Clinical trial NCT02124512
Conditions: Obese Insulin Resistance Metabolic Syndrome
Keywords: obese insulin resistance metabolic syndrome
Sponsor: Philip Kern
Start date: 2015-03-01; Completion date: 2019-05-31
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Metabolic syndrome is a condition involving elevated levels of fat in the blood, a tendency towards diabetes, hypertension, and too much fat around the abdomen (an increased waistline). Individuals with metabolic syndrome often have impaired glucose tolerance, which is a condition where blood sugar is normal when fasting (before eating), but is too high after drinking a sugary drink. This is due to an abnormality in the body's sensitivity to insulin (insulin resistance), which is due in part to an inability of the muscle to take up glucose.

People with metabolic syndrome have inflammation in their fat tissue and in their blood stream, and the changes in the level of inflammatory chemicals produced by cells in your fat tissues will be studied. One possible source of the inflammation may be the bacteria in the intestine. When individuals eat fatty foods, some of the bacterial products become attached to the fat in their blood and then get directed to fat tissue. The investigators wish to determine whether individuals have an excessive amount of inflammation in their fat tissues, and whether this inflammation comes from the bacteria in their intestines. To determine this, the investigators wish to treat individuals with an antibiotic that reduces the bacteria in their intestines and in their blood, and determine whether this reduces their overall level of inflammation.

Detailed description:
This is a randomized, placebo-controlled proof of concept study that will examine the investigational drug Rifaximin Soluble Solid Dispersion (SSD) ability to reduce gut microbiota and thereby reduce adipose inflammation and improve insulin resistance.

Each subject enrolled will undergo a fat tolerance test with a high-fat meal, an oral glucose tolerance test, a fat biopsy, and a euglycemic clamp. Following their successful completion of those procedures subjects will be randomized to study treatment. That treatment will involve receiving the investigational drug,80 mg per day of rifaximin-soluble solid dispersion (SDD), or placebo for 12 weeks. All procedures will be performed on the Clinical Services Core of the CCTS. The initial visit will involve informed consent, and routine labs (comprehensive metabolic panel, lipid panel, TSH, CBC with platelets). These routine labs are for safety purposes and to rule out exclusionary disorders. A stool sample will also be collected and frozen for possible future analysis of bacterial microflora.

Subjects will be asked to allow the principal investigator to bank blood and tissue samples collected during this study that are not used for other study-related tests. No additional blood or tissue samples will be collected. If the subject agrees to the banking of their blood and tissue samples they will be stored in the Principal Investigator's laboratory at the University of Kentucky for an indefinite period of time or until they are used up. Stored samples will be used for future research testing to learn about how to prevent, detect, or treat insulin resistance, metabolic syndrome, diabetes or other health problems.

Each subject will undergo total body composition testing using a total body dual-energy x-ray absorptiometry (DXA) scan. The DXA scan measures the subject's bond density and body fat.

Arms: arm 1: Subjects randomized to this arm of the study will receive 80 mg per day Rifaximin SSD arm 2: Placebo
Interventions: intervention 1: Rifaximin SSD intervention 2: Placebo
Intervention descriptions: intervention 1: Study Drug dosing will be 80 mg SSD once daily intervention 2: 80 mg placebo once daily

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
Official Title: Blood Lipopolysaccharide (LPS) Rifaximin Study 
 
 
Internal title: “Dietary fat, lipoprotein and lipopolysaccharide: role in insulin resistance” 
 
 
ClinicalTrials.gov: NCT02124512 
 
 
IRB: #14-0136 
 
 
Study Date: 05/17/16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
Approach 
Overall Hypothesis and rationale.  Humans with obesity/IR have higher levels of postprandial LPS and 
this will be reduced by treatment with rifaximin.  These changes may not be evident in a fasting blood sample 
because the LPS is carried on gut derived lipoproteins.  The elevation of LPS will coincide with chylomicron TG 
elevation, and the AUC of LPS will depend on the height of the TG elevation, and the rapidity of clearance of 
TG-rich particles.  A consequence of reduced plasma LPS will be improved insulin sensitivity and reduced 
adipose inflammation.  
LPS has been measured in human plasma, but no study has examined postprandial LPS in depth.  The IV 
infusion of LPS induces adipose inflammation and insulin resistance (25), but no studies have examined the 
consequence of gut-derived LPS.  The LPS-LBP-TG-rich lipoprotein complex synergistically increases adipose 
SAA, and would be expected to result in an inflammatory stimulus to adipose tissue.  We hypothesize that the 
chronic reduction in LPS-lipoproteins will result in less chronic inflammatory insult to adipose tissue in obese/IR 
subjects.  This will be reflected in changes in tissue gene expression (decreased inflammation, possible 
changes in extracellular matrix (ECM)), and improved insulin sensitivity.  Although there are several possible 
methods to alter the gut microbiota, the antibiotic rifaximin has been shown to reduce plasma LPS (2;3;28). 
Recruitment of study subjects.  We intend to recruit 40 non-diabetic subjects (sample size below) with 
obesity (BMI 30-40), ages 45-60, and evidence of MetS or IR. Each subject will undergo a fat tolerance test 
with both a low fat and high fat meal.  We wish to avoid very obese subjects (BMI > 40) because of the large 
amount of lipid that will be consumed (see below).  All subjects will initially have a standard 75g OGTT with 
measurement of glucose and insulin to characterize glucose tolerance and to 
obtain measures of insulin sensitivity and secretion using the Matsuda index 
(64;65).  We will include subjects with IGT, IFG, as well as NGT subjects if they 
have at least 3 features of MetS (Table 1).  Based on our considerable 
experience, essentially all of these obese subjects will be IR when the euglycemic 
clamp is performed.  Exclusion criteria will include GI conditions (IBS, lactose 
intolerance) and the use of lipid lowering or antiinflammatory drugs.  These 
subjects will have the following procedures performed at baseline and after 
drug/placebo treatment:  OGTT, lipid tolerance tests, body composition (DEX), 
plasma inflammatory markers, adipose biopsy, insulin sensitivity, and gut 
microbiota assessment, as described below.  Diet information will be recorded 
using a web-based software (9) at baseline, 4 and 8 weeks, and subjects will be 
asked to stay on their usual diet. 
Specific Aim 1.  We will determine whether an alteration in the gut microbiota achieved with rifaximin will 
decrease circulating LPS.  We will recruit obese human subjects with MetS or impaired glucose tolerance.  An 
oral fat tolerance test will be performed at two different fat doses with measurement of plasma chylomicron-
associated LPS and LBP, and measurement of LPS and LBP in the other lipoprotein fractions (using Westerns 
for LBP).  Subjects will then be treated with the antibiotic rifaximin for 8 weeks to alter the gut microbiota.  The 
lipid tolerance tests will be repeated to determine whether the antibiotic treatment reduces post-prandial LPS 
and alters the distribution of LPS in lipoproteins. 
All subjects will undergo a fat tolerance test on two different days, in random order, with two different 
amounts of lipid in the meal, as described above in preliminary data.  From the blood samples, we will measure 
the level of LPS and LBP in plasma, as well as the LPS and LBP in each lipoprotein fraction to determine 
whether more dietary lipid leads to a higher level of LPS in plasma. We will also determine whether LPS-
lipoprotein levels change in a dynamic fashion following the meal.  For example, if LPS remains associated 
with TG-rich lipoproteins, then the LPS will likely be cleared through lipolysis in adipose, and then the 
remaining remnant-LPS cleared by the liver, and liver insulin resistance may be an important effect of 
lipoprotein-LPS.  However, if LPS is transferred to HDL, this could be due to the LBP content of HDL, and 
could represent another important function for HDL (i.e. clearance of LPS).   
Subjects will then begin taking rifaximin 550 mg BID or placebo for 8 weeks.  Rifaximin is poorly absorbed 
from the gut, has been shown to decrease plasma LPS in several studies (2;3;28), and is used acutely for 
traveler’s diarrhea, and chronically for treatment of diverticulitis, hepatic encephalopathy, bacterial overgrowth, 
and irritable bowel syndrome (66;67). In clinical trials, the side effects of rifaximin are generally 
indistinguishable from placebo, and there is no evidence for weight loss or nutrient malabsorption (68) (see 
human subjects).  After 8 weeks of rifaximin, all subjects will repeat the lipid tolerance tests (low- and high fat).  
Table 1.  Inclusion criteria 
Males & females, all ethnic 
groups, A1C<6.5 
BMI 
30-40 
Age 
45-60 
OGTT; features 
of MetS* 
IGT, IFG, or 
NGT +3 
*IGT: FBS< 126 mg/dl, 2 hr: 140-
199;  IFG: FBS 101-125, 2 hr 
<199; MetS: TG>150 mg/dl, 
HDL<40 (M) or <50 (F), 
BP>130/85 or on treatment, 
Waist >40” (M) or >35” (F) ;  
NGT: normal glu tolerance 


