Clinical trial NCT01345175
Conditions: Rectal Cancer
Keywords: rectal colon PLACEBO RIFAXIMIN metronidazole 11-045
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2011-04-26; Completion date: 2023-03-23
Enrollment: 69 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The most common long-term problems after rectal surgery are bowel problems. These problems can include needing to pass bowel movements a lot, loose or mushy stools, inability to fully clear your bowels, and/or poor control of gas and stool. The investigators believe that a major cause of these problems is too much bacteria in the bowel and treatment with antibiotic tablets will hopefully help improve these bowel problems. In order to test this idea, the Colorectal Surgery Service of Memorial Sloan Kettering Cancer Center is sponsoring a clinical trial. This trial will compare the antibiotic rifaximin and a placebo (a harmless tablet that has no effect) in the treatment of these bowel problems. Following this we will attempt to see if another antibiotic metronidazole also helps to treat these bowel problems. Both Metronidazole and rifaximin are well established drugs that have minimal side effects.

Detailed description:

Arms: arm 1: This group will receive rifaximin 400mg bid for 4 weeks. At 1 - 24 months after completion of the phase III portion of the trial, patients will be contacted by phone and given the option of receiving metronidazole in a followup, single arm study in which all patients receive the antibiotic. Patients who wish to participate will be mailed a drug prescription for a 3 week course of metronidazole 500mgs tid as well as the BFI forms and stool diary. Pretreatment and post treatment BFI scores will be collected and analyzed for change in bowel function as was done in the initial Phase III study. arm 2: This group will receive a placebo bid for 4 weeks. At 1 - 24 months after completion of the phase III portion of the trial, patients will be contacted by phone and given the option of receiving metronidazole in a followup, single arm study in which all patients receive the antibiotic. Patients who wish to participate will be mailed a drug prescription for a 3 week course of metronidazole 500mgs tid as well as the BFI forms and stool diary. Pretreatment and post treatment BFI scores will be collected and analyzed for change in bowel function as was done in the initial Phase III study.
Interventions: intervention 1: Rifaximin intervention 2: Placebo
Intervention descriptions: intervention 1: Pt will receive rifaximin 400mg bid for 4 weeks. Patients will at this stage on a volunteer basis be asked to submit stool samples and undertake a breath test. Patients will receive the respective treatment for four weeks. Following cessation of treatment all patients will be assessed using the BFI and respective patients will have repeat stool sampling and breath testing. Patients will then have these tests repeated 4 weeks later. This corresponds to 8 weeks after the start of the trial. For those patients not undertaking stool and breath testing, they will be reminded by phone, mail or email to fill out the BFI. Before and during the trial patients will be asked to fill out a weekly stool diary to evaluate trends on bowel function. intervention 2: Pt will receive placebo bid for 4 weeks. Patients will at this stage on a volunteer basis be asked to submit stool samples and undertake a breath test. Patients will receive the respective treatment for four weeks. Following cessation of treatment all patients will be assessed using the BFI and respective patients will have repeat stool sampling and breath testing. Patients will then have these tests repeated 4 weeks later. This corresponds to 8 weeks after the start of the trial. For those patients not undertaking stool and breath testing, they will be reminded by phone, mail or email to fill out the BFI. Before and during the trial patients will be asked to fill out a weekly stool diary to evaluate trends on bowel function.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 1 of 23 
 
 
MSK PROTOCOL COVER SHEET 
 
Randomized Trial Comparing Rifaximin and Placebo in the Treatment of Bowel Dysfunction After 
Anterior Resection for Rectal Cancer. 
 
Principal Investigator/Department: Philip Paty, MD/Surgery 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-045 A(7)
Approval date: 26-Jan-2021


Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 2 of 23 
 
1.0 
PROTOCOL SUMMARY AND/ORSCHEMA ............................................................................ 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................................................ 4 
3.0 
BACKGROUND AND RATIONALE ......................................................................................... 5 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................ 6 
4.2 
Design ................................................................................................................................ 6 
4.3 
Intervention ......................................................................................................................... 7 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................................................. 8 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY ....................................................................... 8 
6.2 
Subject Inclusion Criteria ..................................................................................................... 8 
6.3 
Subject Exclusion Criteria..................................................................................................... 9 
7.0 
RECRUITMENT PLAN ............................................................................................................ 9 
8.0 
PRETREATMENT EVALUATION ..........................................................................................10 
9.0 
TREATMENT/INTERVENTIONPLAN ....................................................................................10 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .........................................................10 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................12 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT...............................16 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ............................................................................16 
14.0 
BIOSTATISTICS ...................................................................................................................16 
15.1 
 RESEARCHPARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES18 
15.2 
Research Participant Registration .......................................................................................18 
15.3 
Randomization ..................................................................................................................18 
16.1 
DATA MANAGEMENT ISSUES .................................................................................. 19 
16.2 
Quality Assurance..............................................................................................................19 
16.3 
Data and Safety Monitoring ................................................................................................19 
17.1 
PROTECTION OF HUMAN SUBJECTS ...................................................................... 20 
17.2 
Privacy ..............................................................................................................................20 
17.3 
Serious Adverse Event (SAE) Reporting .............................................................................20 
18.0 
INFORMED CONSENT PROCEDURES .................................................................................21 
19.0 
REFERENCES......................................................................................................................21 
20.0 
APPENDICES.......................................................................................................................23
Memorial Sloan Kettering Cancer Center
IRB Number: 11-045 A(7)
Approval date: 26-Jan-2021


Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 3 of 23 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a blinded randomized control trial comparing a four week treatment with 
the antibiotic rifaximin versus placebo in the management of bowel dysfunction after 
Anterior Resection (AR) or Sphincter Preserving Surgery (SPS) for rectal cancer. 
Patients will be randomized into 2 groups, one group will receive rifaximin 400mg bid for 
4 weeks and the other group will receive a placebo bid for 4 weeks. Prior to 
commencement of treatment patients bowel symptoms will be assessed using the 
MSKCC Bowel Function Instrument (BFI score). For those patients that agree, stool 
samples will be taken and stool bacterial content will be assessed. The same patients 
will also undertake breath testing to assess Small Intestinal Bacterial  Overgrowth 
(SIBO). Following treatment, all patients will again be assessed using the BFI, and stool 
sampling and breath testing will be preformed on those patients that agreed to it. Four 
weeks after cessation of treatment all patients will undertake a third round of testing 
using the BFI and in respective patient, a third round if stool sampling and breath testing 
will occur. 1-24months following completion of the study, we will ask patients to 
participate in a follow up study using metronidazole 500mg po tid x 3 weeks on a 
voluntary basis. In this case we will use a phase II design and not compare with a 
placebo control. 
The primary objective of this study is to compare the efficacy of rifaximin and 
placebo in the treatment of bowel dysfunction as measured by MSKCC Bowel Function 
Instrument in patients following AR or SPS for rectal cancer. A study schema is depicted 
below.
Memorial Sloan Kettering Cancer Center
IRB Number: 11-045 A(7)
Approval date: 26-Jan-2021


Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 4 of 23 
 
1-8 months off treatment
MSKCC Bowel Function Instrument 
Volunteer 
Stool Sample 
patients 
Hydrogen Breath Test 
4 weeks on treatment 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.2 
Primary objective. 
 
