Conditions: Drug-drug Interaction
Keywords: drug-drug interaction statin rifampin
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 10
Healthy volunteers: yes

Brief summary:
The effect of organic anion transporting polypeptide 1B1 (OATP1B1) transporter inhibition at clinical doses of fluvastatin, a biopharmaceutics drug disposition classification system (BDDCS) class 1 drug, has not been studied to date. A single dose of IV rifampin can be used as model OATP1B1 inhibitor to evaluate the significance of OATP1B1 transporter effects on fluvastatin disposition. A preinduction regimen of oral rifampin followed by a single IV infusion of rifampin can be used to evaluate the combined effects of enzyme induction and OATP1B1 transporter inhibition on fluvastatin disposition. A two arm, randomized, open label, crossover clinical study in healthy, volunteers will be conducted to evaluate the effects of IV rifampin on fluvastatin disposition in both hepatically induced and uninduced subjects.

Detailed description:
The effect of rifampin on the pharmacokinetics of fluvastatin will be studied in healthy volunteers in a two arms, two-period, randomized, unblinded, crossover clinical trial. In the first arm, subjects will be randomized to one of two treatment groups:

(i)fluvastatin (Lescol®) 20mg capsule (ii) one oral dose of fluvastatin (Lescol®) 20mg capsule immediately following a 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline.

In the second arms, patients will be pretreated with 600mg oral rifampin (two 300mg rifadin capsule) once daily to induce hepatic enzymes (and transporters) for 5 years. Subjects will be randomized to one of two treatment groups:

(i) one oral dose of fluvastatin (Lescol®) 20mg capsule (ii) one oral dose of fluvastatin (Lescol®) 20mg capsule immediately following a 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline

Arms:
arm 1: The effect of rifampin on the pharmacokinetics of fluvastatin will be studied in healthy volunteers with or without hepatic induction in a randomized, unblinded, crossover clinical trial.

For uninduced periods, subjects will be randomized to receive one oral dose of fluvastatin (Lescol®) 20mg capsule first. Separated by one day of washout, they then receive one oral dose of fluvastatin (Lescol®) 20mg capsule immediately following a 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline.

Before starting hepatic induced period, subjects will have a washout for greater than one week.

To induce hepatic enzyme and transporter, Subjects will be pretreated with 5 days with 600mg oral rifampin. Subjects will be then randomized first to receive a single dose of fluvastatin 20mg. Separated by one day of washout, subject will then receive one oral dose of fluvastatin 20mg immediately after a 30-min IV infusion of rifampin 600mg. arm 2: The effect of rifampin on the disposition of fluvastatin will be studied in healthy volunteers with or without hepatic induction in a randomized, unblinded, crossover clinical trial.

For uninduced periods, subjects will be randomized to first receive one oral dose of fluvastatin (Lescol®) 20mg capsule immediately following a 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline.Separated by one day of washout, subjects will be then receive a single dose of fluvastatin (Lescol®) 20mg capsule.

Before starting induction periods, subjects will have a washout greater than one week.

To induce hepatic enzyme and transporter, subjects will be pretreated with 5 days with 600mg oral rifampin. subjects will be randomized to receive first one oral dose of fluvastatin 20mg immediately after a 30-min IV infusion of rifampin 600mg. Separated by one day of washout, subject will then receive one oral dose of fluvastatin 20mg.

Interventions: intervention 1: rifampin IV intervention 2: Rifadin 300Mg Capsule intervention 3: Fluvastatin 20 MG
Intervention descriptions: intervention 1: A 30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline will be used to inhibit hepatic OATP1B1 transporters. intervention 2: Rifadin 600mg by mouth as two 300mg rifadin capsules intervention 3: one oral dose of fluvastatin (Lescol ) 20mg capsule

Protocol document:
Prot_SAP_001.pdf: 
Official Title: The Effects of Single Dose Rifampin on Pharmacokinetics of Fluvastatin in 
Uninduced and Hepatically Induced Healthy Volunteers 
 
NCT number: NCT04029584 
 
Document date: 4/26/2019 


 
 
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LESLIE Z. BENET, PHD 
Clinical Research Protocol 
The Effects of Single Dose Rifampin on Pharmacokinetics of Fluvastatin in Healthy 
Volunteers  
Protocol Number: 
 
Version Date: 
 
Investigational Product: 
 
IND Number: 
 
Development Phase: 
 
Sponsor: 
Leslie Z. Benet, PhD 
Funding Organization: 
 
Principal Investigator: 
Name: Leslie Z. Benet, PhD  
Telephone:(415)476-3853 
 
Fax: (415)476-8887  
E-mail:leslie.benet@ucsf.edu  
 
Medical Monitor: 
Name: Lynda A. Frassetto 
 
Telephone: 415-476-6143 
 
Fax:(415) 885-7396 
E-mail:Lynda.Frassetto@ucsf.edu 
Coordinating Center: 
If applicable 
 
Approval: 
 
 
Dec 27,2018 
PI or Sponsor Signature (Name and Title)  
 
Date 
This confidential information about an investigational product is provided for the 
exclusive use of investigators of this product and is subject to recall at any time.  
The information in this document may not be disclosed unless federal or state law or 
regulations require such disclosure.  Subject to the foregoing, this information may 
be disclosed only to those persons involved in the study who have a need to know, 
with the obligation not to further disseminate this information.   


 
 
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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing sponsor  with complete and timely information, as outlined in the protocol.  It is 
understood that all information pertaining to the study will be held strictly confidential 
and that this confidentiality requirement applies to all study staff at this site. Furthermore, 
on behalf of the study staff and myself, I agree to maintain the procedures required to 
carry out the study in accordance with accepted GCP principles and to abide by the terms 
of this protocol. 
 
Protocol Number:  Number 
 
Protocol Title:  The Effects of Single Dose Rifampin on Pharmacokinetics of Fluvastatin 
in Healthy Volunteers  
 
Protocol Date: 12/20/18 
 
 
 
Dec 27, 2018  
Investigator Signature  
 
Date 
Leslie Z. Benet, PhD, Professor 
Print Name and Title 
Address 
533 Parnassus Ave, U-68 
 
UCSF Box 0912 
 
San Francisco, CA 94143 
 
 
Phone Number 
14154763853 


 
 
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TABLE OF CONTENTS 
 
1 
BACKGROUND 
11 
1.1 
Overview of Non-Clinical Studies 
11 
1.2 
Overview of Clinical Studies 
11 
2 
STUDY RATIONALE 
13 
2.1 
Risk / Benefit Assessment 
13 
3 
STUDY OBJECTIVES 
13 
3.1 Primary Objective 
13 
4.1 Study Overview 
14 
5.1 
Primary Efficacy Endpoint 
15 
5.2 
Secondary Efficacy Endpoints 
15 
5.3 
Safety Evaluations 
15 
6 
SUBJECT SELECTION 
15 
6.1 
Study Population 
15 
6.3 
Exclusion Criteria 
16 
7 
CONCURRENT MEDICATIONS 
16 
7.1 
Allowed Medications and Treatments 
16 
8 
STUDY TREATMENTS 
16 
8.1 
Method of Assigning Subjects to Treatment Groups. 
16 
8.2 
Blinding 
17 
8.3 
Formulation of Test and Control Products 
17 
8.3.1 
Formulation of Test and Control Product 
17 
8.4 
Supply of Study Medications at the Site 
18 
8.4.1 
Administration Instructions 
18 
8.5 
Study Drug Accountability 
19 
8.6 
Measures of Treatment Compliance 
19 
9 
STUDY PROCEDURES AND GUIDELINES 
19 
9.1 
Clinical Assessments 
19 
9.1.1 
Concomitant Medications 
19 
9.1.2 
Demographics 
19 
9.1.3 
Medical History 
19 
9.1.4 
Physical Examination 
19 
9.1.5 
Vital Signs 
20 


 
 