 
 
 
To verify the change in gut microbiota, the major classes of gut bacteria will be assayed from a stool sample 
before and after rifaximin treatment using nexgen targeted sequencing of 16S RNA, as described (69).  
Specific Aim 2.  We will determine whether a change in the gut microbiota from rifaximin treatment will 
decrease adipose inflammation and improve insulin resistance.  In this aim we will determine whether the 
changes in gut microbiota and plasma LPS induced by rifaximin will affect adipose tissue inflammation and 
insulin sensitivity.  After treatment with the antibiotic rifaximin for 8 weeks, the insulin sensitivity testing and 
adipose biopsies will be repeated to determine whether the antibiotic treatment changes inflammation and 
insulin sensitivity.  
The recruitment of insulin resistant, non-diabetic subjects is described above.  In addition to the lipid 
tolerance tests and OGTTs, these subjects will have an adipose biopsy (SQ, abdominal) and a euglycemic 
clamp.  We routinely perform adipose biopsies, and we obtain enough fat for immunohistochemistry, RNA and 
protein assays.  Fasting plasma will be collected pre- and post rifaximin treatment for measurement of plasma 
inflammatory markers (TNFα, IL-6, MCP-1, adiponectin, PAI-1, CRP, etc).  
Peripheral and hepatic insulin sensitivity will be measured with a euglycemic clamp.  For this study, we will 
use a two-step clamp, with an initial low-dose insulin infusion to measure hepatic insulin sensitivity, followed by 
a higher dose insulin infusion to assess near maximal peripheral glucose disposal, as described previously 
(70;71).  Subjects will report fasting to the CRC, IV’s started (including a retrograde IV in a warming box) and a 
priming dose of 3 mg/kg D-[6,6-2H2]glucose will be injected 120 min prior to the start of the insulin infusion 
followed by a continuous infusion at 0.05mg/kg/min for the duration of the study.  A primed insulin infusion 
(0.25 mU/kg/min) is then begun and continued for 120 min.  The blood glucose is allowed to fall during this 
period until it reaches 90 mg/dl, and blood glucose is then maintained by infusion of 20% dextrose.  Following 
the low dose infusion, a re-primed insulin infusion at 1 mU/kg/min begins and is continued for 2 hr.  Blood 
glucose is measured every 5 min, and blood for insulin and [2H2]glucose taken every 10 min. Glucose disposal 
is determined during steady state glucose during the final 30 min of the insulin infusions.  This procedure will 
measure basal hepatic glucose production, suppression at the two glucose concentrations, as well as glucose 
disposal rate at the two different insulin infusion rates.  To assess adipose insulin sensitivity, we will assess 
lipolysis in vivo by measuring plasma FFA levels in relation to fasting insulin, as described recently (17), and 
also by examining the ability of insulin to suppress catecholamine mediated lipolysis in adipocytes from the fat 
biopsies, as described previously (18;19). 
Anticipated Outcomes. We hypothesize that a change in the microbial flora with rifaximin will reduce 
chylomicron-associated LPS, and this in turn will reduce adipose tissue inflammation, which in may lead to 
improved insulin sensitivity.  Therefore, we will examine, before and after rifaximin/placebo treatment:  1. LPS 
associated with lipoproteins, especially TG-rich lipoproteins, during the HF and LF meals,  2. insulin sensitivity 
and hepatic glucose production, 3. plasma inflammatory markers (TNFα, IL-6, MCP-1, adiponectin, PAI-1, 
CRP, etc), 4. adipose inflammatory markers (CD68, MCP1, TNFα, PAI1, SAA, IL12, IL10, TLR4 and others), 5. 
adipose tissue ECM/collagen markers (TSP1, CTGF, collagen VI, collagen V, elastin, and others),  6. 
macrophage number and polarization (markers of M1 vs M2) by immunohistochemistry; 7.  number of 
capillaries and large vessels by immunohistochemistry.  
Changes in plasma and adipose inflammatory markers, ECM, macrophage polarization, and vascularity are 
all features of IR adipose tissue, and we have published many papers that describe these methods 
(21;30;31;35;72;73).  The reduction in adipose inflammation may be reflected in fewer macrophages, a shift in 
macrophage polarization (eg. M1 to M2), a decrease in crown-like structures, a decrease in gene expression of 
inflammatory cytokines (eg. TNFα, IL-6, SAA, etc) and a decreased expression of collagen VI.  Other 
immunohistochemical findings may include increases in elastin, decreased collagen V, and increases in 
capillary number, as suggested by our previous studies (30). From our adipose biopsies, we obtain enough 
tissue for Western blots, which is important since many genes of interest are not regulated at the mRNA level.  
Based on a previous study (37) showing alteration of fasting-induced adipose factor (Fiaf), a LpL inhibitor by 
germ free conditions, we will measure LpL activity and mRNA in adipose of these subjects.  The clamp will 
include an assessment of hepatic insulin sensitivity, which is important because the liver is important to the 
clearance of gut-derived remnant lipoproteins and may be an important target of LPS.  
Potential experimental problems.  Although previous studies in rodents observed decreases in adipose 
inflammation following antibiotic treatment (44), it is possible that rifaximin treatment may have no effect on any 
of these metabolic features, or perhaps an effect may require longer treatment.  We will perform an interim 
analysis of our data and change the time period if warranted.  Although previous studies with rifaximin are 
encouraging (1-3;28), this drug will not eliminate all bacteria, and LPS may still be present in the intestine or 
may come from sources that are not impacted by the antibiotic, such as from food.  Finally, this protocol is 


