimal 
interference with 
usual social & 
functional activities
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment
Life-threatening 
consequences 
(e.g., thyroid 
storm) 
Hypothyroidism 
Asymptomatic 
Symptomatic 
causing greater than 
minimal 
interference with 
usual social & 
functional activities
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment
Life-threatening 
consequences 
(e.g., myxedema 
coma) 
Lipoatrophy 
(e.g., fat loss from 
the face, 
extremities, 
Detectable by 
study participant 
(or by caregiver for 
young children and 
Detectable on 
physical exam by 
health care provider 
Disfiguring OR 
Obvious on casual 
visual inspection 
NA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

 
39
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
HEMATOLOGY             Standard International Units are listed in italics 
Absolute CD4+ count 
– Adult and Pediatric 
> 13 years 
(HIV NEGATIVE ONLY) 
300 – 400/mm3 
300 – 400/µL 
200 – 299/mm3 
200 – 299/µL 
100 – 199/mm3 
100 – 199/µL 
< 100/mm3 
< 100/µL 
Absolute 
lymphocyte count 
– Adult and Pediatric 
> 13 years 
(HIV NEGATIVE ONLY) 
600 – 650/mm3 
0.600 x 109 – 
0.650 x 109/L 
500 – 599/mm3 
0.500 x 109 – 
0.599 x 109/L 
350 – 499/mm3 
0.350 x 109 – 
0.499 x 109/L 
< 350/mm3 
< 0.350 x 109/L 
Comment:  Values in children ≤ 13 years are not given for the two parameters above because the absolute counts 
Absolute neutrophil count (ANC) 
Adult and Pediatric, 
> 7 days 
1,000 – 1,300/mm3 
1.000 x 109 – 
1.300 x 109/L 
750 – 999/mm3 
0.750 x 109 – 
0.999 x 109/L 
500 – 749/mm3 
0.500 x 109 – 
0.749 x 109/L 
< 500/mm3 
< 0.500 x 109/L 
Comment:  Parameter changed from “Infant, < 1 day” to “Infant, ≤1 day” 
Fibrinogen, decreased 
100 – 200 mg/dL 
1.00 – 2.00 g/L 
OR 
0.75 – 0.99 x LLN 
75 – 99 mg/dL 
0.75 – 0.99 g/L 
OR 
0.50 – 0.74 x LLN 
50 – 74 mg/dL 
0.50 – 0.74 g/L 
OR 
0.25 – 0.49 x LLN 
< 50 mg/dL 
< 0.50 g/L 
OR 
< 0.25 x LLN 
OR 
Associated with 
gross bleeding
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
40
 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE 
THREATENING 
Hemoglobin (Hgb) 
Comment: The Hgb values in mmol/L have changed because the conversion factor used to convert g/dL to mmol/L 
has been 
changed from 0.155 to 0.6206 (the most commonly used conversion factor). For grading Hgb results obtained by 
an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using the 
appropriate conversion factor for that lab. 
Adult and Pediatric 
≥ 57 days 
(HIV POSITIVE ONLY) 
8.5 – 10.0 g/dL 
5.24 – 6.23 mmol/L 
7.5 – 8.4 g/dL 
4.62–5.23 mmol/L 
6.50 – 7.4 g/dL 
4.03–4.61 mmol/L 
< 6.5 g/dL 
< 4.03 mmol/L 
Adult and Pediatric 
≥ 57 days 
(HIV NEGATIVE 
ONLY) 
10.0 – 10.9 g/dL 
6.18 – 6.79 mmol/L 
OR 
Any decrease 
2.5 – 3.4 g/dL 
9.0 – 9.9 g/dL 
5.55 - 6.17 mmol/L 
OR 
Any decrease 
3.5 – 4.4 g/dL 
7.0 – 8.9 g/dL 
4.34 - 5.54 mmol/L 
OR 
Any decrease 
≥ 4.5 g/dL 
l/
< 7.0 g/dL 
< 4.34 mmol/L 
Comment:  The decrease is a decrease from baseline 
International 
Normalized Ratio of 
prothrombin time 
(INR) 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 3.0 x ULN 
> 3.0 x ULN 
Methemoglobin 
5.0 – 10.0% 
10.1 – 15.0% 
15.1 – 20.0% 
> 20.0% 
Prothrombin Time (PT) 
1.1 – 1.25 x ULN 
1.26 – 1.50 x ULN 
1.51 – 3.00 x ULN 
> 3.00 x ULN 
Partial Thromboplastin 
Time (PTT) 
1.1 – 1.66 x ULN 
1.67 – 2.33 x ULN 
2.34 – 3.00 x ULN 
> 3.00 x ULN 
Platelets, decreased 
100,000 – 
124,999/mm3 
100.000 x 109 – 
124.999 x 109/L 
50,000 – 
99,999/mm3 
50.000 x 109 – 
99.999 x 109/L 
25,000 – 
49,999/mm3 
25.000 x 109 – 
49.999 x 109/L 
< 25,000/mm3 
< 25.000 x 109/L 
WBC, decreased 
2,000 – 2,500/mm3 
2.000 x 109 – 
2.500 x 109/L 
1,500 – 1,999/mm3 
1.500 x 109 – 
1.999 x 109/L 
1,000 – 1,499/mm3 
1.000 x 109 – 
1.499 x 109/L 
< 1,000/mm3 
< 1.000 x 109/L 
 