 
To compare the efficacy of rifaximin and placebo in the treatment of bowel 
dysfunction as measured by MSKCC Bowel Function Instrument (BFI score) in 
patients following AR or SPS for rectal cancer. 
2.3 
Secondary objectives
70 patients
with bowel
35 patients 
rifaximin 
35 patients 
placebo 
35 patients 
rifaximin 
35 patients 
placebo 
MSKCC Bowel Function Instrument 
Volunteer 
Stool Sample 
patients 4
  weeHkysdorfofgterneaBtrmeaetnht
 Test
 
35 patients 
rifaximin 
35patients 
placebo 
MSKCC Bowel Function Instrument 
Volunteer 
Stool Sample 
patients 
Hydrogen Breath Test 
Treatment with 
Flagyl 
MSKCC Bowel Function Instrument 
1-24 months off treatment 
 
Volunteer
 


Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 5 of 23 
 
 
To determine if reduction in intestinal bacterial quantity correlates with improvement 
in bowel symptoms (BFI score). 
 
To explore the bacterial composition of stool before and after antibiotic treatment. 
 
To identify dynamic changes in bowel function during and after antibiotic treatment 
using a bowel function log. 
 
 
To identify the efficacy of metronidazole in the treatment of bowel dysfunction as 
measured by the MSKCC BFI in patients following AR or SPS for rectal cancer for 
patients who have no improvement following treatment with rifaximin or placebo. 
 
3.0 
BACKGROUND AND RATIONALE 
 
The surgical treatment of rectal cancer has become increasingly directed towards 
sphincter preservation where possible, with the avoidance of a permanent stoma. This 
has been accomplished in part by refinement of the conventional anterior resection with 
surgical techniques such as ultra low anterior resection (LAR), intersphincteric 
dissection, and coloanal anastomosis (CAA). [1, 2] The widespread use of neo-adjuvant 
radiotherapy and chemotherapy has also led to the down staging of low rectal tumors 
pre-operatively which previously would have necessitated an abdomino-perineal 
resection again facilitating sphincter preserving surgery (SPS).[3] 
The large number of patients treated by SPS has led to a greater awareness of 
the bowel dysfunction following surgery or so called anterior resection syndrome 
(ARS).[4] Up to 90% of patients develop symptoms of bowel dysfunction following SPS 
for rectal cancer. The most common symptoms include incomplete evacuation, 
clustering of bowel motions, food affecting frequency, unformed stool, and gas 
incontinence; the less common but more debilitating symptoms are stool frequency and 
incontinence.[5] Several surgical treatment factors are known to affect bowel function. In 
addition, the use of adjuvant or neo-adjuvant radiotherapy to the pelvis has also been 
shown to exacerbate these symptoms and worsen bowel function.[6, 7] These  
symptoms have a significant effect on patient quality of life with 27% of patients 
describing their symptoms as severely affecting their lifestyle and significantly impacting 
on their quality of life.[5] The mechanisms responsible for these symptoms are not 
clearly understood but are thought to involve a combination of etiological factors, 
including loss of fecal reservoir (rectum), injury to pelvic nerves and sphincter injury.[8- 
11] A variety of novel surgical techniques have been developed with the goal of 
minimizing bowel dysfunction: these include creation of a neo-rectum using a colonic-J- 
pouch, coloplasty, end to side colorectal anastomosis, construction of artificial anal 
sphincters, and sacral nerve stimulation.[7, 12] These methods have been met with 
varying degrees of success; however, none have resulted in completely satisfactory 
bowel function.[13] Currently there is no standard of care for the medical management of 
this bowel dysfunction. Patients are generally treated individually based on symptoms
Memorial Sloan Kettering Cancer Center
IRB Number: 11-045 A(7)
Approval date: 26-Jan-2021


Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 6 of 23 
 
with a combination of high fibre diet, antidiarrheal agents, laxatives and/or probiotics 
without significant success. 
Another theory explaining ARS is that denervation of the distal colon and 
reduction of rectal volume leads impaired / inefficient rectal evacuation and a state of 
rectal pseudo-obstruction. The resulting stasis of stool within the colon leads to 
increased numbers of colonic bacteria and subsequently overgrowth of bacteria in the 
large and small bowel contributing to the symptoms of bowel dysfunction. 
Altered bowel function as a consequence of increased intestinal bacteria is not a 
new concept. Antibiotics are used in many intestinal conditions to improve bowel 
function. Patients with Crohns disease and small intestinal bacterial overgrowth SIBO 
have been shown to benefit from treatment with metronidazole and rifaximin individually, 
with both a reduction in SIBO and bowel symptoms.[14, 15] In active inflammatory bowel 
disease, antibiotic therapy also plays a role in its management.  Metronidazole appears 
to induce significant clinical improvement in patients with pouchitis compared to 
placebo,[16] and long term treatment using rifaximin and metronidazole reduces the 
incidence of clinical flare ups of IBD again as compared to placebo.[17, 18] Similarly in 
irritable bowel syndrome, treatment with rifaximin has demonstrated both improvement  
in symptoms and a reduction in SIBO.[19] Finally in patients with chronic liver disease 
antibiotics again specifically both metronidazole and rifaximin have been used to reduce 
ammonia producing bacteria in the intestine and with that the incidence of hepatic 
encephalopathy and spontaneous bacterial peritonitis.[20] 
Within the past two years, the PI has used metronidazole (500mg po tid for 14 
days) to treat severe bowel symptoms in over 20 patients. Over 80% of these rectal 
cancer patients have reported marked improvement in their bowel function, including 
better stool formation, more complete evacuation, fever bowel motions, and less gas 
formation.  No adverse effects were noted.  However, after stopping metronidazole 
bowel symptoms were noted to return gradually over one to two months. More recently 
the PI has begun treating patients with rifaximin 400mg bid as it has fewer side effects, 
with similar results. This experience has led us to the theory that by treating patients with 
antibiotics the quantity of fecal bacteria is reduced, which in turn improves stool 
formation, enhances rectal evacuation, and alleviates the symptoms of bowel 
dysfunction. 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
Consented patients will undertake the MSKCC Bowel Function Instrument, a 
validated questionnaire developed by the Co-PI that assesses bowel function. [5] 
Appendix 2. Patients will then be invited to undertake a hydrogen breath test and fecal
Memorial Sloan Kettering Cancer Center
IRB Number: 11-045 A(7)
Approval date: 26-Jan-2021


Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 7 of 23 
 
sampling to assess for bacterial content in their small intestine and stool. Following 
stratification of patients by the method of anastomosis (stapled or hand sewn), the 
patients will then be randomized into two groups. The patients will receive treatment with 
rifaximin or placebo depending on the arm of the trial to which they have been 
randomized. Patients will at this stage on a volunteer basis be asked to submit stool 
samples and undertake a breath test. Patients will receive the respective treatment for 
four weeks. Following cessation of treatment all patients will be assessed using the BFI 
and respective patients will have repeat stool sampling and breath testing. Patients will 
then have these tests repeated 4 weeks later. This corresponds to 8 weeks after the 
start of the trial. For those patients not undertaking stool and breath testing, they will be 
reminded by phone, mail or email to fill out the BFI. Before and during the trial patients 
will be asked to fill out a weekly stool diary to evaluate trends on bowel function. 
Appendix 3. Both the patients and the physicians will be blinded to the patient 
treatments. The Initial consultation along with subsequent rounds of testing with 
submission of stool samples and breath testing will be undertaken by one of the 
consenting physicians at a specifically arranged and designated “research clinic” at one 
of MSKCC’s network centers. (Sleepy Hollow, Commack, Main Campus and 53rd St). 
Patients may also be seen and  consented at their regular follow up colorectal clinic 
visits. At 1 – 24 months after completion of the phase III portion of the trial, patients will 
be contacted by phone and given the option of receiving metronidazole in a followup, 
single arm study in which all patients receive the antibiotic. Patients who wish to 
participate will be mailed a drug prescription for a 3 week course of metronidazole 
500mgs tid as well as the BFI forms and stool diary. Pretreatment and posttreatment BFI 
scores will be collected and analyzed for change in bowel function as was done in the 
initial Phase III study. 
4.3 
Intervention 
 
The antibiotic used will be rifaximin. Rifaximin acts by inhibition of bacteria 
synthesis of RNA. It is active against gram positive and gram negative bacteria including 
both aerobes and anaerobes however it is not absorbed in the gastro-intestinal system 
facilitating its use in enteric infections. It is licensed for the treatment of acute bacterial 
diarrhea and SIBO. [21] We have chosen to use rifaximin over metronidazole because it 
is not enterically absorbed and as such has less of a side-effect profile. Metronidazole 
causes a higher incidence of nausea and GI upset, has a greater amount of drug 
interactions and it also has a metallic taste which could effect blinding and introduce 
bias. 
For this trial, both rifaximin and placebo will be prepared in identical capsules by 
the research pharmacist at MSKCC and distributed to the outpatient pharmacies. We 
have chosen a rifaximin dose of 400 mg bid for 4 weeks as this has been shown to be 
efficacious in the treatment of SIBO at this dose over 14 days. We have added a further
Memorial Sloan Kettering Cancer Center
IRB Number: 11-045 A(7)
Approval date: 26-Jan-2021


Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 8 of 23 
 
2 weeks to the treatment regime as from prior experience by the PI’s using rifaximin in 
this condition, the beneficial effect tends to reduce over one week. As the BFI is 
validated for use over a 4 week period (ie assessing bowel function over a 4 week 
period), to show an effect on bowel function as assessed by the BFI, treatment is 
needed over a four week period. We plan to assess bowel function at 4 weeks after the 
completion of treatment to determine if the response to treatment is transient or whether 
it is a more durable effect. Following the completion of the trial patients will be offered a 
3 week treatment with 500 mg of metronidazole tid. They will be assessed with the BFI 
at pretreatment and again at 0-1 and 4-6 weeks post treatment. Should the effect be 
transient, this will lead to future studies to assess if adding extra treatment with other 
medications such as pro-biotics may prolong the effect. 
 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.2 
Rifaximin (Xifaxan®) 
 
Rifaximin is a non-aminoglycoside semi-synthetic, nonsystemic antibiotic derived 
from rifamycin SV with a chemical name of 5,6,21,23,25- pentahydroxy-27-methoxy- 
2,4,11,16,20,22,24,26-octamethyl-2,7( epoxypentadeca- 
[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-á]-benzimidazole-1,15(2H)dione, 25- 
acetate. It comes in preparations of 200mg and 550mg tablets. It can be stored at room 
temperature and is FDA licensed for use in the treatment of bacterial intestinal 
infections. 
 
 
5.3 
Metronidazole (Flagyl®) 
 
Metronidazole is an oral synthetic antiprotozoal and antimicrobial agent with a 
chemical name of 1-(β-hydroxy-ethyl)-2-methyl-5-nitroimidazole. It comes in oral 
preparations of 250mgs and 500mgs tablets. It can be stored at room temperature and is 
FDA licensed for the treatment of bacterial intestinal infections. 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
 
Patients with a history of rectal cancer treated with an anterior resection 
preformed at MSKCC (tumor at or below 12cm from anal verge) with 
restoration of bowel continuity ≥1 and ≤ 5 years. (Patients may also have had
Memorial Sloan Kettering Cancer Center
IRB Number: 11-045 A(7)
Approval date: 26-Jan-2021


Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 9 of 23 
 
procedures to construct neo-rectums including j-pouch, coloplasty, and end to 
side anastomosis). 
 
Patients ≥ 21 years of age. 
 