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9.1.6 
Adverse Events 
20 
9.2 
Clinical Laboratory Measurements 
20 
9.2.1 
Hematology 
20 
9.2.2 
Blood Chemistry Profile 
20 
9.2.3 
Pregnancy Test 
20 
9.2.4 
Urinalysis 
20 
9.3 
Pharmacokinetic Measurements 
20 
10 
EVALUATIONS BY VISIT 
21 
10.1 
Screening Visit ( at least one week prior to study period 1) 
21 
10.2 
Study period 1 (Tuesday of the Week): 
21 
10.3 
Study Period 2 (Thursday of the week ) 
22 
11 
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
22 
11.1 
Adverse Events 
22 
11.2 
Serious Adverse Experiences (SAE) 
24 
11.2.1 
Serious Adverse Experience Reporting 
24 
12 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
25 
12.1 
Early Discontinuation of Study Drug 
25 
12.2 
Withdrawal of Subjects from the Study 
25 
12.3 
Replacement of Subjects 
25 
13 
PROTOCOL VIOLATIONS 
26 
14 
DATA SAFETY MONITORING 
26 
15 
STATISTICAL METHODS AND CONSIDERATIONS 
26 
15.1 
Data Sets Analyzed 
26 
15.2 
Demographic and Baseline Characteristics 
26 
15.3 
Analysis of Primary Endpoint 
26 
15.4 
Analysis of Secondary Endpoints 
27 
16 
DATA COLLECTION, RETENTION AND MONITORING 
27 
16.1 
Data Collection Instruments 
27 
16.2 
Data Management Procedures 
28 
16.3 
Data Quality Control and Reporting 
28 
16.4 
Archival of Data 
28 
16.5 
Availability and Retention of Investigational Records 
28 
16.6 
Monitoring 
28 
16.7 
Subject Confidentiality 
29 


 
 
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17 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
29 
17.1 
Protocol Amendments 
29 
17.2 
Institutional Review Boards and Independent Ethics Committees 
29 
17.3 
Informed Consent Form 
30 
17.4 
Publications 
30 
17.5 
Investigator Responsibilities 
30 
 
 


 
 
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LIST OF ABBREVIATIONS 
 
AE 
AUC0-∞ 
 
AUC0-12 
adverse event 
Area under the concentration versus time curve from time = 0 to 
infinity. 
Area under the concentration versus time curve from time = 0 to 
t = 12 hours. 
BUN 
blood urea nitrogen 
CFR 
Cmax 
Code of Federal Regulations 
maximum concentration 
CRF 
case report form 
CRP 
C-reactive protein 
ESR 
erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
intravenous 
PI 
Principal Investigator 
PK 
pharmacokinetic 
SAE 
serious adverse experience 
Tmax 
time to Cmax 


 
 
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PROTOCOL SYNOPSIS 
TITLE 
The Effects of Single Dose Rifampin on Pharmacokinetics of 
Fluvastatin in Healthy Volunteers  
 
 
NUMBER OF SITES 
1 
 
 
RATIONALE 
The effect of OATP1B1 transporter inhibition at clinical doses of 
fluvastatin, a BDDCS class 1 drug, has not been studied to date. A 
single dose of IV rifampin can be used as model OATP1b1 inhibitor 
to evaluate the significance of OATP1B1 transporter effects on 
fluvastatin  disposition.  
 
 
STUDY DESIGN 
This is  two-period, randomized, unblinded, crossover clinical trial. 
 
 
PRIMARY 
OBJECTIVE 
The primary objective is to determine whether or not inhibition of 
OATP1B1-mediated drug transport of fluvastatin will be clinically 
significant.  
 
 
NUMBER OF 
SUBJECTS 
10-12 
 
 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
● Healthy male or female, ages 18-65 years old, with no current 
medical conditions or active diagnoses as determined by the 
study doctor based on history, physical exam, and laboratory 
evaluations.  
● Subjects who take no other medications two weeks prior to the 
study and during the time course of the study including 
prescription medications, over-the-counter medications, 
dietary supplements, or drugs of abuse. 
● Subjects able to maintain adequate birth control during the 
study independent of hormonal contraceptive use (use of 
condoms).  
● Subjects able to abstain from grapefruit, grapefruit juice, 
oranges, orange juice, caffeinated beverages and/or alcoholic 
beverages from 7am the day before the study to completion of 
that study day.   
● Participants determined to have normal liver and kidney 
function as measured at baseline (ALT: ≤ 2x upper level of 


 
 
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normal (ULN), AST: ≤ 2x ULN, SCr: ≤ 1.5x ULN, T. Bili: 
0.1-1.2mg/dL, Albumin: 3.4 – 4.7 mg/dL).   
● BMI between 18.0 - 30 kg/m2 o Subjects capable of fasting 
from food and beverages at least 8 hours prior to medication 
dosing.   
● Be able to read, speak, and understand English.   
● Subjects capable of providing informed consent and 
completing the requirements of the study. 
Exclusion Criteria: 
● Subjects with active medical problems  
●  Subjects on chronic prescription or OTC medication that 
cannot be stopped 2 weeks prior to and during the study.  
● Subjects incapable of multiple blood draws (HCT < 30mg/dL)  
● Subjects with a history of rhabdomyolysis  
● Subjects with a history of drug-related myalgias  
● Subjects with a history or diagnosis of hemorrhagic tendencies 
or blood dyscrasias 
● Subjects with a history of GI bleed or peptic ulcer disease  
● Subjects who smoke tobacco or have ongoing alcohol or 
illegal drug use  
●  Subjects who are pregnant, lactating, or trying to conceive 
during the study period   
●  Subjects allergic to fluvastatin or rifampin or any known 
component of the  medications  
● Anyone who in the opinion of the study investigators is unable 
to do the study 
 
 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
 fluvastatin 20 mg by mouth as a 20 mg Lescol® capsule  
 Rifampin 600mg IV infusion over 30 minutes (t = -30 minutes)  
 
 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
  fluvastatin 20 mg by mouth as a 20 mg Lescol® capsule  
 
 


 
 
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DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
subject will be on study for up to 2 days  
Screening: One 2-hour screening visit one week prior to the study  
Treatment: 13 hours stays in the CRC(separated by at least 1 day) 
The total time required is 27 hours over about 2 day period. 
 
 
CONCOMMITANT 
MEDICATIONS 
Allowed: No concomitant medication allowed  
 
Prohibited: subject will not allow to take any other medications two 
weeks prior to the study and during the time course of the study 
including prescription medications, over-the-counter medications, 
dietary supplements, or drugs of abuse. 
 
 
 
PRIMARY ENDPOINT The primary outcome will be fluvastatin AUC0-12h and AUC0-∞ 
(AUC = area under the plasma concentration versus time curve). 
SECONDARY 
ENDPOINTS 
 Secondary outcomes will include fluvastatin  maximum plasma 
concentration (Cmax) and time to Cmax (Tmax) . 
SAFETY 
EVALUATIONS 
Safety evaluation will be determined by  the incidence of adverse 
events. Subjects will be monitored on an ongoing basis while involved 
with the study by study personnel. Subjects will be screened with a 
medical history and physical examination by the study physician and 
have screening hematology, chemistries, liver, renal and coagulation 
laboratories. Subjects must have normal function of all major organs. 
At study completion, subjects will have repeat physical examination 
and repeat hematology, chemistries, liver, renal and coagulation 
laboratories for safety monitoring. 
 
PLANNED INTERIM 
ANALYSES  
Serious adverse events will be monitored by the committee on an 
ongoing basis throughout the study. 
 
 
STATISTICS 
Primary Analysis Plan 
AUC0-∞ will be calculated using the trapezoidal rule from time 0 to 
Clast + Clast/ke. Parameters such as maximum plasma concentration 
(Cmax) and time to Cmax (Tmax) will be determined from the 
observed data. The terminal elimination rate constant (ke) will be 
obtained using linear regression of log transformed concentrations 
over the terminal log-linear decline phase. Oral clearance (CL/F) will 
be calculated using Dose/AUC0-∞. Other estimated pharmacokinetic 
parameters will be calculated using non-compartmental methods with 


 
 
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WinNonlin Professional software (Pharsight, Inc., Mountain View, 
CA). Log-transformed pharmacokinetic parameters will be compared 
across treatments with analysis of variance for repeated measures. 
Differences will be regarded as statistically significant if p< 0.05. 
Data will be presented as mean values with standard deviations. Each 
subject will serve as his/her own control. Differences in 
pharmacokinetic parameters between treatments will be calculated 
using student’s paired t-test. Statistical calculations will be done using 
STATA 10.0 (StataCorporation, College Station, TX). 
Rationale for Number 
of Subjects 
Using a paired t-test and prior data, a sample size of n=10 in each 
group is needed to detect a 50% difference in AUC0-12 between the 
two study regimens with a statistical power of 80% (two sided alpha = 
0.05) and standard deviation of 50%. Due to the lesser effects of 
rifampin on fluvastatin AUC, the within subject variability can affect 
the sample size. We plan to enroll sample size of 12 subjects to 
maintain an adequate sample size in case of potential attrition. 
 