 
 
 
 
 

 
41
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2  
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
CHEMISTRIES              Standard International Units are listed in italics 
Acidosis 
NA 
pH < normal, but ≥ 
7.3 
pH < 7.3 without 
life- threatening 
consequences
pH < 7.3 with 
life- threatening 
consequences
Albumin, serum, low 
3.0 g/dL – < LLN 
30 g/L – < LLN 
2.0 – 2.9 g/dL 
20 – 29 g/L 
< 2.0 g/dL 
< 20 g/L
NA 
Alkaline Phosphatase 
1.25 – 2.5 x ULN† 
2.6 – 5.0 x ULN† 
5.1 – 10.0 x ULN† 
> 10.0 x ULN† 
Alkalosis 
NA 
pH > normal, but ≤ 
7.5 
pH > 7.5 without 
life- threatening 
consequences
pH > 7.5 with 
life- threatening 
consequences
ALT (SGPT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
AST (SGOT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
Bicarbonate, serum, low 16.0 mEq/L – < LLN 
16.0 mmol/L – < LLN 
11.0 – 15.9 mEq/L 
11.0 – 15.9 mmol/L
8.0 – 10.9 mEq/L 
8.0 – 10.9 mmol/L
< 8.0 mEq/L 
< 8.0 mmol/L
Comment:  Some laboratories will report this value as Bicarbonate (HCO3) and others as Total Carbon Dioxide 
(CO2). These are the same tests; values should be graded according to the ranges for Bicarbonate as listed 
b
Bilirubin (Total) 
Adult and Pediatric > 
14 days 
1.1 – 1.5 x ULN 
1.6 – 2.5 x ULN 
2.6 – 5.0 x ULN 
> 5.0 x ULN 
Calcium, serum, high 
Adult and Pediatric 
≥ 7 days 
10.6 – 11.5 mg/dL 
2.65 – 2.88 mmol/L
11.6 – 12.5 mg/dL 
2.89 – 3.13 mmol/L 
12.6 – 13.5 mg/dL 
3.14 – 3.38 mmol/L
> 13.5 mg/dL 
> 3.38 mmol/L
Calcium, serum, low 
Adult and Pediatric 
≥7 days
7.8  – 8.4 mg/dL 
1.95 – 2.10 mmol/L
7.0  – 7.7 mg/dL 
1.75 – 1.94 mmol/L
6.1  – 6.9 mg/dL 
1.53 – 1.74 mmol/L
< 6.1 mg/dL 
< 1.53 mmol/L
Comment:  Do not adjust Calcium, serum, low or Calcium, serum, high for albumin 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
42
LABORATORY 
PARAMETER 
 