 
 
 
focused on LPS, but this is an emerging field and secondary changes may occur.  Changes in the gut 
microbiota are associated with other hormonal and metabolic effects (74;75); e.g. alterations in the ratio of 
Bifidobacteria/firmicutes could impact insulin sensitivity through mechanisms other than LPS. In humans, diet 
can alter the gut microbiota and this can be associated with small increases in nutrient loss (40), in part 
dependent on obesity and excess calories.  Rifaximin will alter the gut microbiota, but no weight loss or 
malabsorption symptoms are reported in clinical trials (actually there is weight gain and less diarrhea when the 
drug is used for colitis or bacterial overgrowth).  There could be changes in incretins.  This can be assessed by 
examining the insulin response to the OGTT, which is dependent on GLP1 and GIP.  If we observe changes in 
the insulin response or glucose tolerance, we will measure GLP1 levels in the OGTT samples.   
We believe that this trial will significantly impact the field of “metabolic endotoxemia” (76).  The literature is 
full of studies suggesting that the gut flora are important in exacerbating inflammatory pathways. The rodent 
data are exciting, but there are no intervention or mechanistic studies in humans to indicate whether this is 
relevant or significant.  Therefore, this study will help investigators translate important rodent data into humans.   
Sample size.  An important outcome will be the measurement of LPS in plasma and lipoprotein fractions 
from the low-fat and the high-fat meals, and we will examine the peak LPS levels, as well as area under the 
curve.  In a previous study in lean subjects, baseline LPS was 0.39± 0.07 EU/ml and increased to 0.58 EU/ml 
with a fatty meal (53).  Assuming that SD of the group and SD of change is 0.1 and an effect size of 1.0, we will 
need 10 subjects to detect a change of 0.1 EU/ml between a low-fat and high fat meal (paired T-test) and 17 
subjects to detect the same difference between groups (drug vs placebo), with α of 0.05 and 80% power.  Our 
preliminary data support the effect size described.  To estimate the sample size needed to observe changes in 
adipose tissue inflammation, we will target adipose tissue macrophages.  In previous studies of obese/IR 
subjects, macrophage number was 34±5.8/mm2 (31).  Assuming the SD of change is equal to the SD 5.8 in 
these obese subjects, 20 subjects in each group will allow us to detect a change in macrophage number of 
4/mm2 with 80% power using a paired t-test.  For comparisons between groups, if we assume an effect size of 
1.0, we will need to recruit 17 subjects in each group. In previous interventional studies, we detected changes 
in macrophage number in adipose in response to fish oil and pioglitazone treatment (35;77).  These sample 
size calculations project adequate power with a total of 40 subjects (20 in each group) who complete the whole 
protocol.  We recognize that we are asking a lot of these subjects, however we have considerable experience 
performing similar in-depth studies.  We anticipate a higher drop-out rate than usual, and we estimate that we 
will need to recruit 60 subjects to obtain 40 that complete the protocol. 
 
 
 


 
 
 
Protection of Human Subjects. 
1.  Risks to the Subjects 
a. Human Subjects Involvement and Characteristics 
The subjects recruited for this study will be between the ages of 45 and 60.  All subjects will be obese and 
have evidence of insulin resistance or metabolic syndrome (see inclusion criteria, above) and with a BMI 
between 30-40.  Women will be post-menopausal.  Exclusion criteria will include any unstable medical 
condition (recent or unstable cardiovascular disease), cancer, renal insufficiency GFR<30), use of steroids, 
chronic inflammatory conditions, use of anticoagulants, and lipodystrophy.  Subject who may not tolerate the 
lipid tolerance tests because of GI conditions will be excluded, along with subjects who take medications that 
could interfere with the studies, such as lipid lowering drugs, or antiinflammatory drugs.  Other medical 
conditions will be evaluated by the study physicians.   
This study involves a standard oral glucose tolerance test, a euglycemic clamp to measure insulin sensitivity, 
and a lipid tolerance test.  Subjects will consume a low fat meal (Subway sandwich or equivalent) and 
unlimited vegetables and fruit the evening before the study, fast for 12 hr, and refrain from alcohol.  The next 
morning, the subjects will consume either a high-fat or low-fat breakfast shake, consisting of Boost with added 
cream and corn oil in a fixed proportion to provide a mix of fatty acids.  Daily energy requirement will be 
calculated using the Harris-Benedict equation, and the high fat shake will encompass 40% of their daily energy 
requirements, and will be 50% fat.  The low fat shake will use the same formula, but will be 25% fat, through 
the addition of less cream and corn oil, so the amount of CHO and protein in each shake will be very similar.  
Blood samples for lipoprotein isolation will be obtained prior to the meal, and hourly for 8 hr after the meal.  
These studies will take place on the CRC.  Subjects will be able to walk around, watch TV, and drink water 
during this time.  
This study involves fat biopsies from subjects under local anesthesia.  Because it is difficult to obtain enough 
adipose tissue from a needle biopsy, incisional fat biopsies will be necessary.  Dr. Kern has performed 
hundreds of such biopsies on outpatients undergoing studies on the effects of feeding, obesity, and diabetes, 
and insulin sensitizer drugs, and the complication rate has been very low, and patient acceptance of these 
procedures has been excellent. The biopsies will be performed under local anesthesia by the principal 
investigator or his designate (eg, a well-trained physician assistant).  No patient will have a biopsy if it appears 
to represent an unacceptable risk, such as platelets <75,000, evidence of moderate platelet dysfunction, 
chronic aspirin use, or hematocrit < 30.  In addition, we will measure body composition by DEXA.   
We will recruit subjects without regard to ethnicity, and will study no vulnerable populations.   
Intervention.  After the above procedures, subjects will then begin taking rifaximin in a dose of 550 mg BID.  
This antibiotic is poorly absorbed from the gut, and is used routinely for traveler’s diarrhea, and for prolonged 
periods for treatment of diverticulitis, hepatic encephalopathy, bacterial overgrowth, and irritable bowel 
syndrome (66;67).  After 8 weeks of treatment with rifaximin, all subjects will repeat all the procedures above, 
including clamp, OGTT, lipid tolerance tests (low fat and high fat) and fat biopsies.   
Compliance.  It will be critical to retain patients in this program, and we will only select patients that are highly 
motivated.  We have projected the need to recruit 60 subjects to reach 40 complete studies, for a potential 
dropout rate of 33%.  To improve retention, the PIs will interact individually with the patients, and we will make 
maximal use of one-on-one instruction and education, and frequent contact with participants, in addition to 
small financial incentives.  In the past, our drop out rate has been about 10%, once the subject passes the 
initial screening procedures.  This is low, but it reflects the fact that we are experienced at recruiting and 
motivating subjects.  In addition, subjects must be willing to go through a number of initial procedures, so 
casual study subjects do not usually enroll.   
b. Sources of Materials 
Adipose tissue, and blood samples will be obtained from subjects, and these tissues will be used exclusively 
for research purposes.  From a blood sample, DNA will be prepared.  Under no circumstances will the patients' 
clinical care be compromised.   


 
 