Presence of anterior resection symptoms by patients own assessment. 
These symptoms may include any of the following: incomplete evacuation, 
clustering of bowel motions, frequency of bowel motions, unformed stool, 
excessive flatus, or incontinence of flatus and/or feces. 
6.3 
Subject Exclusion Criteria 
 
 
Local recurrence of rectal cancer. 
 
Antibiotic treatment within the last 4 weeks for any condition. 
 
Pregnancy or breast feeding. 
 
7.0 
RECRUITMENT PLAN 
 
Patients who have had an anterior resection for rectal cancer at MSKCC will be 
identified from a prospective database maintained by the Colorectal Surgery Service. 
These patients will be contacted by a letter inviting them to participate in a randomized 
study designed to evaluate the beneficial effects of rifaximin and placebo on bowel 
function. Appendix 1. We will ask patients to participate in the trial based on their own 
personal perception of their symptoms. Patients will be asked in the letter to contact Dr. 
Philip Paty (PI) or Dr. James Smith (Research Fellow) by email, telephone, or letter. 
Patients who have not responded to the letter after one month will be contacted by 
phone and invited to participate. Appendix 4. Every attempt will be made to recruit 
women and minorities to participate in this study. Participation is voluntary. Patients who 
are interested in participating will be scheduled for a research clinic visit with Dr. Philip 
Paty or another of the consenting professionals. Consenting patients will be registered 
and randomized at the initial clinic visit. We hope to recruit 70 patients, 35 in each arm in 
an attempt to have at least 30 patients per arm for analysis allowing for patient dropout. 
Patients will also be asked to volunteer to submit stool samples and breath tests. 
Those who agree will be tested for stool bacteria and SIBO at the relevant time points 
along with the MSKCC BFI. For those patients who do not agree to volunteer to supply 
stool samples and breath test, they will be tested using the MSKCC BFI alone at the 
relevant time periods. All patients will fill out the stool log/diary. We hope to recruit half of 
the patients in each arm to participate in the extra testing. We are not testing all patients 
with stool sampling and breath tests as we feel it will hamper accrual into the trial. 
Patients will be reimbursed with a $100 gift card for each outpatient visit to cover 
transport costs for participating in this trial. Following completion of the phase III portion 
of the trial, patients will be contacted by phone and offered to participate in a follow up 
single arm study to assess the efficacy of metronidazole in the treatment of bowel 
dysfunction.
Memorial Sloan Kettering Cancer Center
IRB Number: 11-045 A(7)
Approval date: 26-Jan-2021


Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 10 of 23 
 
Patients already enrolled on version A(0) or A(1) will also be asked via phone to 
participate in the follow up study. If they wish to participate, they will be reconsented. 
Consent forms will be mailed to them with a self addressed return envelope. 
 
8.1 
PRETREATMENT EVALUATION 
 
 Routine clinic evaluation at MSKCC ≤ 12 months of beginning the trial. 
 Serum beta-HcG levels for pre-menopausal women (last menses within one 
year) ≤ 2 weeks. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
The planned treatment during this trial will be the administration of the antibiotic 
rifaximin 400mg bid for 4 weeks or a placebo bid for 4 weeks to patients with bowel 
dysfunction. Both rifaximin and placebo will be prepared in identical capsules by the 
research pharmacist at MSKCC and distributed to the outpatient pharmacies. Following 
registration to the trial patients will be given a prescription for the trial, which they will be 
able to fill out at one of the MSKCC satellite center outpatient pharmacies. Patients will 
be instructed to take then treatment at the same time in the morning and the evening. 
Any missed doses will be recorded in the stool diary/log. Once treatment has been 
completed patients will be asked to mail back the treatment container along with any un- 
used medication. 
Once the trial has been completed and patients have been unblinded, patients 
may elect to be treated with Rifaximin if they so wish. 
10.1 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Pre-treatment intervention & evaluation all undertaken in an outpatient clinic (day 0) 
 
 MSKCC BFI (for all patients) 
 Breath test (for patient volunteers) 
 Stool Sampling (for patient volunteers) 
Treatment with 400 mg rifaximin bid x 4 weeks or placebo bid x 4 weeks. 
 
Post treatment evaluation at an outpatient clinic, for those patients who volunteered for 
extra testing. (days 26 - 35 and days 53 – 63) 
 MSKCC BFI 
 Breath test 
 Stool Sampling 
Post treatment evaluation for patients not volunteering for extra tests which can be 
undertaken in the patients home during the following periods. (days 26 - 35 and 53 – 63)
Memorial Sloan Kettering Cancer Center
IRB Number: 11-045 A(7)
Approval date: 26-Jan-2021


Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 11 of 23 
 
 MSKCC BFI 
All patients will be required to fill out a weekly stool log/diary for the duration of the trial. 
There are questions in the log/diary to assess patient compliance also. 
One to twenty-four months following completion of the phase III trial patients will be 
offered a 3 week course of metronidazole. They will then be assessed again using the 
BFI at pretreatment and at 0-1 and 4-6 weeks post-treatment. (21-30 days and 49 – 63 
days following starting metronidazole) 
MSKCC BFI 
 
The MSKCC BFI is a validated instrument in the assessment of bowel function 
following rectal cancer surgery over a 4 week period.[5] It consists of 18 items to which 
patients respond using a 5-point Likert scale, ranging  from Always  to Never.  There is 
a summary score, and three subscales with good internal consistency (Frequency 
(α=0.75), Dietary (α=0.78), Urgency (α=0.79)) and test-retest reliability (total score 
=0.84, Frequency=0.74, Dietary=0.62, Urgency=0.87). The instrument has 
demonstrated discriminant and  construct validity.  It is written at  a grade  8 reading 
level, and takes  5-10 minutes  to  complete.  The BFI if filled out at home can  be 
emailed or mailed back  to the investigator where they will be stored on a secure 
database and a locked drawer. Should there be any incomplete or ambiguous answers a 
follow up phone call will be made by one of the consenting physicians to clarify the 
answer. However in a prior trial by the Co-PI (Larissa Temple 06-151), of the 125 
patients who answered the BFI on multiple occasions less then 5 items per question 
were missing or filled out inadequately. 
Breath Test 
 