 


 
 
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1 
BACKGROUND 
Membrane transporters located throughout the body play an important role in drug 
absorption, disposition, metabolism, and elimination1.The inhibition of many of these 
transporters has been linked to significant drug-drug interactions1. Located on the 
sinusoidal membrane of hepatocytes, the Organic Anion Transporter Polypeptide 
transporter OATP1B1 is responsible for the uptake of substrates from the blood into the 
liver where they can be metabolized and cleared1-3. When OATP1B1-mediated transport is 
inhibited with known inhibitors such as ritonavir, rifampin, or cyclosporine, drug 
metabolism and elimination into bile are diminished, resulting in elevated concentrations 
of the drug in the blood. Another important membrane transporter, Breast Cancer 
Resistance Protein or BCRP, present in the intestinal epithelia and liver, is also important 
for drug elimination1.If BCRP is inhibited, drug concentrations in the liver and blood may 
also rise.  
 
Statins are commonly prescribed cholesterol-lowering agents whose efficacy and safety is 
closely linked with the function of the BCRP and OATP1B1 transporters1-3. These drugs 
must enter the liver to exert their efficacy. Compared to other statins like rosuvastatin and 
pravastatin, fluvastatin is extensively metabolized 4. It has a more hydrophobic profile 
making it highly permeable through the membranes and in theory less dependent on 
OATP1B1-mediated transport5.  
 
To predict hepatic uptake transporter effects on drug disposition, Wu and Benet developed 
the Biopharmaceutics Drug Disposition Classification System (BDDCS) system which 
categorizes drugs based on extent of metabolism and solubility characteristics 6. 
According to this classification system, the plasma exposure of  Fluvastatin, a BDDCS 
class I drug should be minimally influenced by transporter effects6.  
 
1.1 
Overview of Non-Clinical Studies 
Available in vitro data demonstrates that inhibition of OATP1B1 by rifampin results in 
reduced rosuvastatin uptake in Human Embroyonic Kidney (HEK293) cells, which 
implies the drug’s significant dependence on the membrane transporter7. Animal studies 
have also confirmed that rifampin significantly alters hepatobiliary transport of 
rosuvastatin and increases its plasma exposure (AUC) and Cmax8. 
1.2 
Overview of Clinical Studies 
Contrary to our expectations, one clinical study has demonstrated that co-administration of 
single-dose rifampin with 2 mg of fluvastatin results in significant increase in exposure of 
the cholesterol-lowering agent9. However this study was conducted with one tenth to one 


 
 
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fortieth of the common dose of fluvastatin10, and we believe that the effect of rifampin on 
fluvastatin exposure in this study to be due to the low concentration of fluvastatin.   
 
Clinical studies have demonstrated that co-administration of single-dose rifampin with the 
BDDCS Class II drug atorvastatin results in marked increases in concentrations of the 
cholesterol-lowering agent11,12. Similar studies with the BDDCS class III drug 
rosuvastatin and class II drug glyburide showed similar transporter effects which 
increased plasma concentrations of the two drugs when co-administered with a single dose 
of rifampin13,14. These studies have demonstrated the significant effects of hepatic uptake 
transporters on the pharmacokinetics of BDDCS class II and III drugs. It is expected that 
these transporter effects will not be significant for BDDCS class I drugs like fluvastatin.  
 
References 
1. Giacomini, K.M. et al. Membrane transporters in drug development. Nat Rev Drug 
Discov 9, 215-236 (2010). 
2.  Niemi, M. Role of OATP transporters in the disposition of drugs. 
Pharmacogenomics 8, 787-802 (2007).  
3. Kalliokoski, A. & Niemi, M. Impact of OATP transporters on pharmacokinetics. 
Br. J. Pharmacol 158, 693-705 (2009).  
4. Wu, CY. & Benet, L. Pharm Res (2005) 22: 11. https://doi.org/10.1007/s11095-
004-9004-4  
5. Fong CW. Statins in therapy: Understanding their hydrophilicity, lipophilicity, 
binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood 
brain barrier and metabolic stability based on electrostatic molecular orbital 
studies. European Journal of Medicinal Chemistry. 2014;85:661-674. 
6. Benet LZ. The role of BCS (biopharmaceutics classification system) and BDDCS 
(biopharmaceutics drug disposition classification system) in drug development. 
Journal of Pharmaceutical Sciences. 2013;102:34-42. 
7. Xun Zhang, et al. Detection of Statin Cytotoxicity Is Increased in Cells Expressing 
the OATP1B1 Transporter. Toxicol. Sci. 134, 73-82 (2013). 
8. Bergman E, et al. The effect of acute administration of rifampicin and imatinib on 
the enterohepatic transport of rosuvastatin in vivo. Xenobiotica 40, 558-68 (2010). 
9. Takehara I, Yoshikado T, Ishigame K, et al. Comparative Study of the Dose-
Dependence of OATP1B Inhibition by Rifampicin Using Probe Drugs and 
Endogenous Substrates in Healthy Volunteers. Pharmaceutical Research. 
2018;35:1-13. 
10. Lescol [package insert]. (Novartis Pharmaceuticals Corporation, 2017). 
11. Lau Y, et al. Pharmacokinetics of Atorvastatin and its Hydroxy Metabolites in Rats 
and the Effects of Concomitant Rifampicin Single doses: Relevance of First-Pass 


 
 
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Effect from Hepatic Uptake Transporters, and Intestinal and Hepatic Metabolism. 
DMD 34, 1175-1181, (2006). 
12. Lau Y et al. Effect of OATP1B Transporter Inhibition on the Pharmacokinetics of 
Atorvastatin in Healthy Volunteers. Clin Pharm& Therapeutics 81, 194-204, 
(2007). 
13. Wu H, Hristeva N, Chang J, et al. Rosuvastatin Pharmacokinetics in Asian and 
White Subjects Wild Type for Both OATP1B1 and BCRP Under Control and 
Inhibited Conditions. JOURNAL OF PHARMACEUTICAL SCIENCES. 
2017;106:2751-2757. 
14. Zheng H, Huang Y, Frassetto L, Benet L. Elucidating Rifampin's Inducing and 
Inhibiting Effects on Glyburide Pharmacokinetics and Blood Glucose in Healthy 
Volunteers: Unmasking the Differential Effects of Enzyme Induction and 
Transporter Inhibition for a Drug and Its Primary Metabolite. Clinical 
Pharmacology & Therapeutics. 2009;85:78-85. 
 
2 
STUDY RATIONALE 
Characterizing the effect of inhibition of hepatic uptake transporters by rifampin, 
on the  pharmacokinetics  of fluvastatin will advance our understanding of statin 
clinical pharmacology. It will give us a better understanding of the effects of hepatic 
uptake transporters on statin pharmacokinetics, statin drug-drug interaction and will 
serve as a validation check for the BDDCS classification system. 
2.1 
Risk / Benefit Assessment 
There is minimum risk  involved in this study. Only approved dosage of FDA 
approved medications are being used in this study. As outlined by the Data and 
Safety Management Plan for the study all precautions are being considered to 
uphold the safety and best interest of all participants. The subject may stop the study 
at any time for any reason. 
There is no direct benefit for subjects to participate in the study. 
 
3 
STUDY OBJECTIVES 
3.1 Primary Objective 
The primary objective is to determine whether or not inhibition of OATP1B1-
mediated drug transport of fluvastatin will be clinically significant. The study will 
assess if a IV dose of rifampin (to inhibit hepatic uptake transporters) immediately 
prior to oral fluvastatin dosing will have any effect on fluvastatin  total drug exposure. 
 
 
 


 
 
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4 
STUDY DESIGN 
4.1 Study Overview 
The effect of rifampin on the pharmacokinetics of fluvastatin will be studied in healthy 
volunteers in a two-period, randomized, unblinded, crossover clinical trial. On period 1 of 
the study, subjects will be randomized to one of two treatment groups: 
  
(i) one oral dose of fluvastatin (Lescol®) 20mg capsule 
(ii) one oral dose of fluvastatin (Lescol®) 20mg capsule immediately following a 30-min 
intravenous infusion of rifampin 600mg in 10ml Normal Saline. 
  
The two study periods will preferentially be on a Tuesday and Thursday, separated by one 
day of washout. Subjects will be instructed to fast overnight the day before study periods 1 
and 2, and for 3h post-dosing.  In both treatments, venous blood samples (~8ml each) will 
be drawn at 0, 0.33, 0.67, 1,1.5, 2, 2.5, 3, 4, 6, 9, 12h after fluvastatin dosing. Period 2 will 
begin after at least a 1-day washout when subjects will receive the second treatment, 
followed by blood draws at the same time points as after fluvastatin dosing alone. 
  