 
c. Potential Risks 
Risks of the biopsies include bleeding, infection, and pain and patients are told of this. Dr. Kern is very 
experienced in this procedure and has an excellent track record.  Rarely (<1%) have oral antibiotics been 
needed following a biopsy. 
The lipid tolerance test involves the consumption of a liquid meal containing corn oil and cream, followed by 
hourly blood draws.  Some subjects may have mild GI symptoms, but this will likely be minimal.  Of the 
subjects studied to date, none have had GI symptoms, and all consumed their beverage within 10 min.  
The clamp involves frequent blood draws and indwelling catheters.  There is some needlestick discomfort, and 
there is a risk of hypoglycemia, although blood glucose is monitored carefully.   
Antibiotic treatment with rifaximin.  In clinical studies of rifaximin, the side effects are very low, usually similar to 
that of the placebo treated group.  In studies involving the use of rifaximin for travelers diarrhea, the only side 
effect of rifaximin that was higher than placebo was flatulence (20% vs 11% in placebo) (Xifaxan® package 
insert:  http://www.salix.com/assets/pdf/prescribe_info/xifaxanpi.pdf).  In the package insert, post-marketing 
experience states that C. difficile associated diarrhea has been reported in patients taking rifaximin, and the 
"Warnings and precautions" statement states that “C. difficile diarrhea has been reported with rifaximin as it 
has been reported with all other antibiotics”.  Notwithstanding these isolated reports of C. difficile, this 
complication has not been a problem with the use of rifaximin in clinical trials.  For example, in the TARGET 
study, 625 subjects with IBS were randomized to rifaximin, and there were no cases of C. difficile (67).  Indeed 
rifaximin is used to treat C. difficile diarrhea, including metronidazole-resistant C. difficile, and to prevent 
recurrence (78;79).   
To minimize the risk of C. difficile associated disease, we will warn subjects of the risk, and we will educate 
them on the symptoms and monitor their symptoms.  Although anyone can get occasional diarrhea, subjects 
will be told to call us immediately if they have persistent watery stools of >4x/day for 3 days, or any bloody 
stools, especially if this is associated with systemic symptoms of fever and abdominal pain.  Drs. Paul Angulo 
and Terrance Barrett, who are gastroenterologists at UK, are consultants on this proposal, and will be involved 
with the care of these subjects.   
The alternatives to this study are to not participate.  The care of the patient will never be compromised by non-
participation.   
2. Adequacy of Protection Against Risks  
a. Recruitment and Informed Consent 
Patients will be compensated $700 for completion of the study (including both sets of biopsies and the 
FSIVGTT and lipid tolerance tests), and we will explain the potential risks and benefits, and the patient will be 
asked to sign a consent form.  This protocol and a consent form will undergo thorough review by our 
institutional IRB. 
Consent for this study will be obtained either by Dr. Kern or his designate (coordinator) on the CRC, where the 
witness for the consent is usually a CRC nurse. Patients will be informed of the voluntary nature of the study, 
and that their clinical care will not be compromised. A consent form will be approved by the institutional IRB. 
b. Protection Against Risk 
All procedures will be performed on the CRC of the Center for Clinical and Translational Sciences, a funded 
CTSA, using skilled nursing, a hospital environment, and sterile procedures. Standard surgical practices 
ensure safety to the patients.  No provision is made to compensate patients for any research related injury, and 
this is stated in the consent form.   
To protect confidentiality, all subjects are assigned a unique number, and this number is used for labeling of all 
samples and the identification of all laboratory material obtained from subjects, and there is no public release 
of the name of the subject from whom the material was derived.  All data are kept in a password protected 
computer file (eg. Redcap) or in locked filing cabinets.  
3. Potential Benefits of the Proposed Research to the Subjects and Others  
Subjects will have an oral glucose tolerance test, which will determine whether the subject has diabetes or 
impaired glucose tolerance.  Routine blood tests of blood count, liver enzymes, cholesterol will be shared with 


 
 
 
the patient.  All subjects will be informed that there will be no likely benefit to their health from this study.  The 
knowledge gained from these studies may have importance to the subject.  However there is no direct benefit 
from the biopsies and the subject is so informed.  The subject is compensated $700 for his/her participation. 
4. Importance of the Knowledge to Be Gained  
Diabetes, obesity, insulin resistance, and metabolic syndrome are diseases that involve over 1/3 of the 
American population, resulting in considerable risk of severe medical problems, including hypertension, 
dyslipidemia, coronary artery disease, and premature death.  Subjects with IGT have a very high likelihood of 
progression to type 2 diabetes.  .   
Data & Safety Monitoring Plan 
All research personnel who work with subjects or subject data or subjects’ research samples in this project will 
have completed training in the protection of human research participants per guidelines issued by the OHRP. 
This protocol will receive final approval by the institutional IRB.  
This protocol will be continuously monitored in real-time by the principal investigators and study coordinator for 
adverse events (AEs). The research coordinator will contact subjects within 48 hours of each procedure to 
assess for pain, infection, and other symptoms indicating possible post-procedure complications. Subjects are 
discharged from the CRC with specific self-monitoring guidelines and instructed to call immediately for any 
concerning signs or symptoms.  
AEs will be graded according to intensity. Mild: Discomfort noticed but no disruption of normal daily activity. 
Moderate: Discomfort sufficient to reduce or affect normal daily activity. Severe: Incapacitating with inability to 
work or perform normal daily activity. 
The attribution scale for AE reporting will be as follows. Probable: AE is related to the procedure (e.g. infection 
from a fat biopsy). Possible: AE follows the procedure within a reasonable period (within 7 days), but may have 
been produced by the subject's clinical state or other factors (e.g. rash 3 days following the clamp). Remote: 
AE does not follow the procedure or drug within a reasonable period and could readily have been produced by 
the subject's clinical state or other factors. Unrelated: AE is judged to be clearly due to extraneous causes and 
does not meet the above criteria. 
Plan for unexpected Adverse event (AE) reporting. Serious AEs will be reported to Human Subjects/IRB within 
48 hr, and will also be reported to the CR-DOC. Unanticipated events will be reported to the CR-DOC real 
time, and to the IRB no later than 15 days after the event. Annual reporting of adverse events will be 
conducted with the Human Subjects annual review/renewal according to their guidelines.  
Monitoring of adverse events. Adverse events will be monitored via exams, vital signs, lab tests, review of 
subject’s medical chart, review of subject diaries, etc. and documented. Signs of infection from the biopsies will 
be monitored by exams. Each visit will be documented with a progress note in the CR-DOC chart.  A data 
safety and monitoring board (DSMB) will oversee the safety of this project.  The University of Kentucky CTSA 
has a Research Participant Advocate who chairs a DSMB, and this DSMB will perform a periodic review of this 
protocol. No provision is made to compensate patients for any research related injury, and this is stated in the 
consent form. 
 
 


 
 
 
 Inclusion of Women and Minorities  
Subjects and patients will be recruited without regard to sex, race, or ethnic status. All of the patients who enter 
the study will either be normal subjects, or will be obese or have metabolic syndrome, which is commonly 
found in obese subjects. Obesity and metabolic syndrome are a common findings in both genders and all 
ethnic groups, and therefore it is likely that the final make up of subjects in this study will be generally reflective 
of the population of Northern Kentucky.  It is likely that approximately 10% of the subjects recruited will be 
African-American, based on the local population. The Hispanic, Asian, and Native American population of 
Kentucky is <1% for each group, although the Hispanic population is increasing rapidly, and the high rate of 
diabetes and metabolic syndrome in this population may result in a higher representation in this study. 
 
 


 
 
 
 
Targeted/Planned Enrollment Table 
Total Planned Enrollment:  60  
 
*The 
“Ethnic 
Category 
Total of 
All 
Subjects” must be equal to the “Racial Categories Total of All Subjects.” 
 
As described in the research plan, we will screen subjects for IGT and other features of metabolic syndrome.  
There are exclusion criteria, enumerated above, so some subjects will sign the consent form but then will be 
excluded.  We anticipate that approximately half of the obese subjects will be excluded, usually because they 
do not have IGT, or do not have features of metabolic syndrome, or have other exclusion criteria.  Therefore, 
we estimate that we will need to recruit about 120 subjects to recruit the 60 subjects needed to start the study.  
However, the demographics on the 120 subjects will likely be the same as the 60 subjects described above.   
 
