Treating Bacterial Overgrowth in Parkinson's Disease
Phase: PHASE2
Conditions: Parkinson's Disease, Small Intestinal Bacterial Overgrowth
Sponsor: University of Cincinnati

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Protocol Title: 
Treating Bacterial Overgrowth in Parkinson’s Disease 
 
Principle Investigator: Alberto Espay, MD 
Co-Investigator: Hilary Wilson-Perez, PhD 
 
Amendment 3 
 
 
 

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HYPOTHESIS AND SPECIFIC AIMS 
 
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that includes motor and non-motor 
impairment, including gastrointestinal (GI) dysfunction, one of the earliest abnormalities. The GI 
dysfunction is expressed as reduction of intestinal motility, which puts PD patients at risk for developing 
small intestinal bacterial overgrowth (SIBO), which develops in about 50% of PD patients, compared to 
only 8-20% of healthy age-matched controls[1, 2].   SIBO-positive PD patients have poorer response to 
therapy and more motor fluctuations than non-SIBO PD patients.  Finally, open-label data suggest that 
the antibiotic rifaximin leads to eradication of SIBO and improvement in motor control in affected PD 
patients. 
 
Here we propose to collect pilot data that would support the submission of a U01 application to the NIH 
for a large randomized controlled trial investigating the effect of SIBO eradication on reducing motor 
complications in PD patients.  Our central hypothesis is that SIBO-positive PD patients treated with 
rifaximin will exhibit an improvement in motor fluctuations as measured by a decrease in daily 
“off” time.   
 
Primary endpoints: to determine the change in “off” time after rifaximin treatment as measured by 
both patient report (the Hauser PD diary) and an objective monitoring system (Kinesia 360).  “Off” 
time will be compared using a between-subjects analysis (rifaximin versus placebo), as well as a within-
subjects analysis comparing each subject’s baseline to 1 and 3 months post-rifaximin treatment.  
Examining 2 post-treatment time points will provide an estimate for the optimal time point for the primary 
outcome measure as well as for treatment duration in a future study. 
  
Secondary endpoints:  
1. to investigate whether the treatment effect of rifaximin varies by method of SIBO 
detection. We propose to use two non-invasive methods of SIBO detection, serum unconjugated 
bile acids versus a combination of lactulose and glucose breath tests.  Thus, we can determine if 
there is a differential treatment effect based on method of detection, and use these data to select 
the detection method for a larger, randomized trial. 
2. To compare outcomes of the Hauser diary versus the Kinesia 360 monitoring system.  
Within-patient results will be compared for sensitivity and effect size, and these data will be used 
to select the primary endpoint for a larger, randomized trial. 
 
Tertiary endpoints: 
1. Change in daily “on” time with no dyskinesia and without troublesome dyskinesia.  
2. Change in daily “on” time with troublesome dyskinesia 
3. Change in motor subscale (part III) of the Movement Disorders Society-Unified Parkinson’s 
Disease Rating Scale (MDS-UPDRS) 
4. Change in the complication of therapy subscale (Part IV) scores of the MDS-UPDRS 
5. Presence/recurrence of SIBO 1 month post-treatment 
6. Correlation between the treatment effect of rifaxmin (change in “off” time) and SIBO eradication 
as measured by both non-invasive methods of SIBO detection. 
7. Change in Patient Global Impression of Change (PGI-C). 
The current proposal is designed to demonstrate our ability to detect and treat SIBO in PD patients with 
motor fluctuations, to estimate the effect size and standard deviation of motor improvements, and to 
inform selection of the best SIBO detection method.  In addition, it will help us determine the optimal 
timeline for assessing motor endpoints, and estimate the duration of benefits after treatment. 
 