Methane and hydrogen breath testing is currently the best non-invasive way of 
assessing small bowel bacterial overgrowth.[22] The test takes 1 hour and can be taken 
in the outpatient clinic. The patient must fast at least 12 hours prior to starting the test. 
The patient takes a baseline breath and exhales into a container. He/she then ingests a 
quantity of lactulose. If there is overgrowth of bacteria in the small intestine the sugar is 
not absorbed but is instead fermented by the bacteria in the gastrointestinal tract 
producing hydrogen and methane. The human body does not endogenously produce 
either of these gasses. These gasses can then be detected in the breaths of patients 
indicating bacterial overgrowth in the small bowel. Subsequent breaths are then taken at 
varying intervals up to 90 minutes from the initial ingestion of the sugar and are 
assessed for methane and hydrogen levels. The samples will be analyzed at Metabolic 
Solutions Incorporated®, a commercial laboratory. 
Stool Sampling
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IRB Number: 11-045 A(7)
Approval date: 26-Jan-2021


Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 12 of 23 
 
Stool samples will be taken during the outpatient visits. Patients can submit a 
sample by defecating into a container or a sample can be taken by gentle rectal 
examination. The samples will be collected in the outpatient setting and frozen at -80 
degrees Celsius. DNA will be extracted using commercial kits (Qiagen®). Bacterial 
culture has proven to be unreliable as a quantitive measure of fecal content as only a 
tiny minority of fecal bacteria will survive in culture. As such we plan to quantify fecal 
bacteria using real time quantitive PCR for the gene for 16s ribosomal RNA as 
previously described.[23] This gene is present in all bacteria and has both conserved 
and variable domains. For quantification of total fecal bacteria, PCR primers amplifying 
the conserved domain will be used and the PCR product will be measured using the 
Syber Green method. 
To evaluate the spectrum of fecal bacteria, a PCR plus 454 pyrosequencing 
technique optimized by one of the Co-Investigators (Eric Pamer) will be used. The 
conserved and variable domains of the gene 16S ribosomal RNA will be amplified as 
one PCR product using previously described primers. From this product, the variable 
domain will be analyzed using 454 pyrosequencing technique. Microbial complexity will 
be determined and comparisons between samples will be performed using UniFrac and 
Principal Coordinates Analysis. Approximately 120 species of bacteria will be 
represented in the various Pyrosequencing primers. The read out of the assay will give 
a positive fluorescent signal for each bacterial species present in the feces. 
Expertise in both quantifying total bacterial load and identifying fecal colonization 
patterns will be provided by Dr Eric Pamer and his laboratory.[24] 
 
Stool Diary/Log 
 
The stool diary/log will allow the investigators to follow trends in bowel function 
and to assess how long the antibiotic effect lasts. Patients will be asked to fill the diary 
out once per week (+/- 2 days) on paper or by email before and through the duration of 
the trial. The questions asked will address range of stools per day, stool formation, 
flatus, incontinence, ability to completely evacuate. Patient compliance will also be 
assessed in the log. It will not take longer than 3 minutes to fill out. Once the log is 
competed it can be posted or emailed back to the investigator where it will be stored on 
a secure database and a locked drawer. 
11.1 
TOXICITIES/SIDE EFFECTS 
 
11.2 
Rifaximin 
 
The safety of Rifaximin for the treatment of infectious diarrhea was assessed in 2 
placebo controlled trials. Discontinuation of the drug due to adverse reactions occurred 
in < 0.4% of patients. Those adverse reactions were taste loss, diarrhea, weight loss 
anorexia, nausea and nasal passage irritation.
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Side effects include: [25] 
 
>10%: 
 
Cardiovascular: Peripheral edema (15%) 
 
Central nervous system: Dizziness (13%), fatigue (12%) 
 
Hepatic: Ascites (11%) 
 
Gastrointestinal: 
Nausea (14%) 2% to 10%: 
 
Cardiovascular: Chest pain (>2% to 5%), hypotension (>2% to 5%) 
 
Central nervous system: Headache (10%), depression (7%), fever (6%), amnesia 
(>2% to 5%), attention disturbance (>2% to 5%), confusion (>2% to 5%), 
hypoesthesia (>2% to 5%), pain (>2% to 5%), tremor 
 
Dermatological: Pruritus (9%), rash (5%), cellulitis (>2% to 5%) 
 
Endocrine and metabolism: Hyper-/hypoglycemia (>2% to 5%), hyperkalemia 
(>2% to 5%), hyponatremia (>2% to 5%) 
 
Gastrointestinal: Abdominal pain (6% to 9%), anorexia (>2% to 5%), dehydration 
(>2% to 5%), esophageal varices (>2% to 5%), weight gain (>2% to 5%), 
xerostomia (>2% to 5%) 
 
Hematologic: Anemia (8%) 
 
Neuromuscular & skeletal: Muscle spasms (9%), arthralgia (6%), myalgia (>2% 
to 5%) 
 
Respiratory: Nasopharyngitis (7%), dyspnea (6%), epistaxis(>2% to 5%), 
pneumonia (>2% to 5%), rhinitis (>2% to 5%), upper respiratory tract infection 
(>2% to 5%) 
 
Miscellaneous: Influenza-like illness (>2% to 5%) 
<2%, postmarketing, and/or case reports (limited to important or life-threatening): 
Abnormal dreams, allergic   dermatitis, anaphylaxis, angioneurotic edema 
(including tongue and facial edema with dysphagia), CDAD, dysuria, exfoliative 
dermatitis,  flushing, 
hematuria, 
hypersensitivity 
reactions, 
insomnia, 
lymphocytosis, monocytosis, motion sickness, neutropenia, polyuria, proteinuria, 
sunburn, tinnitus, urticaria 
 
Drug interactions: [25] 
 
Although in vitro studies have suggested that rifaximin induces CYP3A4, no 
differences in midazolam (also induces CYP3A4) concentrations were found after 
administration of midazolam alone and midazolam and rifaximin together. Rifaximin had 
also been shown to have no effect on the oral contraceptive pill. No drug interactions 
have been reported to date. 
11.3 
Metronidazole
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The two most significant adverse reactions reported when taking metronidazole 
are convulsive seizures and peripheral neuropathy; these occur in <0.5% of patients and 
are nearly always associated with prolonged administration. The most commonly 
experienced side effect is nausea (12% of patients). 
Other side effects include: (Taken from Lexi-Drugs online) 
 