GRADE 1 
MILD 
 
GRADE 2 
MODERATE 
 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Cardiac troponin I (cTnI) NA 
NA 
NA 
Levels consistent 
with myocardial 
infarction or 
unstable angina as 
Cardiac troponin T 
(cTnT) 
NA 
NA 
NA 
≥ 0.20 
ng/mL OR 
Levels consistent 
with myocardial 
infarction or 
unstable angina as 
Cholesterol (fasting) 
Adult ≥ 18 years 
200 – 239 mg/dL 
5.18 – 6.19 mmol/L
240 – 300 mg/dL 
6.20 – 7.77 mmol/L
> 300 mg/dL 
> 7.77 mmol/L 
NA 
Creatine Kinase 
3.0 – 5.9 x ULN† 
6.0 – 9.9 x ULN† 
10.0 – 19.9 x ULN† 
≥ 20.0 x ULN† 
Creatinine 
1.1 – 1.3 x ULN† 
1.4 – 1.8 x ULN† 
1.9 – 3.4 x ULN† 
≥ 3.5 x ULN† 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
43
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Glucose, serum, high 
Nonfasting 
116 – 160 mg/dL 
6.44 – 8.88 mmol/L
161 – 250 mg/dL 
8.89 – 13.88 mmol/L
251 – 500 mg/dL 
13.89 – 27.75
> 500 mg/dL 
> 27.75 mmol/L
Fasting 
110 – 125 mg/dL 
6.11 – 6.94 mmol/L 
126 – 250 mg/dL 
6.95 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75
> 500 mg/dL 
> 27.75 mmol/L
Glucose, serum, low 
Adult and Pediatric 
≥ 1 month 
55 – 64 mg/dL 
3.05 – 3.55 mmol/L
40 – 54 mg/dL 
2.22 – 3.06 mmol/L
30 – 39 mg/dL 
1.67 – 2.23 mmol/L 
< 30 mg/dL 
< 1.67 mmol/L
Lactate 
ULN - < 2.0 x ULN 
without acidosis 
≥ 2.0 x ULN 
without acidosis 
Increased lactate 
with pH < 7.3 
without life- 
th
t
i
Increased lactate 
with pH < 7.3 with 
life- threatening 
 
Comment: Added ULN to Grade 1 parameter 
LDL cholesterol (fasting) 
Adult ≥ 18 years 
130 – 159 mg/dL 
3.37 – 4.12 mmol/L 
160 – 190 mg/dL 
4.13 – 4.90 mmol/L 
≥ 190 mg/dL 
≥ 4.91 mmol/L 
NA 
Lipase 
1.1 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 5.0 x ULN 
> 5.0 x ULN 
Magnesium, serum, low 1.2  – 1.4 mEq/L 
0 60 – 0 70 mmol/L
0.9 – 1.1 mEq/L 
0.45 – 0.59 mmol/L
0.6 – 0.8 mEq/L 
0.30 – 0.44 mmol/L
< 0.60 mEq/L 
< 0 30 mmol/L
Pancreatic amylase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN 
Phosphate, serum, low 
Adult and Pediatric 
> 14 years 
2.5 mg/dL – < LLN 
0.81 mmol/L – < LLN 
2.0 – 2.4 mg/dL 
0.65 – 0.80 mmol/L 
1.0 – 1.9 mg/dL 
0.32 – 0.64 mmol/L 
< 1.00 mg/dL 
< 0.32 mmol/L
Potassium, serum, high 5.6 – 6.0 mEq/L 
5.6 – 6.0 mmol/L 
6.1 – 6.5 mEq/L 
6.1 – 6.5 mmol/L 
6.6 – 7.0 mEq/L 
6.6 – 7.0 mmol/L
> 7.0 mEq/L 
> 7.0 mmol/L
Potassium, serum, low 
3.0 – 3.4 mEq/L 
3.0 – 3.4 mmol/L
2.5 – 2.9 mEq/L 
2.5 – 2.9 mmol/L
2.0 – 2.4 mEq/L 
2.0 – 2.4 mmol/L
< 2.0 mEq/L 
< 2.0 mmol/L
Sodium, serum, high 
146 – 150 mEq/L 
146 – 150 mmol/L 
151 – 154 mEq/L 
151 – 154 mmol/L 
155 – 159 mEq/L 
155 – 159 mmol/L 
≥ 160 mEq/L 
≥ 160 mmol/L 
Sodium, serum, low 
130 – 135 mEq/L 
130 – 135 mmol/L 
125 – 129 mEq/L 
125 – 129 mmol/L 
121 – 124 mEq/L 
121 – 124 mmol/L 
≤ 120 mEq/L 
≤ 120 mmol/L 
Triglycerides (fasting) 
NA 
500 – 750 mg/dL 
5.65 – 8.48 mmol/L
751 – 1,200 mg/dL 
8.49 – 13.56 mmol/L
> 1,200 mg/dL 
> 13.56 mmol/L
 