BACKGROUND AND SIGNIFICANCE 
 

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Parkinson’s disease and Motor Fluctuations:  Parkinson’s disease (PD) is the second most common 
neurodegenerative disorder, affecting 1-2% of the population over the age of 65 years [3]. It is a chronic, 
progressive disease characterized by degeneration of several neuronal cell types, including dopaminergic 
neurons of the substantia nigra pars compacta [4]. The symptomatic treatment for PD relies, in part, on 
the restoration of dopaminergic tone in the motor circuits of the brain, which is accomplished mainly 
through oral levodopa therapy, a precursor of dopamine.  As PD progresses, many patients develop 
motor fluctuations – that is, alternating periods of “on” time, during which the patient enjoys a good 
response to medication, and “off” time, during which the patient experiences symptoms of their underlying 
parkinsonism, including impaired mobility [5].  Other motor fluctuations related to suboptimal therapy are 
episodes of no-on, delayed on (or prolonged time-to-on), predictable wearing off, and unpredictable on-off 
fluctuations, all of which collectively contribute to increasing a patient’s total “off” time. In addition, many 
advanced PD patients experience dyskinesia (involuntary movements) as a side effect of levodopa during 
the peak of a dosing cycle. These motor complications are associated with the erratic pharmacokinetic 
profile of levodopa, which has been suggested to be related to delayed GI transit and SIBO (see below).   
 
Small intestinal bacterial overgrowth: SIBO is a condition of increased bacterial density in the small 
intestine, and is defined as having greater than 105 colony forming units of colonic type bacterial flora per 
milliliter [6, 7].  SIBO is associated with various GI disorders including intestinal dysmotility, gastric 
achlorhydria, and anatomical abnormalities [8].  In such circumstances, bacteria that normally colonize 
the colon migrate proximally into the small bowel. 
 
SIBO in PD:  Recent studies have shown that SIBO develops in about 54% of PD patients with motor 
fluctuations, compared to only 8-20% of healthy age-matched controls [1, 2].  A third study found SIBO 
prevalence of only 25% in PD [9]; however there are important methodological differences between these 
studies.  The latter study used only one diagnostic breath test, the lactulose breath test (LBT, described 
below) as opposed to LBT and glucose breath test (GBT), to detect SIBO, and secondly, their study 
population included PD patients without motor fluctuations.  Thus, 54% is likely a more accurate estimate 
of SIBO prevalence in the study population proposed here.  These recent studies report that PD patients 
with concurrent SIBO have poorer response to levodopa and more motor fluctuations than non-SIBO PD 
patients.  Finally, they showed, using an unblinded design, that SIBO eradication using the antibiotic 
rifaximin leads to improved motor control in affected PD patients. 
 
SIBO diagnosis and treatment: Currently, the “gold standard” for the diagnosis of SIBO is duodenal 
aspirate to quantify number of bacterial organisms. However, this method of diagnosis is invasive and 
expensive, rendering this diagnostic tool of limited clinical application.  The alternative of greater use in 
clinical practice is the hydrogen breath tests LBT and GBT.  These tests are based on the fact that the 
only source of hydrogen in the human body is from bacterial metabolism of carbohydrates.  When 
ingested carbohydrates are exposed to intestinal bacteria, hydrogen is produced and expired.  The most 
common carbohydrate substrates used for this test are glucose and lactulose.  Glucose, which is readily 
absorbed in the proximal small bowel, in healthy conditions rarely reaches the colon or the hydrogen-
producing bacteria found there.  Thus, the GBT test is an attractive method for the detection of proximal 
SIBO [10, 11].  Lactulose is absorbed more distally, and the LBT is therefore a better indicator of distal 
SIBO.  However, the sensitivity and specificity of the GBT has been reported to be only 62% and 83%, 
and for the LBT 68% and 44%, causing the clinical utility of these methods used in isolation to be 
questioned [12], and lending rationale to the combined use of these tests to increase the diagnostic yield. 
 
A third, less commonly-used diagnostic tool for SIBO is the measurement of unconjugated bile acids 
(UBA), which relies on the physiology of bile acids and their relationship with bacteria.  Bile acids are 
synthesized from cholesterol in the liver, where they are conjugated with glycine or taurine prior to 
secretion into the biliary tract and subsequently the intestinal lumen.  Intestinal bacteria, mainly those 
normally found in the distal part of the gut, deconjugate a portion of those bile acids, and those UBA are 
absorbed and released into systemic circulation.  Thus, the concentration and fraction of serum UBA are 
indicative of intestinal bacterial activity and can be used as a diagnostic tool for SIBO [13, 14]. 
 