 Cardiovascular: Flattening of the T-wave, flushing, syncope 
 Central nervous system: Aseptic meningitis, ataxia, confusion, coordination 
impaired, depression, dizziness, encephalopathy, fever, headache, insomnia, 
irritability, seizure, vertigo 
 Dermatologic: Erythematous rash, pruritus, Stevens-Johnsonsyndrome, urticaria 
 Endocrine & metabolic: Disulfiram-like reaction, dysmenorrhea 
 Gastrointestinal: Nausea (~12%), anorexia, abdominal cramping, constipation, 
diarrhea, epigastric distress, furry tongue, glossitis, pancreatitis (rare), proctitis, 
stomatitis, unusual/metallic taste, vomiting, xerostomia 
 Genitourinary: Cystitis, darkened urine (rare), dyspareunia, dysuria, incontinence, 
libido decreased, pelvic pressure, polyuria, vaginal dryness, vaginitis 
 Hematologic: Neutropenia (reversible), thrombocytopenia (reversible, rare) 
 Local: Thrombophlebitis 
 Neuromuscular & skeletal: Dysarthria, peripheral neuropathy, weakness 
 
Ocular: Optic neuropathy 
 
Respiratory: Nasal congestion, pharyngitis, rhinitis, sinusitis, pharyngitis 
 
Miscellaneous: Flu-like syndrome, joint pains resembling serum sickness, 
moniliasis. 
 
Drug interactions include: (Taken from Lexi-Drugs online) 
 
 Alcohol (Ethyl): Metronidazole may enhance the adverse/toxic effect of Alcohol 
(Ethyl). A disulfiram-like reaction may occur. 
 BCG: Antibiotics may diminish the therapeutic effect of BCG. 
 Busulfan: Metronidazole may increase the serum concentration of Busulfan. 
 Calcineurin Inhibitors: Metronidazole may decrease the metabolism of 
Calcineurin Inhibitors. 
 Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration 
of Colchicine. Management: Reduce colchicine dose as directed when using with 
a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related 
toxicity. Use extra caution in patients with impaired renal and/or hepatic function.
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 
 CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the 
metabolism of CYP3A4 Substrates. 
 Disulfiram: Metronidazole may enhance the adverse/toxic effect of Disulfiram. 
 Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum 
concentration of Eplerenone. Management: A lower starting dose of eplerenone 
(25 mg once daily for adults) is recommended in patients with hypertension who 
are also taking drugs that are moderate inhibitors of CYP3A4. 
 Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum 
concentration of Everolimus. Management: Use of this combination is not 
recommended without close everolimus concentration monitoring/dose 
adjustments. For renal cell carcinoma, an initial everolimus dose reduction to 2.5 
mg/day (adult dose) is recommended. 
 Fentanyl: CYP3A4 Inhibitors (Moderate) may increase the serum concentration 
of Fentanyl. Management: Monitor patients extra closely for several days 
following initiation of the combination, and fentanyl dosage reductions should be 
made as appropriate. 
 Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum 
concentration of Halofantrine. 
 Mebendazole: May enhance the adverse/toxic effect of Metronidazole. 
Particularly the risk for Stevens-Johnson Syndrome or Toxic Epidermal 
Necrolysis may be increased. 
 Mycophenolate: Metronidazole may decrease the serum concentration of 
Mycophenolate. Specifically, metronidazole may decrease concentrations of the 
active metabolite of mycophenolate. 
 Phenobarbital: May decrease the serum concentration of Metronidazole. 
 Phenytoin: Metronidazole may increase the serum concentration of Phenytoin. 
Phenytoin may decrease the serum concentration of Metronidazole. 
 Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of 
Pimecrolimus. 
 Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum 
concentration of Ranolazine. Management: Limit the ranolazine adult dose to a 
maximum of 500 mg twice daily in patients concurrently receiving moderate 
CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). 
 Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration 
of Salmeterol. 
 Saxagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum 
concentration of Saxagliptin. 
 Tipranavir: Metronidazole may enhance the adverse/toxic effect of Tipranavir. 
 Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration 
of Tolvaptan.
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 
 Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid 
Vaccine. Only the live attenuated Ty21a strain is affected. Management: 
Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in 
patients being treated with systemic antibacterial agents. Use of this vaccine 
should be postponed until at least 24 hours after cessation of antibacterial 
agents. 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
The ultimate response to treatment with antibiotics for ARS will be with the 
MSKCC bowel function instrument. This is an 18 point questionnaire which takes about 
10 minutes to complete. It can be completed either in the outpatient setting or at home. 
This instrument has been validated in the assessment of bowel function following rectal 
cancer surgery over a 4 week period.[5] The BFI score will be calculated by the 
consenting physicians. 
The purpose of the correlative studies is to assess if symptoms of ARS, 
indicated by a reduced MSKCC bowel function instrument score are associated with 
increased bacterial content in the gastro-intestinal tract or with a specific pattern of 
bacterial colonization. To this end bacterial content in the small intestine will be 
assessed using the breath test and bacterial content and colonization patterns will be 
assessed from fecal stool samples. 
 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
A patient has the right to withdraw from the study at any time without prejudice to 
his/her future medical care by his/her physician at the institution 
Criteria for removal for the study include: 
 
 Patient discretion 
 Significant noncompliance by the patient (<75% of drug dose taken) 
 Development of an grade 3 or 4 adverse reaction to rifaximin 
 Recurrence of their rectal cancer 
 Should a treating physician deem it necessary in the best interest of the patient 
14.0 
BIOSTATISTICS 
 
This is a blinded randomized control trial to compare the efficacy of a four week 
treatment with the rifaximin versus placebo in the management of Anterior Resection 
Syndrome (ARS) following Sphincter Preserving Surgery (SPS) for low rectal cancers. 
Patients will be randomized into 2 groups, one to receive rifaximin 400mg bid for 4 
weeks and one group to receive a placebo bid for 4 weeks.
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Page 17 of 23 
 