 
 
 
 
 
 

 
44
 
LABORATORY 
PARAMETER 
 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Uric acid 
7.5 – 10.0 mg/dL 
0.45 – 0.59 mmol/L 
10.1 – 12.0 mg/dL 
0.60 – 0.71 mmol/L 
12.1 – 15.0 mg/dL 
0.72 – 0.89 mmol/L
> 15.0 mg/dL 
> 0.89 mmol/L
URINALYSIS                 Standard International Units are listed in italics 
Hematuria 
(microscopic) 
6 – 10 RBC/HPF 
> 10 RBC/HPF 
Gross, with or 
without clots OR 
with RBC casts
Transfusion indicated 
Proteinuria, 
random collection 
1 + 
2 – 3 + 
4 + 
NA 
Proteinuria, 24 hour collection 
Adult and Pediatric 
≥ 10 years 
200 – 999 mg/24 h 
0.200 – 0.999 g/d 
1,000 – 1,999 mg/24 
h 
2,000 – 3,500 mg/24 
h 
> 3,500 mg/24 h 
> 3.500 g/d 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
45
Appendix 5. 
Fecal Microbiota Transplantation - Record of Side Effects 
 
This diary is one way researchers will get information from you regarding any possible problems 
or side effects in this study. 
 
❖ What you are going to do is simple.  Just keep a record of any unpleasant thing that 
happens to you while you are in the study, before, during, and after we have completed 
the stool transplant.  We even want you to record things that do not seem to be part of 
the stool therapy, at all. 
❖ When do you start?  When do you end?  You will record one entry 1-week prior and on 
the day of the transplant.  You will then complete one entry per day for the first week 
following the treatment and then once a week thereafter for 12-weeks.   
❖ What do you look for?  What do you report?  Any symptom or problem whether or not 
it may be from the medicine, stool therapy.  This could include: fever, abdominal pain, a 
big belly, lots of gas, diarrhea, nosebleeds, and anything else you know is not quite right. 
❖ What will you do? In the first 7 days after the transplant, you will report some of the 
specific things that have bothered you by checking the boxes in the diary (see below).  You 
can also write any other problems that you may have had during that time.  Additionally, 
you will record your temperature once for each day for the first 7 days after the 
transplant, unless you feel hot.  If you feel hot, please take your temperature again.  
Please make sure to record the highest temperature taken that day if you take it more 
than once. 
 
Continue to record any problem up to 6 months after the transplant. 
 
How will you record it?  Like this… 
EVENT 
DATE 
OF 
ONSET 
INTENSITY 
ACTION 
TAKEN 
MEDICATION 
DATE 
RESOLVED 
Fever 
3/1/12 
3 
Missed 
2 
days 
of 
school 
Tylenol-200mg 
3/3/12 
Sore throat 
3/5/12 
1 
None 
None 
3/6/12 
 
OTHER SYMPTOMS 
Record each symptom at its worst level for each day. 
For example, a sore throat that starts at ‘Grade 1” but increases to ‘Grade 2’ should be recorded 
as ‘Grade 2”. 
 
Examples of Grades: 
Grade 1 – Mild: I noticed the symptom.  It did not keep me from doing my normal activities. 
Grade 2 – Moderate: I noticed the symptom and it kept me from doing some of my normal 
activities. 
Grade 3 – Severe: I really noticed the symptom and it kept me from doing activities that I wanted 
or needed to do. 
Grade 4 – Very severe: The symptom made me unable to perform basic self-care functions such 
as washing myself OR medical or surgical intervention was needed to prevent serious 
consequences. 