Treatment of SIBO relies on antibiotics, with Rifamixin being the most common and well-validated for this 
indication.  Treatment duration aimed at SIBO eradication is seven days, with a dose of 1600 mg/day 

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shown to be most effective, without affecting patient compliance or increasing incidence of side effects 
[15]. 
 
Significance: Our proposal gathers input from a multidisciplinary team of experts from neurology, 
endocrinology, and gastroendocrinology to evaluate a novel therapeutic option that has the potential to 
reduce motor fluctuations in more than half of all PD patients and improve functional outcomes. Thus, our 
proposal explores a heretofore untapped management strategy and may positively alter the standard of 
care in PD. 
 
INVESTIGATOR EXPERIENCE 
 
Dr. Alberto Espay is a licensed neurologist who has been conducting research in Parkinson’s disease and 
other movement disorders for more than 10 years.  He serves as the director of the James J and Joan A 
Gardner Center for Parkinson’s disease and Movement Disorders at the University of Cincinnati, is staffed 
by five fellowship-trained movement disorders specialists and four dedicated full-time research 
coordinators. He oversees over 4,000 annual patient visits and directly manages over 1,245 patients with 
PD each year.  
 
Dr. Hilary Wilson-Perez received her PhD in Neuroscience in 2012.  She has experience in basic and 
clinical research in neuroendocrinology (diabetes and obesity), and has been working as a research 
coordinator in Movement Disorders since January 2014. Thus, she has the training and hands-on 
experience to handle the scientific and logistical aspects of the current study. 
 
 
RESEARCH DESIGN AND METHODS 
 
Study Plan: PD patients with motor fluctuations (≥4 hours of self-reported “off” time per day) will be 
screened for SIBO using breath tests (LBT and GBT).  Subjects testing positive by either method will be 
eligible for enrollment, whereas those testing negative by both methods will be considered screen 
failures, and will be discontinued from the study.  We expect that approximately 50% of screened patients 
will be SIBO-positive [1, 2]; therefore we plan to screen 48 subjects to achieve an enrollment of 24.  
SIBO-positive subjects will be asked to return for a baseline visit 2-4 weeks after screening, and to 
complete the standardized Hauser diary[16, 17] capturing daily “on” and “off” time for 3 days prior to the 
baseline visit.  Daily “off” time must average at least 4 hours per day to proceed with enrollment.  They will 
also use the Kinesia 360 monitoring system during this time. 
 
 
Subjects meeting all inclusion/exclusion criteria will be enrolled and randomly assigned to one of two 
groups in a randomized, double-blind, crossover fashion (see Figure), each treated with a one-week 
course of the antibiotic rifaximin as well as a one-week course of matching placebo.  Group A will receive 
rifaximin at baseline and placebo at 3 months, whereas group B will receive placebo at baseline and 
Group A 
N=12 
Group B 
N=12 
Rifaximin 
Baseline 
1 month  
Follow-up 
3 month 
Follow-up 
4 month 
Follow-up 
6 month 
Follow-up 
Screen 
N=48 
SIBO+ 
Screen Fail N=24 
SIBO- 
Placebo 
Rifaximin 
Placebo 

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rifaximin at 3 months.  Outcome measures including motor control will be assessed at the following time 
points: baseline (BL, pre-treatment), 1 month, 3 months, 4 months, and 6 months.    
 
Clinical assessments will include a motor examination and evaluation of motor complications using 
sections III and IV of the MDS-UPDRS, respectively. Patients will be trained in the correct use of the PD 
Hauser diary to log “on” and “off” time, as described below. 
 
Blinding: Amendment 3 modifies this study to be a fully double-blind crossover, such that neither 
participants nor researchers will know when the subject receives rifaximin or placebo.  This will be 
explained to the participants, so they will know that they will receive one treatment course of each during 
the study, but they will not know in which order they were treated.  The results of the breath tests (SIBO-
positive or SIBO-negative) will only be revealed to the subject at screening, which determines their ability 
to enroll in the study.  The results of subsequent breath tests on enrolled subjects will not be revealed to 
subjects or the motor assessor to avoid bias on symptomatic outcome measures. 
 