 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
 
Sex/Gender 
 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
29 
29 
58 
Ethnic Category Total of All Subjects* 
30 
30 
60 
Racial Categories 
 
 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
0 
0 
0 
Native Hawaiian or Other Pacific 
Islander 
0 
0 
0 
Black or African American 
4 
4 
8 
White 
26 
26 
52 
Racial Categories: Total of All 
Subjects* 
30 
30 
60 


 
 
 
 
Inclusion of Children 
Childhood obesity and the resulting insulin resistance are also epidemic and a serious health concern. 
However, based on recent ruling from the Office of Human Research Protection, the studies proposed herein 
would be considered too invasive to be appropriate for young children. In addition, we could not properly match 
the BMIs of children with adults because of the different scales. Although obese children may have IGT, it is 
much less common than in adults, unless one involves very obese children. Finally, we do not wish to recruit 
young adults or older adolescents because of the importance of minimizing age-related differences in our 
subject groups. Because IGT is much less common in young people, this study will concentrated on subjects 
between the ages of 30 and 60 of both genders and all ethnic groups. 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
An important outcome will be the measurement of LPS in plasma and lipoprotein fractions from the low-fat and 
the high-fat meals, and we will examine the peak LPS levels, as well as area under the curve.  In a previous 
study in lean subjects, baseline LPS was 0.39± 0.07 EU/ml and increased to 0.58 EU/ml with a fatty meal (53).  
Assuming that SD of the group and SD of change is 0.1 and an effect size of 1.0, we will need 10 subjects to 
detect a change of 0.1 EU/ml between a low-fat and high fat meal (paired T-test) and 17 subjects to detect the 
same difference between groups (drug vs placebo), with α of 0.05 and 80% power.  Our preliminary data 
support the effect size described.  To estimate the sample size needed to observe changes in adipose tissue 
inflammation, we will target adipose tissue macrophages.  In previous studies of obese/IR subjects, 
macrophage number was 34±5.8/mm2 (31).  Assuming the SD of change is equal to the SD 5.8 in these obese 
subjects, 20 subjects in each group will allow us to detect a change in macrophage number of 4/mm2 with 80% 
power using a paired t-test.  For comparisons between groups, if we assume an effect size of 1.0, we will need 
to recruit 17 subjects in each group. In previous interventional studies, we detected changes in macrophage 
number in adipose in response to fish oil and pioglitazone treatment (35;77).  These sample size calculations 
project adequate power with a total of 40 subjects (20 in each group) who complete the whole protocol.  We 
recognize that we are asking a lot of these subjects, however we have considerable experience performing 
similar in-depth studies.  We anticipate a higher drop-out rate than usual, and we estimate that we will need to 
recruit 60 subjects to obtain 40 that complete the protocol. 
 
 

ICF_001.pdf: 
  
 
 
 
 
Combined Consent and Authorization to Participate in a Research Study  
“Dietary fat, lipoprotein and lipopolysaccharide: role in insulin resistance” 
 
 
WHY ARE YOU BEING INVITED TO TAKE PART IN THIS RESEARCH? 
You are being invited to take part in a research study about dietary fat, lipoprotein and 
lipopolysaccharide and their role in insulin resistance and its underlying causes. You are being 
invited to take part in this research study because you are between the ages of 35 and 65, 
overweight or lean, have a slightly abnormal blood sugar, evidence of metabolic syndrome, or 
are in good overall health.  If you volunteer to take part in this study, you will be one of about 
40 people to do so. 
WHO IS DOING THE STUDY? 
The person in charge of this study is Dr. Philip Kern M.D. of University of Kentucky, 
Department of Medicine, and Division of Endocrinology. There may be other people on the 
research team assisting at different times during the study.  
WHAT IS THE PURPOSE OF THIS STUDY? 
Metabolic syndrome is a condition involving elevated levels of fat in the blood, a tendency 
towards diabetes, hypertension, and too much fat around the abdomen (an increased 
waistline). Individuals with metabolic syndrome often have impaired glucose tolerance, which 
is a condition where your blood sugar is normal when fasting (before you eat), but is too high 
after drinking a sugary drink. This is due to an abnormality in your body’s sensitivity to insulin 
(insulin resistance), which is due in part to an inability of your muscle to take up glucose. 
People with metabolic syndrome have inflammation in their fat tissue and in their blood stream, 
and the changes in the level of inflammatory chemicals produced by cells in your fat tissues 
will be studied.  One possible source of the inflammation may be the bacteria in your intestine.  
When you eat fatty foods, some of the bacterial products (endotoxin, or lipopolysaccharide) 
become attached to the fat in your blood and then get directed to your fat tissue.  We wish to 
determine whether you have an excessive amount of inflammation in your fat tissues, and 
whether this inflammation comes from the bacteria in your intestines.  
To determine this, we wish to treat you with an experimental antibiotic (rifaximin SSD) that 
reduces the bacteria in your intestines and in your blood, and determine whether this reduces 
your overall level of inflammation 
 
Rifaximin Study 
Version dated 12 May 2016 
 
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IRB Approval of 14-0136 
Valid from 05/17/16 to 02/13/17


Rifaximin is an FDA approved antibiotic that is minimally absorbed by the intestine and is used 
to treat gut bacterial infections and to lower the amount of bacterial products that get into the 
blood in patients with serious liver disease.  You will be receiving rifaximin SSD.  This is a new 
formulation of the same drug which is not yet FDA approved 
There are a number of factors, including your age, weight, and medical history, that may make 
you eligible or ineligible to participate in this study.  Certain medications that you may be taking 
could make you ineligible, but if these medications can be safely altered, you may become 
eligible.  Any such changes will be discussed with you and your primary care provider.   
ARE THERE REASONS WHY YOU SHOULD NOT TAKE PART IN THIS STUDY? 
You should not participate in this study if you are pregnant or breastfeeding, if you have a 
bleeding disorder, or if you have an allergy to the local anesthetic lidocaine.  If you are of 
childbearing potential, you must be using adequate contraception.  You should not participate 
in this study if you have a history of coronary disease or stroke, chronically use aspirin/NSAID 
or any other anticoagulant.  If you have a lactose intolerance, inflammatory bowel disease, 
chronic or frequent diarrhea or other chronic gastrointestinal disturbance, you should not 
participate.  
WHERE IS THE STUDY GOING TO TAKE PLACE AND HOW LONG WILL IT LAST?  
The research procedures will be conducted at the UK Medical Center at the Center for Clinical 
Translational Sciences research unit (CCTS). You will need to come to the CCTS Unit for 9 
research visits; 4 visits for procedures, then you take the antibiotic rifaximin SSD (or a 
placebo/”sugar pill”) and return to the clinic for a compliance visit, and then the procedures are 
repeated.  The study itself lasts for about a 12 week period.  Each of these visits will vary in 
time ranging from 4 hour to 9 hours.  
WHAT WILL YOU BE ASKED TO DO? 
You will report to the CCTS research unit 4 times over the first 2-3 weeks of the study for 
baseline testing. After the initial procedures, you will take the study drug, rifaximin SSD or 
placebo, for 4 weeks and then you will report back to the CCTS research unit for a compliance 
visit to obtain additional study drug. After 4 more weeks of taking the study drug, you’ll return 4 
more times over a period of 2-3 weeks to complete the same procedures you did for baseline 
testing. Your participation will then be completed. Your total participation will be 9 visits over a 
12 week period. Each of these visits will vary in time ranging from 4 hours to 9 hours. 
CCTS Baseline Visits: 
The first visit: 
• You will be fasting.  
• You will complete the Informed Consent process. 
• We will go over your medical history and diet and make measurements of your waist 
and hips. 
• You will have blood taken for labs. 
• You will complete an Oral Glucose Tolerance Test (OGTT) to measure your tendency 
towards diabetes. 
• You will have a DEXA Scan that measures your bone density and body fat. 
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 The second visit: 
• The night before you will have a low fat meal, suggested are: Subway low fat combo 
meal, Healthy Choice or Smart Ones. You will also abstain from alcohol.  
• You will be fasting after 9pm. 
• You will drink a high fat shake and have hourly blood draws for up to 8 hours. 
 