The primary endpoint is the change in the MSKCC bowel function index from 
baseline to 4 weeks after the start of therapy. At 4 weeks the patients will have been on 
therapy for 4 consecutive weeks. The MSKCC bowel function index has been validated 
to examine 4 week changes in the bowel function. [5] It consists of 18 items to which 
patients respond using a 5-point Likert scale, ranging  from Always  to Never.  There is 
a summary score, and three subscales with good internal consistency (Frequency 
(α=0.75), Dietary (α=0.78), Urgency (α=0.79)) and test-retest reliability (total score 
=0.84, Frequency=0.74, Dietary=0.62, Urgency=0.87).Each subscale is scored by 
summing up the responses to the items in the subscale. If there are missing items within 
a subscale, the mean of the completed subscale items will be substituted for the item 
when >50 percent of the items in the subscale is completed. A global score will be 
calculated  by adding the subscale scores. An additional aggregate score (total score) 
will also be calculated with the subscales and the single items. A subscale will be 
considered missing if more than one-half of the items are missing. The global score will 
be considered missing if any of the subscales or single items were missing. The average 
total score (frequency, urgency, dietary, plus four single items) among the 129 MSKCC 
rectal patients following SPS used to develop the bowel function index was 63.7 with 
standard deviation of 11.6 and range of 35 – 83. Larger BFI scores indicate better 
function. In this study the main comparison of interest is to examine whether the change 
in global-BFI from baseline to 4 weeks after four weeks of rifaximin is different from the 
change from baseline to 4 weeks of placebo. The analysis will be a done using an 
ANCOVA model, with baseline BFI and treatment indicator as covariates and  4 week 
BFI as the dependent variable. 
Based on clinical observation, we expect the difference in BFI between the two 
treatments to be fairly large. We would like to accrue 30 patients in each arm stratified 
by surgical procedure (hand sewn versus stapled anastomosis) for randomization to 
ensure the two arms are balanced, as surgical procedure is known to correlate with BFI. 
Power calculations are based on the global score on the BFI. Based on Dr 
Temple’s work when developing the BFI score in 129 MSKCC rectal cancer patients, the 
lowest mean BFI score was found among the hand sewn patients. The mean BFI score 
for these patients was 42 with a standard deviation of 8and 51.6 with a standard 
deviation of 9 among patients with stapled anastomosis.  In a current prospective study 
of 225 patients which is still maturing, we have found that at 6 months, the BFI 
discriminates between many clinical parameters with one of the most significant 
predictors being hand sewn vs stapled anastomosis (a surrogate for tumor level) (Mean 
43.3, std 7 (n=36) vs Mean 49.4, std 8 (n=81). Based on these data, we anticipate that a 
difference of 6 points on the BFI is clinically and statistically meaningful. 
For our power calculation, we set the type I error at 5%. We assume that the 
placebo arm will have no change in BFI from baseline to 4 weeks after the start of 
therapy. We also assume that the baseline for both treatment groups will be on a similar
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magnitude. In line with the above average scores and standard deviations in Dr 
Temple’s past and ongoing studies, we assume that the standard deviation of the 
differences to be 8 and the average BFI score at baseline to be 44. Using a two-sided, 
two sample t-test, we will have 80% power to detect a difference of differences from 0 in 
the placebo arm to 5.8 in the rifaximin arm with 30 patients in each arm. We expect to 
accrue the 60 patients for this study in 1 year, with a plan to recruit 35 in each arm to 
account for dropout. 
In secondary analyses, we will examine the change in BFI scores adjusted for 
possible cofounders, such as peri-op radiotherapy. We will also examine bowel function 
data from the weekly logs in order to learn in what time frame (onset, duration) the 
effects of rifaximin and placebo occur. The data will be evaluated by graphical display 
without rigorous statistical testing. The weekly logs will also record drug compliance. 
Bacterial quantity and content in stool along with presence of SBIO will also be assessed 
in secondary analysis. These are both exploratory analyses. 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND 
RANDOMIZATION PROCEDURES 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the 
PPR Electronic Registration System (http://ppr/). The completed signature page of the 
written consent/RA or verbal script/RA, a completed Eligibility Checklist and other 
relevant documents must be uploaded via the PPR Electronic Registration System. 
15.3 
Randomization 
 
This is a double blind randomized comparison of the antibiotic rifaximin and 
placebo in the treatment of bowel dysfunction following rectal resection for cancer. After 
eligibility is established and immediately after consent is obtained, patients will be 
registered in the Protocol Participant Registration (PPR) system and randomized using 
the Clinical Research Database (CRDB), by calling the MSKCC PPR Office at 646-735- 
8000 between the hours of 8:30 am and 5:30 pm, Monday - Friday. Randomization will
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be accomplished by the method of random permuted block, and patients will be stratified 
by the variable of type of anastomosis (stapled or hand sewn). Since this is a double 
blind study, the patients’ treatment assignments can be viewed in the CRDB only by the 
hospital pharmacists who are dispensing the study drugs. 
16.1 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study at MSKCC. The 
RSA will be responsible for project compliance, data collection, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the 
protocol study team. The data collected from this study will be entered into a secure 
MSKCC database  in regulation with HIPAA guidelines. Hard copies of  the MSKCC 
bowel function instrument questionnaire will be kept in a locked drawer. 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration of data. Routine data quality reports will be generated to 
asses missing data and inconsistencies. Accrual rates and extent and accuracy of 
evaluations and follow-up will be monitored periodically throughout the study period and 
potential problems will be brought to the attention of the study team for discussion and 
action. 
Random-sample data quality and protocol compliance audits will be conducted 
by the study team, at a minimum of two times per year, more frequently if indicated. 
 
16.3 
Data and Safety Monitoring 
 
The Data and  Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering 
Cancer Center were approved by the National Cancer Institute in September 2001. The 
plans address the new policies set forth by the NCI in the document entitled “Policy of 
the National Cancer Institute for Data and Safety Monitoring of Clinical Trials” which can 
be found at: http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans 
at MSKCC were established and are monitored by the Office of Clinical Research. The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 
There are several different mechanisms by which clinical trials are monitored for 
data, safety and quality. There are institutional processes in place for quality assurance 
(e.g., protocol monitoring, compliance and data verification audits, therapeutic response, 
and staff education on clinical research QA) and departmental procedures for quality 
control, plus there are two institutional committees that are responsible for monitoring  
the activities of our clinical trials programs. The committees: Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring
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Board (DSMB) for Phase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board 
 