Period 1 
Period 2 
Group 1 
A 
B 
Group 2 
B 
A 
A= fluvastatin; B =rifampin +fluvastatin  
 
5 
CRITERIA FOR EVALUATION 


 
 
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5.1 
Primary Efficacy Endpoint 
Primary Outcome: The primary outcome will be fluvastatin AUC0-12h and AUC0-∞. 
5.2 
Secondary Efficacy Endpoints 
Secondary outcomes will include fluvastatin  maximum plasma concentration (Cmax) and 
time to Cmax (Tmax) 
5.3 
Safety Evaluations 
Subjects will be monitored on an ongoing basis while involved with the study by study 
personnel. Subjects will be screened with a medical history and physical examination by 
the study physician and have screening hematology, chemistries, liver, renal and 
coagulation laboratories. Subjects must have normal function of all major organs. At study 
completion, subjects will have repeat physical examination and repeat hematology, 
chemistries, liver, renal and coagulation laboratories for safety monitoring. The safety 
evaluations include change in clinical laboratory finding( Creatinine, phosphokinase) and 
also the Incidence of adverse events 
6 
SUBJECT SELECTION 
6.1 
Study Population 
Subjects who meet the inclusion and exclusion criteria will be eligible for participation in 
this study. 
6.2 
Inclusion Criteria 
1. Healthy male or female, ages 18-65 years old, with no current medical conditions 
or active diagnoses as determined by the study doctor based on history, physical 
exam, and laboratory evaluations. 
2. Subjects who take no other medications two weeks prior to the study and during 
the time course of the study including prescription medications, over-the-counter 
medications, dietary supplements, or drugs of abuse. 
3. Subjects able to maintain adequate birth control during the study independent of 
hormonal contraceptive use (use of condoms). 
4. Subjects able to abstain from grapefruit, grapefruit juice, oranges, orange juice, 
caffeinated beverages and/or alcoholic beverages from 7am the day before the 
study to completion of that study day. 
5. Participants determined to have normal liver and kidney function as measured at 
baseline (ALT: ≤ 2x upper level of normal (ULN), AST: ≤ 2x ULN, SCr: ≤ 1.5x 
ULN, T. Bili: 0.1-1.2mg/dL, Albumin: 3.4 – 4.7 mg/dL).  
6. BMI between 18.0 - 30 kg/m2 o Subjects capable of fasting from food and 
beverages at least 8 hours prior to medication dosing. 
7. Be able to read, speak, and understand English. 
8. Subjects capable of providing informed consent and completing the requirements 
of the study. 


 
 
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6.3 
Exclusion Criteria 
1. Subjects with active medical problems  
2.  Subjects on chronic prescription or OTC medication that cannot be stopped 2 weeks 
prior to and during the study.  
3. Subjects incapable of multiple blood draws (HCT < 30mg/dL)  
4. Subjects with a history of rhabdomyolysis  
5. Subjects with a history of drug-related myalgias  
6. Subjects with a history or diagnosis of hemorrhagic tendencies or blood dyscrasias 
7. Subjects with a history of GI bleed or peptic ulcer disease  
8. Subjects who smoke tobacco or have ongoing alcohol or illegal drug use  
9.  Subjects who are pregnant, lactating, or trying to conceive during the study period   
10.  Subjects allergic to fluvastatin or rifampin or any known component of the  
medications  
11. Anyone who in the opinion of the study investigators is unable to do the study 
7 
CONCURRENT MEDICATIONS 
All subjects should not take any other concurrent medication  
7.1 
Allowed Medications and Treatments 
Subjects will take no other medications two weeks prior to the study and 
during the time course of the study including prescription medications, over-the-
counter medications, dietary supplements, or drugs of abuse. 
7.2 
Prohibited Medications and Treatments 
No other medications besides study medications are allowed. 
8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups. 
Once included in the study, patients will be randomized using computer-generated random 
numbers, corresponding to each treatment. This will be performed by someone other than 
the investigator and will ensure equal number of patients in each treatment sequence. 


 
 
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8.2 
Blinding 
The study is not blinded  
8.3 
Formulation of Test and Control Products 
8.3.1 Formulation of Test and Control Product 
Fluvastatin capsule, develop by Norvatis Pharmaceutical Corporation, is an HMG-CoA 
reductase inhibitor to reduce elevated TC, LDL-C, Apo B, and TG, and to increase HDL-
C in adult patients with hypercholesterolemia. Fluvastatin sodium is a white to pale 
yellow, hygroscopic powder soluble in water, ethanol and methanol. LESCOL is supplied 
as capsules containing fluvastatin sodium, equivalent to 20 mg or 40 mg of fluvastatin.  
 
Trade Drug Name  
Lescol  
Generic Drug name  
Fluvastatin sodium  (capsules) 
Investigational Drug Name  
 
Identify the name of the 
manufacturer or source of 
investigational drug/biologic: 
 
 
Novartis Pharmaceuticals Corporation  
Active ingredient  
fluvastatin sodium  
Inactive  ingredient  
calcium carbonate, gelatin, magnesium 
stearate, microcrystalline cellulose, 
pregelatinized starch (corn), red iron 
oxide, sodium bicarbonate, talc, titanium 
dioxide, yellow iron oxide, and other 
ingredients.  
 
PH  
4.5  
 
Rifampin is used only to treat or prevent infections that are proven or strongly 
suspected to be caused by bacteria. Rifampin is a red-brown crystalline powder very 
slightly soluble in water at neutral pH, freely soluble in chloroform, soluble in ethyl 
acetate and in methanol. 
Trade Drug Name: 
RIFADIN IV 
Generic Drug Name: 
RIFAMPIN  


 
 
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Identify the name of the manufacturer or 
source of investigational drug/biologic: 
Sanofi-Aventis 
Active Ingredient  
rifampin 600 mg 
Inactivate Ingredient  
sodium formaldehyde sulfoxylate 10 
mg, and sodium hydroxide to adjust pH 
PH  
7.8–8.8 
 
 
 
8.4 
Supply of Study Medications at the Site 
The investigator will supply study drug to the investigational sites.   
Dosage/Dosage Regimen 
fluvastatin 20 mg by mouth as a 20 mg Lescol® capsule 
30-min intravenous infusion of rifampin (Rifadin®, Sanofi-Aventis, Bridgewater, NJ) 600 
mg in 10 ml sterile normal saline 
 
Dispensing 
The investigator has authority to dispense the drug  
8.4.1 Administration Instructions  
During study period 1 or 2, subjects will take fluvastatin 20 mg by mouth as a 20mg lescol 
capsule. Subjects will also receive 30-min intravenous infusion of rifampin (Rifadin®, 
Sanofi-Aventis, Bridgewater, NJ) 600 mg in 10 ml sterile normal saline at a rate of 20 
mg/min immediately prior to fluvastatin dosing on one of the study periods. All subjects 
will be asked to abstain from caffeinated beverages, alcoholic beverages, all fruit juices, 
oranges, and grapefruits from 7am the day before each study period until the study is 
complete.  
 
Storage 
Study drugs should be stored by the study site at controlled room temperature, 15 to 30ºC 
(59 to 86ºF). If the temperature of study drug storage in the clinic/pharmacy exceeds or 
falls below this range, this should be reported to the Sponsor or designee and captured as a 
deviation. It is important store the medication in original packaging (foil pouch and 
protected from light) at room temperature according to the instructions outlined on the 
Drug Administration Instructions. 


 
 
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8.5 
Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each 
subject will be maintained on an ongoing basis by a member of the study site staff.  The 
number of study drug dispensed and returned by the subject will be recorded on the 
Investigational Drug Accountability Record.  The study monitor will verify these 
documents throughout the course of the study. 
8.6 
Measures of Treatment Compliance 
Investigator will monitor the subjects when they take fluvastatin and when they undergo 
30-min intravenous infusion of rifampin (Rifadin®, Sanofi-Aventis, Bridgewater, NJ) 600 
mg in 10 ml sterile normal saline at a rate of 20 mg/min 
 
9 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject.  If appropriate, assent must also be obtained prior to conducting any 
study-related activities. 
9.1 
Clinical Assessments 
9.1.1 Concomitant Medications 
Only subjects who take no other medications two weeks prior to the study and during the 
time course of the study including prescription medications, over-the-counter medications, 
dietary supplements, or drugs of abuse will be allowed to participate in the trial. 
9.1.2 Demographics  
A descriptive analysis of the demographic characteristics of the study subjects will be 
performed. Demographic characteristics of interest are age, race, height, weight and 
gender will be recorded at  screening. 
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at screening  
9.1.4 Physical Examination 
A complete physical examination will be performed by either the investigator who is a 
physician at screening visit.  Qualified staff (MD) may complete the abbreviated physical 
exam at all other visits.  New abnormal physical exam findings must be documented and 
will be followed by a physician or other qualified staff at the next scheduled visit. 