The third visit: 
• You will be fasting after 9pm the previous night. 
• A fat biopsy will be taken from your abdomen under local anesthesia. You will have the 
sutures removed after 7 days. 
 
The fourth visit: 
• You will be fasting after 9pm the previous night. 
• You will complete a measurement of insulin sensitivity with a clamp study.   
• We will check up on the biopsy site. 
Note that scheduling conflicts may change the order of some of the procedures above.   
 
The fifth visit: 
After the baseline procedures you will take the study drug, rifaximin SSD for 8 weeks, or a 
sugar pill/placebo.  You will be asked to return after 4 weeks for a compliance visit consisting 
of having labs drawn and a count of your study drug. After eight weeks you will report back to 
the CCTS research unit to repeat the same procedures you did for the baseline testing. You 
will then complete the study. 
CCTS Post Visits: 
The sixth visit: 
• You will be fasting after 9pm. 
• Blood taken for labs, measurement of waist and hips. 
• You will complete an Oral Glucose Tolerance Test (OGTT) to measure your tendency 
towards diabetes. 
• You will have a DEXA Scan that measures your bone density and body fat. 
The seventh visit: 
• The night before you will have a low fat meal, suggested are: Subway low fat combo 
meal, Healthy Choice or Smart Ones. You will also abstain from alcohol.  
• You will be fasting after 9pm. 
• You will drink a high fat shake and have hourly blood draws for up to 8 hours. 
 
The eighth visit: 
 
• You will be fasting after 9pm. 
• A fat biopsy will be taken. You will have the sutures removed after 7 days. 
 
The ninth visit: 
 
• You will be fasting. 
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Version dated 12 May 2016 
 
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• You will complete a measurement of insulin sensitivity with a clamp study.   
• We will check up on the biopsy sites. End of Study. 
Glucose tolerance test, and body composition measurements:  To determine whether you 
qualify for this study, we will first ask you some questions about your medical history, obtain 
vital signs, and determine whether you have impaired glucose tolerance.  You will be expected 
to come to the CCTS at the UK Medical Center in the morning after an overnight fast for an 
oral glucose tolerance test (OGTT).  A blood sample will be drawn.  You will be asked to drink 
a sweet liquid (sugar water), which contains 75 grams of glucose, followed by blood draws at 
30 minute intervals for 2 hours.  The total amount of blood drawn will be about 1 tablespoon.  
This test will determine whether you have impaired glucose tolerance, diabetes, or are normal.   
From a fasting blood sample, we will conduct routine blood tests that are a normal part of a 
physical exam, such as cholesterol, liver enzymes and electrolytes.  The amount of blood 
taken will be about 2 tablespoons.  You will be asked to have your weight, height, waist and 
hip measurements recorded.  Measurement of total body fat will be performed to determine 
your percent body fat using dual energy X-ray absorptiometry (DXA).  DXA uses very low 
levels of X-ray to measure the amount of fat, muscle, and bone in different body areas.  You 
will be asked to lie on a table while wearing light clothing or a gown.  The test will take only 5 - 
10 minutes, and involves no discomfort.   
Based on the blood tests, the OGTT, and other measurements, we will determine whether you 
have impaired glucose tolerance or a normal glucose level, and whether you fit the other 
criteria of the study.  If you meet the criteria of the study, you will be invited to participate in the 
rest of the study.   
Lipid tolerance test.  You will consume a low fat meal the evening before the test, and then you 
will be asked to come to the CCTS Outpatient Clinic in the morning after an overnight fast for 
the lipid tolerance test. You will be asked to drink a high fat shake which will encompass 40% 
of your daily energy requirements, and will be 50% fat.  Blood will be drawn at time points 0, 30 
min, 1 hour, and hourly to 8 hours. 
 
Insulin sensitivity and secretion measurements:  These procedures will be performed to 
measure your insulin sensitivity.  This procedure is called a Clamp study.  For these 
measurements, you will come to the CCTS after fasting overnight.  Two intravenous plastic 
tubes will be inserted into veins in your arm. You will be given an injection of a small amount of 
non-radioactive “heavy glucose”, which will be used to measure how much glucose is put out 
by your liver.  You will then be given a constant injection of glucose along with a constant 
injection of insulin.  The glucose and insulin are balanced such that your blood glucose stays 
constant between 90-100 mg/dl.  Blood will then be drawn from the intravenous line frequently 
(about every 2 to 5 minutes) for measurement of blood glucose and insulin.  These blood 
measurements will continue for 4 hours; the total amount of blood that will be withdrawn will be 
about 150 cc (about 10 tablespoons), which is about one third as much as would be taken if 
you were to donate blood, and then the test is over and you will be provided with a meal.     
Fat biopsies:  After an overnight fast, the biopsy procedures will be performed as follows: A 
sample of your fat (called a fat biopsy) will be removed by Dr. Kern from an area of your lower 
abdomen.  The skin at the biopsy site will be anesthetized using the local anesthetic, lidocaine, 
then a 1.5-inch incision will be made through the skin and a small amount of fat tissue will be 
removed.  The incision will be about ½ inch deep and will be closed using stitches.  This 
procedure normally takes about 30-45 minutes.  After the procedure, you will be provided with 
a snack. 
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Version dated 12 May 2016 
 
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Study drug.  After the initial procedures, you will be assigned to one of two groups: rifaximin 
SSD 80 mg taken once per day, or placebo (a pill containing no drug).  The assignments will 
be random (by chance, like flipping a coin) and you will not know whether you are on the 
placebo or rifaximin SSD, but the study coordinator and the PI (Dr. Kern) will be able to 
determine the drug assignment if it is necessary.  You will take your assigned drug for 8 
weeks.  After you have taken the medication for 8 weeks, all the above studies (blood tests, 
insulin sensitivity testing, body composition, lipid tolerance, fat biopsies) will be repeated.  Your 
participation in the study will then be concluded, and we will reveal to you the study 
assignment.   
If you qualify for the full study, your total duration of participation in this study, including the 
time to perform the procedures will be approximately 12 weeks.  Your participation is voluntary, 
and you may withdraw from the study at any time. All of the above procedures are being 
performed because of the research study, and none are intended to diagnose or treat a 
medical condition. If you are of child bearing age and not using adequate contraception, a 
pregnancy test may be performed at the time of initial screening.  
WHAT ARE THE POSSIBLE RISKS AND DISCOMFORTS? 
Fat biopsy:  During the biopsy, there will be some discomfort (a burning sensation) while the 
anesthetic (lidocaine) is being injected.  Following completion of the procedure, the site of the 
biopsy will be mildly tender for a period of 3-4 days.  There is also a small chance (less than 1 
in 100) that a problem with excessive bleeding or infection of the biopsy site may occur.  In 
case of bleeding, you might need to have the incision site opened to evacuate the blood clot or 
you might need antibiotics to control the infection. The biopsy could result in a small area of 
numbness on the skin around the site of the incision. There will be a permanent scar; the scar 
from the fat biopsy will be approximately one to two inches in length. You should avoid heavy 
lifting and strenuous physical activity for two weeks after the biopsy.  After this time, you can 
participate in any activity according to your tolerance.  You may take acetaminophen 
(Tylenol®) after the biopsy.  If necessary, the investigators will prescribe other medications for 
pain.  There is a slight risk that you may have an allergic reaction to local anesthetic lidocaine 
and experience a rash, itching or anaphylaxis. If this happens you may be given an 
antihistamine (Benadryl). 
DEXA Scan/Body fat measurement:  DXA is a test that is routinely performed for measurement 
of bone mass, and involves a very small exposure to X-rays.  
OGTT/fat tolerance test/clamp measurement of insulin sensitivity. Some discomfort may be 
present at the sites of needle insertion and catheter location, and there could be some 
soreness, bruising, pain, bleeding, or fainting.  There is a small chance of infection or 
inflammation around the site of needle insertion.  There is a small risk of temporary 
hypoglycemia (low blood sugar).  Although insulin is known to cause a drop in blood sugar if 
given alone, you will receive insulin along with glucose (sugar), and we will measure your 
blood sugar repeatedly and feed you or give you glucose if your blood glucose falls.     
Study drug (rifaximin SSD).  In large studies, people taking rifaximin have reported very few 
side effects:  some subjects have reported mild gastrointestinal disturbances, and in some 
circumstances there has been mild fluid retention.  Other antibiotics can sometimes cause a 
severe diarrhea called “C. Diff” (clostridium difficile), which can even be life threatening.  
Although this complication has been reported with rifaximin, it has been very rare.  You will be 
receiving rifaximin SSD.    Rifaximin SSD is more soluble, which permits the use of a lower 
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Version dated 12 May 2016 
 