Breath Tests: GBT and LBT will be performed according to standard procedures on separate days.  
Subjects are placed on a restricted, low-carbohydrate diet the day before the test, and fast for 12 hours 
prior to GBT and LBT.  A baseline alveolar air sample will be collected before ingestion of glucose (1g/kg 
of body weight) or lactulose (10g), followed by sampling every 20 minutes for 3 hours. The diagnosis of 
SIBO is established by expert review by an experienced Gastroenterologist.  Generally, a positive GBT is 
defined as an increase in exhaled hydrogen ≥ 10 parts per million above baseline.  A positive LBT is 
characterized by two distinguishable hydrogen peaks (SIBO and colonic peaks) after lactulose ingestion 
[19].  However, individual variances in hydrogen dynamics require expert review for a final determination.   
• 
Screening breath tests (LBT and GBT) that do not exhibit a rise in hydrogen levels of at least 8 
ppm in the first 80 minutes will be discontinued and considered negative.  All others will be 
completed for later determination. 
• 
After screening, all enrolled subjects will have breath tests performed to completion to avoid 
revealing the results of the test to the participant. 
 
Measurement of Serum Unconjugated Bile Acids: Serum will be obtained from subjects in order to 
measure concentration and fractionation of UBA.  Batched samples will be analyzed in a post-hoc 
fashion, and not used for screening (study inclusion) purposes. The major primary and secondary 
unconjugated and conjugated bile acids will be measured in serum using a routine validated LC-MS/MS 
method according to CCHMC SOP # PATH.CMS.1033. 
 
Study Drug and Placebo: Rifaximin treatment will be a 7-day course of 550mg three times per day  
(1650mg/day). The drug is supplied as 550mg tablets.  Matching placebo tablets will be administered in 
the same fashion.   
 
PD Diary: Patients will be instructed to use the Hauser diary [16] to log their motor fluctuations for three 
consecutive days prior to each study visit (concurrent with Kinesia monitoring).  Each diary page is a grid 
representing a 24-hour day in which patients mark each half-hour period as one of 5 categories: Asleep, 
OFF, ON without dyskinesia, ON with non-troublesome dyskinesia, or ON with troublesome dyskinesia.   
 
Kinesia 360 Monitoring.  Kinesia is an FDA cleared to market device for objectively assessing 
Parkinson’s disease symptom severity.  The system includes wireless motion sensors and a tablet PC.  
Subjects will be trained in its use at screening, and will use it for 3 consecutive days prior to each 
subsequent study visit (concurrent with PD diary completion). 
 
 
MDS-UPDRS On/off evaluation:  The MDS-UPDRS part III (motor examination) will be used to evaluate 
subjects in both the “on” and “off” conditions.  MDS-UPDRS part IV (motor complications) is an interview-
based assessment that refers to the subject’s functioning over the past week, and thus can be conducted 
in either the “on” or “off” state.  These will be completed at all study visits except screening.  The “off” 

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portion will be conducted after subjects have abstained from PD medications for 12 hours.  Following 
motor evaluation, they will take their normal dose of PD medication(s), and will be evaluated again one 
hour later, or when the subject reports feeling fully “on”. 
 
Patient Global Impression of Change.  The subject will rate his/her impression of change in PD 
symptoms from baseline (i.e., just before subject’s most recent study drug treatment) to the time of 
assessment. The PGI-C is assessed on a 7-point scale ranging from “very much improved” to “very much 
worse”. 
 
 
Screen Failures and Rescreening: 
 
Subjects whose breath tests are negative will be considered screen failures and will not be enrolled in the 
study.  However, bacterial populations in the intestine may change with diet, antibiotic treatment, or other 
conditions.  For these reasons, the investigator and subject may elect re-screening following negative 
results.  Elective rescreening following two negative breath tests must be at least 14 days after previous 
breath testing.   
 