 
 
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9.1.5 Vital Signs 
Body temperature, blood pressure, pulse and respirations will be performed after resting 
for 5 minutes at the screening  
9.1.6 Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation 
to study drug will be recorded on the case report form (CRF). 
9.2 
Clinical Laboratory Measurements 
9.2.1 Hematology 
Blood will be obtained and sent to the site’s clinical hematology lab for a complete blood 
count (hemoglobin, hematocrit, red blood cell count, white blood cell count, white blood 
cell differential, and platelet count), erythrocyte sedimentation rate (ESR), and serum C-
reactive protein (CRP) determinations for assessment of systemic evidence for infection 
and/or inflammation. 
9.2.2 Blood Chemistry Profile 
Blood will be obtained and sent to each site’s clinical chemistry lab forHgb, HCT, RBC, 
Plt, WBC with differential, Ca++, Na+, K+, Cl-, CO2, glucose, serum creatinine, BUN, 
phosphorus, AST,ALT, alkaline phosphatase, CPK, total bilirubin, albumin, total protein, 
cholesterol, and triglycerides.  
9.2.3 Pregnancy Test 
A urine or serum pregnancy test will be obtained from female subjects who are of 
childbearing age prior to their participation in the study. 
9.2.4 Urinalysis 
Urine will be obtained and sent to each site’s clinical laboratory for determination of (list 
as applicable) color, specific gravity, pH, protein, glucose, ketones, and blood. 
9.3 
Pharmacokinetic Measurements 
Blood for determination of serum concentrations of fluvastatin will be collected  0, 0.33, 
0.67, 1,1.5, 2, 2.5, 3,4, 6, 9, and 12h after fluvastatin dosing.Plasma will be separated and 
stored at –80°C until analysis of drug levels.   
Plasma concentrations of fluvastatin and rifampin in all collected plasma samples will be 
measured via a previously validated tandem liquid chromatography mass spectrometry 
(LC-MS/MS) method. Determined plasma concentrations of fluvastatin will then be 
modeled using pharmacokinetic modeling software to calculate the corresponding AUC, 
oral clearance, and oral volume of distribution of fluvastatin in the treatment groups. 
 
9.4 
Research Laboratory Measurements 


 
 
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Cell Count and Differential blood sample (30mL) for determination of Hgb, HCT, 
RBC, Plt, WBC with differential will be collected during screen. 
 
 
10 EVALUATIONS BY VISIT 
10.1 Screening Visit ( at least one week prior to study period 1)  
1) Written informed consent will be obtained.  
2) A medical history and a physical exam including vital signs (oral temperature, heart 
rate, blood pressure, and respiratory rate), height, and weight will be performed. 
Subjects will also be asked about prescriptions, dietary supplements, and illegal drug 
use. 
 3) Blood (30 ml) and urine tests (Hgb, HCT, RBC, Plt, WBC with differential, Ca++, 
Na+, K+, Cl-, CO2, glucose, serum creatinine, BUN, phosphorus, AST,ALT, alkaline 
phosphatase, CPK, total bilirubin, albumin, total protein, cholesterol, triglycerides, 
urinalysis.   
4) For female subjects, a urine pregnancy test will be required. 
10.2 Study period 1 (Tuesday of the Week): 
1) Admit to Clinical Research Center (CRC) at UCSF - subjects will be admitted 
to the Clinical Research Center (CRC) at UCSF (12th Floor Moffitt Hospital). 
Subjects will be discharged after the 12 hour blood sample. 
2) Urine Pregnancy Test - For female subjects, a urine pregnancy test will be 
performed. 
3) Catheter placement- For the purpose of administering rifampin and drawing 
blood samples, two indwelling peripheral venous catheters will be inserted 
aseptically into the forearm vein by a nurse in the CRC immediately prior to 
medication administration. The rifampin catheter will be removed immediately 
after rifampin administration, the second catheter will be removed after the final 
blood draw. If the catheter malfunctions and needs to be removed prior to the last 
blood draw, a subject may choose to have remaining blood draws via peripheral 
venous needle sticks or have a new catheter placed. 
4) Dose study medications: Subjects will receive one of  the following dose of 
medications:  
a. Dose fluvastatin 20 mg by mouth as a 20 mg Lescol® capsule (t = 0)  
b. Dose rifampin 600mg IV infusion over 30 minutes (t = -30 minutes) followed 
by a dose of fluvastatin 20 mg by mouth as a 20 mg Lescol® capsule (t = 0)  
The order in which subjects receive the above treatments will be randomized via 
random number generator. 
 


 
 
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5) Serial blood sampling- Venous blood samples (8 mL) will be drawn at 0, 0.33, 
0.67, 1,1.5, 2, 2.5, 3,4, 6, 9, and 12h after fluvastatin dosing.Plasma will be separated 
and stored at –80°C until analysis of drug levels.  
 
 
 
10.3 Study Period 2 (Thursday of the week ) 
 
1) Admit to Clinical Research Center (CRC) at UCSF - During each study period, 
subjects will be admitted to the Clinical Research Center (CRC) at UCSF (12th Floor 
Moffitt Hospital). Subjects will be discharged after the 12 hour blood sample.  
2) Urine Pregnancy Test - For female subjects, a urine pregnancy test will be performed. 
3) Catheter placement- For the purpose of administering rifampin and drawing blood 
samples, two indwelling peripheral venous catheter will be inserted aseptically into the 
forearm vein by a nurse in the CRC immediately prior to medication administration. The 
rifampin catheter will be removed immediately after rifampin administration, the second 
catheter will be removed after the final blood draw. If the catheter malfunctions and needs 
to be removed prior to the last blood draw, a subject may choose to have remaining blood 
draws via peripheral venous needle sticks or have a new catheter placed. 
4) Dose study medications: Subjects will receive one of  the following dose of 
medications:  
a. Dose fluvastatin 20 mg by mouth as a 20 mg Lescol® capsule (t = 0)  
b. Dose rifampin 600mg IV infusion over 30 minutes (t = -30 minutes) followed 
by a dose of fluvastatin 20 mg by mouth as a 20 mg Lescol® capsule (t = 0)  
The order in which subjects receive the above treatments will be randomized via 
random number generator. 
 
5) Serial blood sampling- Venous blood samples (8 mL) will be drawn at 0, 0.33, 0.67, 1, 
1.5, 2, 2.5, 3, 4, 6, 9 and 12h after fluvastatin dosing.Plasma will be separated and stored 
at –80°C until analysis of drug levels.  
 
6) Safety Monitoring- At study completion, subjects will have repeat physical 
examination and repeat hematology, chemistries, liver, renal and coagulation laboratories 
for safety monitoring. 
 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 


 
 
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relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 
severity, or frequency in the current Investigator’s Brochure or of greater severity or 
frequency than expected based on the information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF.  Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to study 
drug, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be 
found in the study manual.  If the experience is not covered in the modified criteria, the 
guidelines shown in Table 1 below should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no 
medical intervention or therapy required. The subject may be 
aware of the sign or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required, hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 


 
 
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Definitely 
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or 
expected response pattern to the suspected drug; that is confirmed by stopping 
or reducing the dosage of the drug; and that is not explained by any other 
reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to the suspected 
drug; that is confirmed by stopping or reducing the dosage of the drug; and 
that is unlikely to be explained by the known characteristics of the subject’s 
clinical state or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to that suspected 
drug; but that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the 
study drug. 
11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
● death 
● a life-threatening adverse experience 
● inpatient hospitalization or prolongation of existing hospitalization 
● a persistent or significant disability/incapacity 
● a congenital anomaly/birth defect  
● Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention 
to prevent one of the outcomes listed.  
 
11.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per 
UCSF CHR Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed. 
 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.   


 
 
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12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Discontinuation of Study Drug 
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  
The following is a list of possible reasons for study treatment discontinuation:  
● Subject withdrawal of consent (or assent) 
● Subject is not compliant with study procedures 
● Adverse event that in the opinion of the investigator would be in the best interest of 
the subject to discontinue study treatment 
● Protocol violation requiring discontinuation of study treatment 
● Lost to follow-up 
● Sponsor request for early termination of study 
● Positive pregnancy test (females) 
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation 
visit as soon as possible and then should be encouraged to complete all remaining 
scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents Refer to Section 10 for early termination procedures.  
12.2 Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.  Subjects who withdraw after study period 1 but prior to 
study period 2 should be encouraged to come in for a final visit (and the procedures to be 
followed would include those for their next scheduled visit). 
12.3 
Replacement of Subjects 
Subjects who withdraw from the study treatment will  be replaced.   


 
 
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Subjects who withdraw from the study will  be  replaced.   
 