17.1 PROTECTION OF HUMAN SUBJECTS 
 
Patient wellbeing will always take precedence in this trial however there will be 
minimal patient risk during this trial. Adverse drug reactions will be the most significant 
risk to patient health; however rifaximin carries minimal side effects. Should patients 
develop grade 3 or 4 toxicity to the antibiotic treatment, their treatment will be stopped 
and they will be removed from the study. The patient will be responsible for all costs 
related to treatments and complications of treatment except the antibiotic treatment, the 
placebo, breath testing and stool sampling which will be provided by MSKCC. 
Participation in this clinical trial is voluntary and at any stage patients may opt out to 
pursue any alternative treatment they wish. Once the trial is unblinded patients who 
received placebo during the trial may be treated with rifaximin if they so wish. 
17.2 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form. The use 
and disclosure of protected health information will be limited to the individuals described 
in the Research Authorization form. A Research Authorization form must be completed 
by the Principal Investigator and approved by the IRB and Privacy Board (IRB/PB). 
17.3 
Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 
calendar days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report 
be submitted electronically to the SAE Office at sae@mskcc.org. The report should 
contain the following information: 
Fields populated from CRDB: 
 
 
Subject’s name (generate the report with only initials if it will be sent 
outside of MSKCC) 
 Medical record number 
 Disease/histology (if applicable) 
 Protocol number and title 
Data needing to be entered: 
 The date the adverse event occurred 
 The adverse event 
 Relationship of the adverse event to the treatment (drug, device, or intervention)
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 If the AE was expected 
 The severity of the AE 
 The intervention 
 Detailed text that includes the following 
 A explanation of how the AE was handled 
 A description of the subject’s condition 
 Indication if the subject remains on the study 
 If an amendment will need to be made to the protocol and/or consent 
form. 
The PI’s signature and the date it was signed are required on the completed report. 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent form 
meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions 
and to withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information. 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
 
19.0 
REFERENCES 
 
1. 
Rullier, E., et al., Sphincter-saving resection for all rectal carcinomas: the end of the 2- 
cm distal rule. Ann Surg, 2005. 241(3): p. 465-9.
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2. 
Schiessel, R., et al., Technique and long-term results of intersphincteric resection for low 
rectal cancer. Dis Colon Rectum, 2005. 48(10): p. 1858-65; discussion 1865-7. 
3. 
Ceelen, W.P., Y. Van Nieuwenhove, and K. Fierens, Preoperative chemoradiation 
versus radiation alone for stage II and III resectable rectal cancer. Cochrane Database 
Syst Rev, 2009(1): p. CD006041. 
4. 
Karanjia, N.D., D.J. Schache, and R.J. Heald, Function of the distal rectum after low 
anterior resection for carcinoma. Br J Surg, 1992. 79(2): p. 114-6. 
5. 
Temple, L.K., et al., The development of a validated instrument to evaluate bowel 
function after sphincter-preserving surgery for rectal cancer. Dis Colon Rectum, 2005. 
48(7): p. 1353-65. 
6. 
Lundby, L., et al., Long-term anorectal dysfunction after postoperative radiotherapy for 
rectal cancer. Dis Colon Rectum, 2005. 48(7): p. 1343-9; discussion 1349-52; author 
reply 1352. 
7. 
Emmertsen, K.J. and S. Laurberg, Bowel dysfunction after treatment for rectal cancer. 
Acta Oncol, 2008. 47(6): p. 994-1003. 
8. 
Lee, W.Y., et al., Surgical autonomic denervation results in altered colonic motility: an 
explanation for low anterior resection syndrome? Surgery, 2008. 143(6): p. 778-83. 
9. 
Sun, W.M., et al., Anorectal function after restorative proctocolectomy and low anterior 
resection with coloanal anastomosis. Br J Surg, 1994. 81(2): p. 280-4. 
10. 
Horgan, P.G., et al., Effect of anterior resection on anal sphincter function. Br J Surg, 
1989. 76(8): p. 783-6. 
11. 
Lewis, W.G., et al., Why do some patients experience poor functional results after 
anterior resection of the rectum for carcinoma? Dis Colon Rectum, 1995. 38(3): p. 259- 
63. 
12. 
Brown, S.R. and F. Seow-Choen, Preservation of rectal function after low anterior 
resection with formation of a neorectum. Semin Surg Oncol, 2000. 19(4): p. 376-85. 
13. 
Ho, Y.H., F. Seow-Choen, and M. Tan, Colonic J-pouch function at six months versus 
straight coloanal anastomosis at two years: randomized controlled trial. World J Surg, 
2001. 25(7): p. 876-81. 
14. 
Castiglione, F., et al., Antibiotic treatment of small bowel bacterial overgrowth in patients 
with Crohn's disease. Aliment Pharmacol Ther, 2003. 18(11-12): p. 1107-12. 
15. 
Biancone, L., et al., Effect of rifaximin on intestinal bacterial overgrowth in Crohn's 
disease as assessed by the H2-Glucose Breath Test. Curr Med Res Opin, 2000. 16(1): 
p. 14-20. 
16. 
Madden, M.V., A.S. McIntyre, and R.J. Nicholls, Double-blind crossover trial of 
metronidazole versus placebo in chronic unremitting pouchitis. Dig Dis Sci, 1994. 39(6): 
p. 1193-6. 
17. 
Rutgeerts, P., et al., Controlled trial of metronidazole treatment for prevention of Crohn's 
recurrence after ileal resection. Gastroenterology, 1995. 108(6): p. 1617-21. 
18. 
Gionchetti, P., et al., Rifaximin in patients with moderate or severe ulcerative colitis 
refractory to steroid-treatment: a double-blind, placebo-controlled trial. Dig Dis Sci, 1999. 
44(6): p. 1220-1. 
19. 
Pimentel, M., Review of rifaximin as treatment for SIBO and IBS. Expert Opin Investig 
Drugs, 2009. 18(3): p. 349-58. 
20. 
Phongsamran, P.V., et al., Pharmacotherapy for hepatic encephalopathy. Drugs, 2010. 
70(9): p. 1131-48.
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21. 
Garey, K.W., et al., Rifamycin antibiotics for treatment of Clostridium difficile-associated 
diarrhea. Ann Pharmacother, 2008. 42(6): p. 827-35. 
22. 
Bures, J., et al., Small intestinal bacterial overgrowth syndrome. World J Gastroenterol, 
2010. 16(24): p. 2978-90. 
23. 
Turnbaugh, P.J., et al., A core gut microbiome in obese and lean twins. Nature, 2009. 
457(7228): p. 480-4. 
24. 
Ubeda, C., et al., Intestinal domination by Vancomycin-resistant Enterococcus precedes 
bloodstream invasion in humans. Journal of Clinical Investigation. In press. 
25. 
http://online.lexi.com/crlsql/servlet/crlonline. 
 
 
 
 
20.0 
APPENDICES 
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IRB Number: 11-045 A(7)
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