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dose.  In testing thus far, the side effect profile of rifaximin SSD are not different from that of 
rifaximin. 
Venipuncture. There may be some slight bleeding or bruising at the venipuncture site which 
may last for a short duration. You may feel faint which will last for a short duration. You may 
experience some soreness or pain at the site for a few days as well. There is also the slight 
possibility of infection at the venipuncture site. 
There is always a chance that any medical treatment can harm you, and the investigational 
treatment in this study is no different.  In addition to the risks listed above, you may experience 
a previously unknown risk or side effect. 
 
WILL YOU BENEFIT FROM TAKING PART IN THIS STUDY? 
There is no guarantee that you will get any personal benefit from taking part in this study. Your 
willingness to take part may, in the future, help doctors better understand and/or treat others 
who have your condition.  
DO YOU HAVE TO TAKE PART IN THE STUDY? 
If you decide to take part in the study, it should be because you want to volunteer.  You will not 
lose any benefits or rights you would normally have if you choose not to volunteer.  You can 
stop at any time during the study and still keep the benefits and rights you had before 
volunteering.  If you decide not to take part in this study, your decision will have no effect on 
the quality of medical care you receive. 
IF YOU DON’T WANT TO TAKE PART IN THE STUDY, ARE THERE OTHER CHOICES? 
If you do not want to be in the study, there are no other choices except not to take part in the 
study. 
 
Possible 
Risk/Side Effect 
How often has it 
occurred? 
(percentage/likelihood) 
How serious is it? 
Can it be corrected? 
Pain, bruising, 
following biopsies 
Pain and bruising, 
common 
Pain:  mild-moderate 
Yes; pain medications; 
bruising resolves in 3-10 
days 
Infection from 
biopsy 
Rare (less than 1:100) 
Mild-moderate 
Yes, antibiotics 
Scar from biopsies 
Always 
small 
It will be permanent 
Radiation from 
DEXA, CT scan 
Common 
Minimal 
It will be part of your overall 
environmental exposure 
Possible infection 
from IV 
Uncommon 
Not serious 
Yes, with anti-inflammatory 
medications and/or 
antibiotics 
Hypoglycemia 
during insulin test 
Uncommon (less than 
1:100) 
Mild 
Temporary; resolved with 
eating 
C. Diff from 
rifaximin 
Very rare. Less than 
1:1000 
Potentially severe  
Stopping drug, other 
medications 
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Version dated 12 May 2016 
 
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WHAT WILL IT COST YOU TO PARTICIPATE? 
All of the procedures that are part of this research will be provided at no cost to you, and The 
University of Kentucky may not be allowed to bill your insurance company, Medicare or 
Medicaid for the medical procedures done strictly for research.  Therefore, these costs will be 
paid by The University of Kentucky.   
WHO WILL SEE THE INFORMATION THAT YOU GIVE? 
We will make every effort to keep private all research records that identify you to the extent 
allowed by law.  Your information will be combined with information from other people taking 
part in the study. When we write about the study to share it with other researchers, we will 
write about the combined information we have gathered. You will not be personally identified in 
these written materials. We may publish the results of this study; however, we will keep your 
name and other identifying information private.  You will be asked to provide your social 
security number.  This is necessary to provide you with payment for participation in the study 
and is not being collected for actual research purposes.  Your social security number will be 
kept on a separate form and will be destroyed after you receive your payment.  If you would 
rather not provide your social security number you may still take part in the research study but 
will not be eligible for payment.  
We will make every effort to prevent anyone who is not on the research team from knowing 
that you gave us information, or what that information is.  Your personal information (name, 
address, phone number) will be kept in a paper chart that is stored in a locked filing cabinet.  A 
unique number will be assigned to you and your data, and any data in electronic records will 
only contain your unique number, and will not contain information that could identify you.   
You should know, however, that there are some circumstances in which we may have to show 
your information to other people. For example, the law may require us to show your 
information to a court.  Officials of the Food and Drug Administration, the National Institutes of 
Health, and the University of Kentucky, may look at or copy pertinent portions of records that 
identify you. 
CAN YOUR TAKING PART IN THE STUDY END EARLY? 
If you decide to take part in the study you still have the right to decide at any time that you no 
longer want to continue. You will not be treated differently if you decide to stop taking part in 
the study. If you choose to withdraw from the study early, the data collected until that point will 
remain in the study database and may not be removed. 
The individuals conducting the study may need to withdraw you from the study. This may occur 
if you are not able to follow the directions they give you, if they find that the procedures or drug 
are technically difficult or result in medically unacceptable side effects, or if the agency funding 
the study decides to stop the study early for a variety of scientific reasons. 
ARE YOU PARTICIPATING OR CAN YOU PARTICIPATE IN ANOTHER RESEARCH 
STUDY AT THE SAME TIME AS PARTICIPATING IN THIS ONE? 
You may take part in this study if you are currently involved in another research study, but this 
depends on the nature of the other study.  It is important to let the investigator/your doctor 
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know if you are in another research study.  You should also discuss with the investigator 
before you agree to participate in another research study while you are enrolled in this study. 
WHAT HAPPENS IF YOU GET HURT OR SICK DURING THE STUDY? 
If you believe you are hurt or if you get sick because of something that is due to the study, you 
should call Dr. Kern at (859) 323-4933 during regular working hours. During evenings or 
weekends, you should call the University of Kentucky page operator at 859-323-5321 and ask 
for Dr. Philip Kern, or for the Endocrinology fellow on call. If you are experiencing an 
emergency, you should call 911. 
It is important for you to understand that the University of Kentucky does not have funds set 
aside to pay for the cost of any care or treatment that might be necessary because you get 
hurt or sick while taking part in this study. Also, the University of Kentucky will not pay for any 
wages you may lose if you are harmed by this study.   
The medical costs related to your care and treatment because of research related harm will be 
your responsibility or may be paid by your insurer if you are insured by a health insurance 
company. Please contact your insurer to determine if they will pay for a research related injury. 
You do not give up your legal rights by signing this form. 
WILL YOU RECEIVE ANY REWARDS FOR TAKING PART IN THIS STUDY? 
You will receive a payment for participating in this study as follows:  $20 for the screening 
procedures (medical history and glucose tolerance test); $200 after the first set of procedures 
(insulin sensitivity testing, fat tolerance, and the fat biopsy); $400 after taking the study 
medication for 8 weeks and completing the final study procedures.  Thus, the total 
compensation for completing the study will be $620 for participants who complete all study 
procedures and the follow-up procedures.  If you receive $600 or above by participating in 
research, it is potentially reportable for tax purposes. 
WHAT IF YOU HAVE QUESTIONS, SUGGESTIONS, CONCERNS, OR COMPLAINTS? 
Before you decide whether to accept this invitation to take part in the study, please ask any 
questions that might come to mind now.  Later, if you have questions, suggestions, concerns, 
or complaints about the study, you can contact the investigator, Dr. Kern at 859-323-4933.  If 
you have any questions about your rights as a volunteer in this research, contact the staff in 
the Office of Research Integrity at the University of Kentucky at 859-257-9428 or toll free at 1-
866-400-9428. We will give you a signed copy of this consent form to take with you. 
WHAT IF NEW INFORMATION IS LEARNED DURING THE STUDY THAT MIGHT AFFECT 
YOUR DECISION TO PARTICIPATE? 
If the researcher learns of new information in regards to this study, and it might change your 
willingness to stay in this study, the information will be provided to you.  You may be asked to 
sign a new informed consent form if the information is provided to you after you have joined 
the study.  
 