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigator, or sponsor fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, subject safety and 
primary endpoint criteria.  Protocol violations for this study include, but are not limited to, 
the following: 
● Failure to meet inclusion/exclusion criteria 
● Use of a concomitant medication 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The sponsor will determine if a protocol violation will result in 
withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a 
Sponsor representative and the Investigator. A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files. 
14 DATA SAFETY MONITORING 
The study does not required a Data and Safety Monitoring Board 
15 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.   
15.1 Data Sets Analyzed 
All eligible patients who are randomized into the study will be included in the data 
analysis. 
15.2 Demographic and Baseline Characteristics 
A descriptive analysis of the demographic characteristics of the study subjects will be 
performed. Demographic characteristics of interest are age, race, height, weight and 
gender.   
15.3 Analysis of Primary Endpoint 
AUC0-∞ will be calculated using the trapezoidal rule from time 0 to Clast + Clast/ke. 
Parameters such as maximum plasma concentration (Cmax) and time to Cmax (Tmax) 
will be determined from the observed data. The terminal elimination rate constant (ke) 
will be obtained using linear regression of log transformed concentrations over the 
terminal log-linear decline phase. Oral clearance (CL/F) will be calculated using 
Dose/AUC0-∞. Other estimated pharmacokinetic parameters will be calculated using non-


 
 
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compartmental methods with WinNonlin Professional software (Pharsight, Inc., Mountain 
View, CA). Log-transformed pharmacokinetic parameters will be compared across 
treatments with analysis of variance for repeated measures. Differences will be regarded 
as statistically significant if p< 0.05. Data will be presented as mean values with standard 
deviations. Each subject will serve as his/her own control. Differences in pharmacokinetic 
parameters between treatments will be calculated using student’s paired t-test. Statistical 
calculations will be done using STATA 10.0 (StataCorporation, College Station, TX). 
15.4 Analysis of Secondary Endpoints 
Parameters such as maximum plasma concentration (Cmax) and time to Cmax (Tmax) 
will be determined from the observed data. The terminal elimination rate constant (ke) 
will be obtained using linear regression of log transformed concentrations over the 
terminal log-linear decline phase. Oral clearance (CL/F) will be calculated using 
Dose/AUC0-∞. 
 
15.5 Interim analysis  
There is no scheduled interim analysis, as the trial is short in duration, but serious adverse 
events will be monitored by the committee on an ongoing basis throughout the study. 
 
15.6 Sample Size and Randomization 
Using a paired t-test and prior data, a sample size of n=10 in each group is needed to 
detect a 50% difference in AUC0-12 between the two study regimens with a statistical 
power of 80% (two sided alpha = 0.05) and standard deviation of 50%. Due to the lesser 
effects of rifampin on fluvastatin AUC, the within subject variability can affect the sample 
size. We plan to enroll sample size of 12 subjects to maintain an adequate sample size in 
case of potential attrition.  
Once included in the study, patients will be randomized using computer-generated random 
numbers, corresponding to each treatment. This will be performed by someone other than 
the investigator and will ensure equal number of patients in each treatment sequence. 
16 DATA COLLECTION, RETENTION AND MONITORING 
16.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated with the 
study drug. The investigator will enter data from source documents corresponding to a 
subject’s visit into the protocol-specific electronic Case Report Form (eCRF) when the 
information corresponding to that visit is available.   
The Investigator is responsible for all information collected on subjects enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.  A copy of the CRF will remain at the 
Investigator’s site at the completion of the study. 


 
 
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16.2 Data Management Procedures 
The data will be entered into a validated database.  The Data management group will be 
responsible for data processing, in accordance with procedural documentation.  Database 
lock will occur once quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
16.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis. The 
study database will be updated in accordance with the resolved queries.  All changes to the 
study database will be documented. 
16.4 Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures. 
16.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., 
FDA) inspectors upon request.  A file for each subject must be maintained that includes 
the signed Informed Consent, HIPAA Authorization and Assent Form and copies of all 
source documentation related to that subject.  The Investigator must ensure the reliability 
and availability of source documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years following marketing of 
the investigational product or for two years after centers have been notified that the IND 
has been discontinued.  There may be other circumstances for which the Sponsor is 
required to maintain study records and, therefore, the Sponsor should be contacted prior to 
removing study records for any reason. 
16.6 Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor according to the 
U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).    By signing 
this protocol, the Investigator grants permission to the Sponsor (or designee), and 
appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all 
appropriate study documentation. 


 
 
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16.7 Subject Confidentiality 
Only the investigators listed on this application and research personnel directly involved 
in the study will have access to personal information. All personal and medical data will 
be considered confidential. All subject information will be kept confidential as possible 
under the law. 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be 
kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet.  Clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA.  The Investigator must also comply with all 
applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act 
of 1996, EU Data Protection Directive 95/46/EC). 
17.1 Protocol Amendments 
Any amendment to the protocol will be written by the investigator.  Protocol amendments 
cannot be implemented without prior written IRB/IEC approval except as necessary to 
eliminate immediate safety hazards to patients.  A protocol amendment intended to 
eliminate an apparent immediate hazard to patients may be implemented immediately, 
provided the IRBs are notified within five working days. 
17.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB/IEC in accordance with the standard operating 
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC 
informed as to the progress of the study.  The Investigator will obtain assurance of 
IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the 
study protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated.  The IRB/IECs unconditional approval statement will be 
transmitted by the Investigator prior to the shipment of study supplies to the site.  This 
approval must refer to the study by exact protocol title and number and should identify the 
documents reviewed and the date of review. 


 
 
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Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed. 
17.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to the Sponsor or designee for approval prior to submission to 
the IRB/IEC.  The consent form generated by the Investigator must be acceptable to the 
Sponsor and be approved by the IRB/IEC.  The written consent document will embody the 
elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations. The Investigator will send an 
IRB/IEC-approved copy of the Informed Consent Form to the Sponsor (or designee) for 
the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written 
form and subjects (or their legal representatives) must be given ample opportunity to 
inquire about details of the study.  If appropriate and required by the local IRB/IEC, assent 
from the subject will also be obtained.  If a subject is unable to sign the informed consent 
form (ICF) and the HIPAA authorization, a legal representative may sign for the subject.   
A copy of the signed consent form (and assent) will be given to the subject or legal 
representative of the subject and the original will be maintained with the subject’s records. 
17.4 Publications  
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996.  
17.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 


 
 
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1. Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or 
welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to 
include amendments and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312. 
 
 
 


 
 
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APPENDIX 1.  SCHEDULE OF STUDY VISITS 
 
SCREENING 
VISIT  
(Day/Week/Month 
#)a 
STUDY PERIOD 
1  
(Day/Week/Month 
#)a 
STUDY PERIOD  
2 
(Day/Week/Month 
#)a 
Informed Consent 
X 
 
 
Medical History 
X 
 
 
Complete Physical Exam 
X 
 
 
Abbreviated Physical Exam 
 
X 
X 
Height  
X 
X 
X 
Weight  
X 
X 
X 
Vital Signs  
X 
X 
X 
Pharmacokinetics 
 
X 
 
Chemistry 
X 
 
 
Pregnancy Test (Urine or 
Serum)  
X 
 
 
Hematology 
X 
 
 
ESR 
X 
 
 
C-Reactive Protein 
X 
 
 
Urinalysis 
X 
 
 
Randomization 
X 
 
 
Dispensing or 
Administration of Study 
Drug 
X 
X 
X 
Counting of Returned Study 
Drug 
 
X 
X 
Initiate Subject Diary 
X 
 
 
Concomitant Medication 
Review 
X 
X 
X 
Adverse Experiences 
 
 
 
 
 
 
 
 
APPENDIX 2. DIAGRAM  OF STUDY PLAN  
 


 
 
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The Effect of Rifampin on Pharmacokinetics of 
Fluvastatin in Healthy Volunteers (Non-induced)
Telephone screening to 
determined the eligibility
Sign Consent form enrollment (12 
healthy volunteers for each group)
Admit to CRC at UCSF, 
Pregnancy Test for 
female
Period 1, Group 1: 
fluvastatin 20mg PO 
X1 
Wash out for 1 days 
Period 1, Group 2: 
30-min intravenous infusion of
rifampin 600mg in 10ml
Normal Saline 
+
fluvastatin 20mg PO x 1
Period 2, Group 1: 
30-min intravenous infusion of
rifampin 600mg in 10ml
Normal Saline  
+
fluvastatin 20mg PO x 1
wash out for 1 day 
Period 2, Group 2:
fluvastatin 20mg PO 
x1 
ll patient will
monitored fo
edication rela
SEs  
1 day of Fluvastatin 
Washout   
LC-MS/MS Analysi
PK parameter 
modeling in WinNoli
Serial of the blood 
ple will be performe
at 0, 0.33, 0.67, 1, 
 1.5, 2, 2.5, 3, 
4, 6, 9, 12 
night the night prior 
h treatment and until 
Fluvastatin dosing. A
jects will avoid eatin
pefruit and oranges an
ing alcoholic beverag
affeinated beverages,
efruit juice, and oran
e from 7am before ea
study period  