In other cases, breath test results may be borderline, incomplete, or otherwise undetermined as deemed 
by expert review.  These subjects may return for rescreening 1-60 days following previous breath testing.  
At minimum, the previously-undetermined breath test (GBT or LBT) must be repeated.  Both breath tests 
may be repeated at investigator discretion.  If more than 60 days have passed following breath testing, 
then both GBT and LBT must be completed. 
 
Randomization, Sample Size Estimation and Statistical Analysis Plan: PD patients testing positive 
for SIBO will be randomized to group A or B in equal numbers using a randomization code generated by 
the statistician.  
 
Our primary outcome, change in “off” time, will be analyzed using two separate analyses.  A within-
subjects comparison (paired t-test) will compare all subjects (n=24) before and after rifaximin treatment, 
whereas a between-subjects analysis (two-sample t-test) will compare placebo treatment (n=12) to 
rifaximin treatment (n=12).  Therefore, we will have one analysis with greater power to detect a treatment 
effect, and a second analysis with greater validity for designing a future placebo-controlled trial. 
 
Based on previous data, we have estimated that SIBO-positive PD patients have 5.1 hours of “off” time, 
with a treatment effect of rifaximin to decrease “off” time by 2 hours.  Standard deviation is estimated to 
be approximately 1.5 to 2 hours [2].  
 
Because all subjects will ultimately receive rifaximin treatment, a within-subjects analysis will compare all 
24 subjects before and (1 and 3 months) after treatment using paired t-tests. For group A, this 
corresponds to baseline versus 1 month, and baseline versus 3 months.  For group B, this corresponds to 
3 months (end of placebo treatment, and baseline for rifaximin treatment) versus 4 months, and 3 months 
versus 6 months. Assuming a mean “off” time before treatment of 5.1 hours, a conservative estimate of 
standard deviation of 2.5 hours, and a moderate correlation of 0.7 between the measurements before and 
after treatment, we will have 99.8% power to detect a difference of 2 hours, and 95.3% power to detect a 
difference of 1.5 hours of “off” time.  
 
A second analysis will compare placebo treatment versus rifaximin treatment between subjects. 
We will use a two-sample t-test to compare the “off” time between groups A and B at 1 month and 3 
months past baseline. Assuming initial “off” time in both groups to be 5.1 hours, a decrease in “off” time of 
2 hours in the rifaximin group, and no change in the placebo group, we will have 87.7% power or 64.9% 
power to detect the difference between groups based on standard deviations of 1.5 and 2.0 hours, 
respectively. Due to the nature of this pilot study, and the imprecise estimates of standard deviation, it is 
possible that this analysis will not have the power to detect a treatment difference between groups.  
However, these data will provide valuable estimates of mean and standard deviation which can be used 

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to design a larger clinical trial.  Furthermore, the within-subjects analysis described above should have 
ample power to detect a treatment effect. 
 
We expect some people to be identified as having SIBO using serum unconjugated bile acids only, some 
to be identified using breath tests only, and others to test positive by both methods. To determine whether 
treatment effect varies by detection method, we will compare the change in “off” time at one month after 
the start of treatment in the three groups using a one-way ANOVA. 
 
All power estimations were made using PROC POWER in SAS 9.3. The generation of codes for 
randomization and all the analyses will also be conducted using SAS 9.3. 
 
Treatment of missing data will be handled on a case-by-case basis.  The pilot nature and modest sample 
size of this study makes imputation not appropriate.  The decision to exclude a single missing value, 
series of longitudinal values for a patient, or a patient’s entire data set will vary depending on time of 
drop-out (if applicable) and type of missing data. 
 
Strategies to mitigate potential pitfalls: To avoid normal day-to-day PD-associated variability to 
substantially alter the “off” and “on” diary outcomes, we will conduct all measurements at the same time of 
day in each subject. Also, we do anticipate a number of early drop-outs due to inability to comply with the 
extensive set of study-related procedures. This might pre-select more motivated patients and bias 
recruitment in favor of those willing and able to invest the time and effort. However, it is likely these 
subjects will have an “off” time substantially above that of the inclusion cutoff, thus increasing the range of 
effect by rifaximin. Finally, SIBO measurements have not been previously applied to PD patients. We will 
closely monitor for quality metrics and patient adherence given the unique features of the PD population 
compared to patients with primary GI disorders. 
 