 
46
 
 
Subject ID:_____________________ 
 
Date:____/____/______ 
 
   Check here is no side effects present:                   
Highest temperature of the day:______oF 
              Total Number of Stools:__________ 
 
Check 
if 
symptom 
present 
Event 
Date of 
Onset 
Intensity 
Action 
taken 
Medications 
Date 
Resolved 
 
 
Fever 
 
 
 
 
 
 
 
Abdominal Pain/ 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
Nausea/Vomiting 
 
 
 
 
 
 
 
Blood in Stool 
 
 
 
 
 
 
 
Other 1 
 
 
 
 
 
 
 
Other 2 
 
 
 
 
 
 
 
Other 3 
 
 
 
 
 
 
 
Grade 1 – Mild: I noticed the symptom.  It did not keep me from doing my normal activities. 
Grade 2 – Moderate: I noticed the symptom and it kept me from doing some of my normal 
activities. 
Grade 3 – Severe: I really noticed the symptom and it kept me from doing activities that I wanted 
or needed to do. 
Grade 4 – Very severe: The symptom made me unable to perform basic self-care functions such 
as washing myself OR medical or surgical intervention was needed to prevent serious 
consequences. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
47
 
 
Appendix 6.  
Sensormedics Vmax Encore 29(VIASYS Respiratory Care Inc.,Yorba Linda, CA) 
Indirect Calorimetry Measurements information use in protocols.  
During a metabolic study we are measuring Resting Energy Expenditure (REE) or the 
number of calories being burned at rest per day. Depending on body size, a healthy adult 
may burn from 1000 to 3000 Kcal per day just to maintain normal body functions. 
Traditionally, predicted equations were used to estimate REE based on age, height, and 
weight. Unfortunately these equations do not account for stress factors that could be 
affecting the patient (fever, burns, disease, medications, etc.). 
Indirect Calorimetry calculates heat production by measuring gas exchange; in other words, 
oxygen consumption and carbon dioxide production. During resting conditions food sources 
are broken down to produce energy (heat or KCALS). The oxygen consumed and the carbon 
dioxide produced are measured to provide an indirect assessment of caloric expenditure. 
REE provides the total energy expenditure in 24 hours and is calculated from the gas 
exchange data (VO2, VCO2) collected by the Vmax. The parameter RQ will assist in 
determining subject’s caloric needs. RQ provides information on what the subject is utilizing 
for energy; carbohydrates, fats, or proteins.  
RQ = VCO2/VO2 
Carbohydrates .90 - 1.00 
Fats .70 - .78 
Proteins .80 
Combination Fats/Carbohydrates .80 - .82 
RQ greater than 1.00 – 1.20 may indicate overfeeding (Lipogenesis) 
RQ less than .70 may indicate underfeeding (Ketogenesis) 
NOTE: Hyperventilation can cause the RQ to exceed 1.00 
 
Testing Procedure: 
Energy expenditure (EE), respiratory quotient (RQ) and substrate utilization will be 
calculated from measurements of oxygen (VO2) and carbon dioxide (VCO2) in inspired and 
expired air .The fasted subject (12 hours prior to testing) is placed in a supine position in a 
quiet environment where subject will be undisturbed. Subject is also fully rested and has 
not performed an exercise prior to testing. The Sensormedics Vmax Encore equipment 

 
48
(VIASYS Respiratory Care Inc.,Yorba Linda, CA) is use to collect measurements at specified 
study times. 
A clear plastic canopy is placed over the subject head and torso with the pump turned on.  
FECO2 is monitored the pump is adjusted and stabilized within desired range of 0.75-0.85.  
Once FECO2 is within range, test will begin and data will be collected for 30 minutes. During 
the study subject should refrain from sleeping.  The goal of the test is to obtain Resting 
Energy Expenditure (REE), therefore the first five minutes are not accounted for in final 
analysis, to allow patient to meet a steady state condition.  Once test is completed the 
canopy is removed from subject and pump is turned off.  In order to accurate info on RQ 
substrate utilization for the subject, a 24 hour Urinary N2 test must be collected prior to 
Vmax test. Data from 24 hour urinary N2 test will be entered into computer to be analyzed 
with results from the Vmax indirect calorimetry test to obtain RQ substrate unitization and 
REE.   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
49
 
 
 
 
 
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