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LESLIE Z. BENET, PHD 
Clinical Research Protocol 
The Effects of Rifampin on Pharmacokinetics of Fluvastatin in 
hepatically induced Healthy Volunteers 
Protocol Number: 
 
Version Date: 
 
Investigational Product: 
 
IND Number: 
 
Development Phase: 
 
Sponsor: 
Leslie Z. Benet, PhD  
 
Funding Organization: 
 
Principal Investigator: 
Name: Leslie Z. Benet, PhD  
Telephone:(415)476-3853 
 
Fax: (415)476-8887  
E-mail:leslie.benet@ucsf.edu  
Medical Monitor: 
Name: Lynda A. Frassetto 
 
Telephone: (415)476-6143 
 
Fax:(415) 885-7396 
E-mail:Lynda.Frassetto@ucsf.edu 
Coordinating Center: 
If applicable 
 
Approval: 
 
 
Dec 27, 2018 
PI or Sponsor Signature (Name and Title)  
 
Date 
This confidential information about an investigational product is provided for the 
exclusive use of investigators of this product and is subject to recall at any time.  
The information in this document may not be disclosed unless federal or state law or 
regulations require such disclosure.  Subject to the foregoing, this information may 
be disclosed only to those persons involved in the study who have a need to know, 
with the obligation not to further disseminate this information.   


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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my 
duties include ensuring the safety of the study subjects enrolled under my 
supervision and providing with complete and timely information, as outlined in the 
protocol.  It is understood that all information pertaining to the study will be held 
strictly confidential and that this confidentiality requirement applies to all study 
staff at this site. Furthermore, on behalf of the study staff and myself, I agree to 
maintain the procedures required to carry out the study in accordance with accepted 
GCP principles and to abide by the terms of this protocol. 
 
Protocol Number:  Number 
 
Protocol Title:  The Effects of Rifampin on Pharmacokinetics of Fluvastatin in 
hepatically induced Healthy Volunteers  
 
Protocol Date: 12/20/18  
 
 
 
12/27/18 
Investigator Signature  
 
Date 
Leslie Z. Benet, PhD, Professor 
Print Name and Title 
Site # 
 
 
Site Name 
 
Address 
533 Parnassus Ave, U-68 
 
UCSF Box 0912 
 
San Francisco, CA 94143 
 
 
Phone Number 
14154763853 


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TABLE OF CONTENTS 
 
1 
BACKGROUND 
9 
1.1 
Overview of Non-Clinical Studies 
10 
1.2 Overview of Clinical Studies 
10 
2.  STUDY RATIONALE 
12 
2.1 Risk / Benefit Assessment 
13 
3. STUDY OBJECTIVES 
13 
3.1 Primary Objective 
13 
4.  STUDY DESIGN 
13 
4.1  Study Overview 
13 
5. CRITERIA FOR EVALUATION 
14 
5.1 Primary Efficacy Endpoint 
14 
Primary Outcome: The primary outcome will be fluvastatin AUC(0-12h) and 
AUC(0-∞). 
14 
5.2 Secondary Efficacy Endpoints 
14 
5.3 Safety Evaluations 
14 
6. SUBJECT SELECTION 
14 
6.1 Study Population 
14 
6.2 Inclusion Criteria 
15 
6.3 Exclusion Criteria 
15 
7. CONCURRENT MEDICATIONS 
16 
7.1 Allowed Medications and Treatments 
16 
8. STUDY TREATMENTS 
16 
8.1 Method of Assigning Subjects to Treatment Groups 
16 
8.2 Blinding 
16 
8.3 Formulation of Test and Control Products 
16 
Formulation of Test and Control Product 
16 
8.4 Supply of Study Drug at the Site 
18 
Dispensing 
18 
8.41 Administration Instructions 
18 
8.5 Study Drug Accountability 
18 
8.6 Measures of Treatment Compliance 
19 
9. STUDY PROCEDURES AND GUIDELINES 
19 


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9.1 Clinical Assessments: 
19 
10 EVALUATIONS BY VISIT 
21 
10.1 Screening Visit (at least one week prior to study period 1) 
21 
10.2 Study period 1 (Tuesday of the Week): 
21 
10.3 Visit 3 (Thursday of the week ) 
22 
11.1 Adverse Events 
23 
11.2 Serious Adverse Experiences (SAE) 
24 
Serious Adverse Experience Reporting 
24 
12.1 Early Discontinuation of Study Drug 
25 
12.2 Withdrawal of Subjects from the Study 
25 
14. DATA SAFETY MONITORING 
26 
15. STATISTICAL METHODS AND CONSIDERATIONS 
26 
15.1 Data Sets Analyzed 
26 
15.2 Demographic and Baseline Characteristics 
27 
15.3 Analysis of Primary Endpoint 
27 
15.4 Analysis of Secondary Endpoints 
27 
15.6 Sample Size and Randomization 
27 
16. DATA COLLECTION, RETENTION AND MONITORING 
28 
16.1 Data Collection Instruments 
28 
16.2 Data Management Procedures 
28 
16.3 Data Quality Control and Reporting 
28 
16.4 Archival of Data 
28 
16.5 Availability and Retention of Investigational Records 
28 
16.6 Monitoring 
29 
16.7 Subject Confidentiality 
29 
17. ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
29 
17.1 Protocol Amendments 
30 
17.2 Institutional Review Boards and Independent Ethics Committees 
30 
17.3 Informed Consent Form 
30 
17.4 Publications 
31 
17.5 Investigator Responsibilities 
31 
 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
AUC0-∞ 
Area under the concentration versus time curve from time = 0 to 
infinity. 
AUC0-12 
Area under the concentration versus time curve from time = 0 to 
t = 12 hours. 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentration 
CRF 
case report form 
ESR 
erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
intravenous 
PI 
Principal Investigator 
PK 
pharmacokinetic 
SAE 
serious adverse experience 
Tmax 
time to Cmax 


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PROTOCOL SYNOPSIS 
TITLE 
The Effects of Rifampin on Pharmacokinetics of Fluvastatin in in 
hepatically induced Healthy Volunteers  
 
NUMBER OF SITES 
1 
 
 
RATIONALE 
The effect of OATP1B1 transporter inhibition after a rifampin pre-
induction regimen on fluvastatin, a BDDCS class 1 drug, has not been 
studied to date. A preinduction regimen of rifampin followed by a 
single IV infusion of rifampin can be used to evaluate the combined 
effects of enzyme induction and OATP1B1 transporter inhibition on 
fluvastatin disposition. 
 
 
STUDY DESIGN 
This is a two-period, randomized, unblinded, crossover clinical trial. 
 
 
PRIMARY 
OBJECTIVE 
The primary objective is to determine whether or not inhibition of 
OATP1B1-mediated drug transport of fluvastatin will be clinically 
significant when hepatic enzymes are induced. 
 
 
NUMBER OF 
SUBJECTS 
10-12 
 
 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
● Healthy male or female, ages 18-65 years old, with no current 
medical conditions or active diagnoses as determined by the 
study doctor based on history, physical exam, and laboratory 
evaluations.  
● Subjects who take no other medications two weeks prior to the 
study and during the time course of the study including 
prescription medications, over-the-counter medications, 
dietary supplements, or drugs of abuse. 
● Subjects able to maintain adequate birth control during the 
study independent of hormonal contraceptive use (use of 
condoms).  
● Subjects able to abstain from grapefruit, grapefruit juice, 
oranges, orange juice, caffeinated beverages and/or alcoholic 