Next steps: Data gathered in this study will inform the design of a large, definitive NIH-sponsored study 
on the value of rifaximin as a promising management strategy in the care of patients with PD. 
 
 
Data Storage and Confidentiality: All records from this study will be maintained in a secure setting. 
Electronic records will be stored on a password protected computer. Records will not have any patient 
health information (PHI) associated with them. These records will be kept indefinitely to allow for re-
analysis of data, if needed. The data will be verified by multiple members of the research team, including 
the PI. The data will never be accessible without a secured password. 
 
Setting: Study visits will take place at the Medical Arts Building Neurology Suite 3200. 
 
HUMAN SUBJECTS   
 
Consecutive consenting patients will be recruited from the University of Cincinnati Movement Disorders 
Center.  We expect to screen 4-5 patients per month, and to complete enrollment in one year (48 
screened, 24 enrolled).  Assessments will be ongoing for an additional 6 months. 
 
Inclusion criteria: 
1. Diagnosis of PD according to the UK Brain Bank criteria[18]  
2. Daily “off” time ≥4 hours according to subject-completed Hauser diary. 
3. No changes in levodopa or any other dopaminergic medications will be expected during the 
course of the study, at the judgment of the treating clinician. 
4. Montreal Cognitive Assessment (MoCA) ≥ 24. 
5. Age 18 and older. 
 
Exclusion criteria: 
1. Any comorbid non-PD-associated gastrointestinal (e.g., achlorhydria) or systemic disease that 
may alter absorption or confound the study results, including immune disease. 

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2. Concurrent exposure to immunosuppressive drugs or antibiotic treatment, or within 30 days of 
screening. 
3. Known allergy to rifaximin 
4. Women who are pregnant, lactating, or plan to become pregnant. 
 
Risk/Benefits:  This study involves more than minimal risk due to use of study drug and the breath tests 
(which involve ingestion of sugar).  The risks associated with Rifaximin treatment are similar to placebo, 
and include flatulence, headache, abdominal pain, rectal tenesmus, defecation urgency, nausea, 
constipation, pyrexia, and vomiting.  The risks associated with breath testing are related to the possibility 
of poor digestion and absorption of carbohydrates, and may include bloating, distention, pain, diarrhea, 
and hypoglycemia.  These risks are similar to what participants would experience any time they would 
take an antibiotic or ingest a moderate amount of carbohydrate.   
 
Withholding PD medications for the MDS-UPDRS On/off evaluation may cause a temporary worsening in 
PD symptoms including tremor, bradykinesia, rigidity, freezing, and other PD-associated symptoms. 
 
There are no controlled data regarding the use of Rifaximin during pregnancy or lactation, and it is not 
known whether Rifaximin is excreted in breastmilk.  Subjects may not participate if they are pregnant, 
lactating, or plan to become pregnant or cause a pregnancy.  Subjects will be counseled on birth control 
methods. 
 
Risks will be managed by inquiring subjects at each visit of any new symptoms, and encouraging them to 
contact the study team with any new symptoms or concerns.  Adverse events will be reported according 
to the reporting requirements of UC Human Research Protection Institutional Policy II.02 Reporting 
Unanticipated Problems. Participants will be promptly discontinued from study medication or study 
procedures if the investigator believes it is in his/her best interest. 
 
This research may benefit the subjects directly by eradicating SIBO, which may in turn improve motor 
symptoms.  Furthermore, this study has the potential to impact more than half of all Parkinson’s patients 
to positively improve their PD symptoms.  
 
 
Payment: Subjects will not be paid for their participation in this study. 
 
Subject Costs:  There will be no costs to the research participants.  Study drug, procedures, and 
assessments will be provided at no cost. 
 
Consent:  See separate document. 
 
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