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POTENTIAL FUTURE USE 
Banking of tissue and blood specimens 
Dr. Philip Kern would like to keep some of the blood and fat samples collected during the main 
study participation but which is not used for other tests for that study. No additional blood or 
tissue will be taken. If you agree, the blood and fat samples may be used in future research.  
Researchers may also need health information about the people who provide specimens. We 
are also asking for your consent to place information from your medical record and/or research 
record in a database to be used for research. Your name and other information that could 
identify you will not be placed in the database.  There are no additional risks to you from this 
banking of specimens. 
 
Please read each sentence below and think about your choice. After reading each sentence, 
mark “yes” or “no.” If you have questions, please talk to the investigator or staff. Remember, no 
matter what you decide to do about the storage, or banking, and future use of your blood and 
fat samples, you may still take part in the main study.  If you answer yes to either choice below 
you also give your authorization for your accompanying health information to be used and 
disclosed along with the blood and fat samples. 
 
1. Do you give permission for your blood and fat samples to be kept by Dr. Philip Kern 
in a central location/specimen bank at University of Kentucky, indefinitely or until 
they are used up for use in future research to learn more about how to prevent, 
detect, or treat insulin resistance, metabolic syndrome or diabetes? 
 
   Yes 
 
   No 
 
_________Initials 
 
2. Do you give permission for your blood and fat samples to be used for future 
research about other health problems, for example bowel disorders? 
 
   Yes 
 
   No 
 
_________Initials 
 
The blood and fat samples that you are giving will no longer belong to you and might be used 
in studies that lead to new products for research, diagnosis or treatment. There is no plan to 
keep you informed of findings from these studies.  These products might have some 
commercial value.  There are no plans to provide financial compensation to you should this 
occur. 
  
Contacting Research Subjects for Future Studies 
 
Do you give your permission to be contacted in the future by Dr. Philip Kern regarding your 
willingness to participate in future research studies about how to prevent, detect, or treat 
insulin resistance?   
 
   Yes 
 
   No 
 
_________Initials 
 
If you later decide to withdraw your permission for the banking of leftover samples, please 
contact Dr. Philip Kern, MD; Wethington 521; 900 S. Limestone St, Lexington KY 40536 and 
request that your leftover samples be discarded after this protocol is completed.   
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WHAT ELSE DO YOU NEED TO KNOW? 
The National Institute of Diabetes and Digestive and Kidney Diseases (a branch of the 
National Institutes of Health) is providing funding for this study and the maker of rifaximin SSD, 
Salix pharmaceuticals Inc., a division of Valeant Pharmaceuticals North American, LCC is 
providing drug and matching placebo.   
The sample(s) (blood, tissue or fluids) that you are giving might be used in studies that lead to 
new products for research, diagnosis or treatment.  These products might have some 
commercial value.  There are no plans to provide financial compensation to you should this 
occur. 
 
A description of this clinical study will be available on http://www.ClinicalTrials.gov, as required 
by U.S. law. This website will not include information that can identify you. At most, the website 
will include a summary of the results. You can search this website at any time. 
 
AUTHORIZATION TO USE OR DISCLOSE YOUR IDENTIFIABLE HEALTH INFORMATION  
 
The privacy law, HIPAA (Health Insurance Portability and Accountability Act), requires 
researchers to protect your health information.  The following sections of the form describe 
how researchers may use your health information.   
 
Your health information that may be accessed, used and/or released includes: 
• Demographic information (eg. name, address, phone number), medical history, 
results of routine blood tests, glucose tolerance tests, and the results of research 
procedures (eg. Results of biopsies) 
  
The Researchers may use and share your health information with: 
• The University of Kentucky’s Institutional Review Board/Office of Research Integrity. 
• Law enforcement agencies when required by law. 
• UK Hospital or University of Kentucky representatives, for purposes of administration 
of the study (eg. Lab results, payment of compensation).  
• Officials at the funding agency, the National Institutes of Health, if necessary. 
• The Food and Drug Administration (FDA), if necessary 
• Center for Clinical and Translational Science (CCTS)  
• Collaborating physicians and staff, as required for safety purposes. 
•  If necessary, my primary physician will be contacted if the researcher in the course 
of the project learns of a medical condition that needs immediate attention. 
• Salix Pharmaceuticals Inc., a division of Valeant Pharmaceuticals North America, 
LLC or their agents, who supplies the drug used for this study 
 
The researchers agree to only share your health information with the people listed in this 
document.   
Should your health information be released to anyone that is not regulated by the privacy law, 
your health information may be shared with others without your permission; however, the use 
of your health information would still be regulated by applicable federal and state laws.   
You will not be allowed to participate in the research study if you do not sign this form.   If you 
decide not to sign the form, it will not affect your: 
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10 
IRB Approval of 14-0136 
Valid from 05/17/16 to 02/13/17


• Current or future healthcare at the University of Kentucky 
• Current or future payments to the University of Kentucky   
• Ability to enroll in any health plans (if applicable) 
• Eligibility for benefits (if applicable) 
 
After signing the form, you can change your mind and NOT let the researcher(s) release 
or use your health information (revoke the Authorization). If you revoke the 
authorization: 
• You will send a written letter to: Dr. Philip Kern, MD; Wethington 521; 900 S. Limestone 
St, Lexington KY 40536 of your decision. 
• Researchers may use and release your health information already collected for this 
research study. 
• Your protected health information may still be used and released should you have a bad 
reaction (adverse event). 
• You may not be allowed to participate in the study. 
 
The use and sharing of your information has no time limit.  
 
If you have not already received a copy of the Privacy Notice, you may request one.  If 
you have any questions about your privacy rights, you should contact the University of 
Kentucky’s Privacy Officer between the business hours of 8am and 5pm EST, Mon-Fri 
at: (859) 323-1184. 
 
You are the subject or are authorized to act on behalf of the subject.  You have read this 
information, and you will receive a copy of this form after it is signed. 
 
 
_________________________________                        ____________________________ 
Signature of research subject or *research 
 
 
Date 
subject’s legal representative 
 
_________________________________ 
 
__________________________ 
Printed name of research subject or 
 
 
Representative’s relationship to  
*research subject’s legal representative  
 
research subject 
 
*(If, applicable) Please explain Representative’s relationship to subject and include a 
description of Representative’s authority to act on behalf of subject: 
___________________________________________________________________________ 
 
__________________________________________________________________________           
Name of [authorized] person obtaining informed consent/HIPAA authorization     
Date 
  
 
_________________________________________ 
Signature of Principal Investigator or Sub/Co-Investigator 
 
   
Rifaximin Study 
Version dated 12 May 2016 
 
11 
IRB Approval of 14-0136 
Valid from 05/17/16 to 02/13/17