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beverages from 7am the day before the study to completion of 
that study day.   
● Participants determined to have normal liver and kidney 
function as measured at baseline (ALT: ≤ 2x upper level of 
normal (ULN), AST: ≤ 2x ULN, SCr: ≤ 1.5x ULN, T. Bili: 
0.1-1.2mg/dL, Albumin: 3.4 – 4.7 mg/dL).   
● BMI between 18.0 - 30 kg/m2 o Subjects capable of fasting 
from food and beverages at least 8 hours prior to medication 
dosing.   
● Be able to read, speak, and understand English.   
● Subjects capable of providing informed consent and 
completing the requirements of the study. 
Exclusion Criteria: 
● Subjects with active medical problems  
●  Subjects on chronic prescription or OTC medication that 
cannot be stopped 2 weeks prior to and during the study.  
● Subjects incapable of multiple blood draws (HCT < 30mg/dL)  
● Subjects with a history of rhabdomyolysis  
● Subjects with a history of drug-related myalgias  
● Subjects with a history or diagnosis of hemorrhagic tendencies 
or blood dyscrasias 
● Subjects with a history of GI bleed or peptic ulcer disease  
● Subjects who smoke tobacco or have ongoing alcohol or 
illegal drug use  
●  Subjects who are pregnant, lactating, or trying to conceive 
during the study period   
●  Subjects allergic to fluvastatin or rifampin or any known 
component of the  medications  
● Anyone who in the opinion of the study investigators is unable 
to do the study 
 
 
 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Fluvastatin 20 mg by mouth as a 20 mg Lescol® capsule  
Rifampin 600mg IV infusion over 30 minutes (t = -30 minutes)  
Rifadin 600mg by mouth as two 300mg rifadin capsules 
 
 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Fluvastatin 20 mg by mouth as a 20 mg Lescol® capsule  
 
 


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DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
The time required for this study will include approximately: 5 minutes 
each day taking the rifampin capsule for 6 days, one 2-hour screening 
visit, and two 13 hour stays in the CRC (separated by at least 1 day). 
The total time required is 27 ½ hours over about a 8 day period. 
Additional time maybe required if study is prolonged for any reasons.  
 
 
CONCOMMITANT 
MEDICATIONS 
Allowed: No concomitant medications allowed  
 
Prohibited: subjects will not be allowed to take any other 
medications 
two weeks prior to the study and during the time course of the 
study 
including prescription medications, over-the-counter medications, 
dietary supplements, or drugs of abuse 
 
 
PRIMARY ENDPOINT 
The primary outcome will be fluvastatin AUC0-12h and AUC0-∞ 
(AUC = area under the plasma concentration versus time curve). 
SECONDARY 
ENDPOINTS 
Secondary outcomes will include fluvastatin  maximum plasma 
concentration (Cmax) and time to Cmax (Tmax) . 
 
 
SAFETY 
EVALUATIONS 
Safety evaluation will be determined by the incidence of adverse 
events. Subjects will be monitored on an ongoing basis while involved 
with the study by study personnel. Subjects will be screened with a 
medical history and physical examination by the study physician and 
have screening hematology, chemistries, liver, renal and coagulation 
laboratories. Subjects must have normal function of all major organs. 
At study completion, subjects will have repeat physical examination 
and repeat hematology, chemistries, liver, renal and coagulation 
laboratories for safety monitoring 
PLANNED INTERIM 
ANALYSES  
Serious adverse events will be monitored by the committee on an 
ongoing basis throughout the study. 
 
 
STATISTICS 
Primary Analysis Plan 
AUC0-∞ will be calculated using the trapezoidal rule from time 0 to 
Clast + Clast/ke. Parameters such as maximum plasma concentration 
(Cmax) and time to Cmax (Tmax) will be determined from the 
observed data. The terminal elimination rate constant (ke) will be 
obtained using linear regression of log transformed concentrations 
over the terminal log-linear decline phase. Oral clearance (CL/F) will 


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be calculated using Dose/AUC0-∞. Other estimated pharmacokinetic 
parameters will be calculated using non-compartmental methods with 
WinNonlin Professional software (Pharsight, Inc., Mountain View, 
CA). Log-transformed pharmacokinetic parameters will be compared 
across treatments with analysis of variance for repeated measures. 
Differences will be regarded as statistically significant if p< 0.05. 
Data will be presented as mean values with standard deviations. Each 
subject will serve as his/her own control. Differences in 
pharmacokinetic parameters between treatments will be calculated 
using student’s paired t-test. Statistical calculations will be done using 
STATA 10.0 (StataCorporation, College Station, TX). 
Rationale for Number 
of Subjects 
Using a paired t-test and prior data, a sample size of n=10 in each 
group is needed to detect a 50% difference in AUC(0-12) between the 
two study regimens with a statistical power of 80% (two sided alpha = 
0.05) and standard deviation of 50%. Due to the lesser effects of 
rifampin on fluvastatin AUC, the within subject variability can affect 
the sample size. We plan to enroll sample size of 12 subjects to 
maintain an adequate sample size in case of potential attrition. 
 
1 
BACKGROUND 
 
Membrane transporters located throughout the body play an important role in drug 
absorption, disposition, metabolism, and elimination1.The inhibition of many of 
these transporters has been linked to significant drug-drug interactions1. Located on 
the sinusoidal membrane of hepatocytes, the Organic Anion Transporter 
Polypeptide transporter OATP1B1 is responsible for the uptake of substrates from 
the blood into the liver where they can be metabolized and cleared1-3. When 
OATP1B1-mediated transport is inhibited with known inhibitors such as ritonavir, 
rifampin, or cyclosporine, drug metabolism and elimination into bile are 
diminished, resulting in elevated concentrations of the drug in the blood. Another 
important membrane transporter, Breast Cancer Resistance Protein or BCRP, 
present in the intestinal epithelia and liver, is also important for drug elimination1.If 
BCRP is inhibited, drug concentrations in the liver and blood may also rise.  
 
Statins are commonly prescribed cholesterol-lowering agents whose efficacy and 
safety is closely linked with the function of the BCRP and OATP1B1 transporters1-
3. These drugs must enter the liver to exert their efficacy. Compared to other statins 
like rosuvastatin and pravastatin, fluvastatin is extensively metabolized 4. It has a 


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more hydrophobic profile making it highly permeable through the membranes and 
in theory less dependent on OATP1B1-mediated transport5.  
 
To predict hepatic uptake transporter effects on drug disposition, Wu and Benet 
developed the Biopharmaceutics Drug Disposition Classification System (BDDCS) 
system which categorizes drugs based on extent of metabolism and solubility 
characteristics 6. According to this classification system, the plasma exposure of  
Fluvastatin, a BDDCS class I drug should be minimally influenced by transporter 
effects6.   
1.1 
Overview of Non-Clinical Studies 
Available in vitro data demonstrates that inhibition of OATP1B1 by rifampin 
results in reduced rosuvastatin uptake in Human Embroyonic Kidney (HEK293) 
cells, which implies the drug’s significant dependence on the membrane 
transporter7. Animal studies have also confirmed that rifampin significantly alters 
hepatobiliary transport of rosuvastatin and increases its plasma exposure (AUC) and 
Cmax8. 
 
Similar results to those observed in clinical studies have been observed in in vivo 
and in vitro rat studies where the effects of inhibition of hepatic uptake transporters 
offset the effect of the hepatic enzyme induction for the BDDCS class IV drug 
digoxin9. In this study, hepatic enzyme induction by dexamethasone decreased 
AUC values relative to control, but when hepatic uptake transporters were inhibited 
by rifampin, the AUC values matched those of the control. Unfortunately, a direct 
comparison to the human glyburide trial cannot be made because no analogous 
uninduced, rifampin treatment was conducted in this rat study. Interestingly, similar 
AUC ratios for the induced treatment (1.99(in vitro), 2.15 (in vivo)) were observed, 
which may indicate a similar effect of hepatic uptake transporters in rats and 
humans9.    
 
1.2 Overview of Clinical Studies 
 
Clinical studies have demonstrated that co-administration of single-dose rifampin 
with the BDDCS Class II drug atorvastatin results in marked increases in 
concentrations of the cholesterol-lowering agent10,11. Similar studies with the 
BDDCS class III drug rosuvastatin and class II drug glyburide showed similar 
transporter effects which increased plasma concentrations of the two drugs when 
co-administered with a single IV dose of rifampin12,13. These studies have 
demonstrated the significant effects of hepatic uptake transporters on the 


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pharmacokinetics of BDDCS class II and III drugs. It is expected that these 
transporter effects will not be significant for BDDCS class I drugs like fluvastatin.  
 
Contrary to this expectation, one clinical study has demonstrated that co-
administration of single-dose rifampin with 2 mg of fluvastatin  results in 
significant increase in exposure of the cholesterol-lowering agent14. However this 
study was conducted with one tenth to one fortieth of the common dose of 
fluvastatin15, and we believe that the effect of rifampin on fluvastatin exposure in 
this study to be due to the low concentration of fluvastatin.  
 
Clinical studies have demonstrated that the effects of hepatic OATP1B1 
transporters on the BDDCS Class II drug glyburide are the same under induced and 
non-induced conditions13.  Concomitant rifampin treatment under the the induced 
condition yielded a glyburide AUCIVrif:AUCnoIVrif ratio of 2.06, which is 
comparable to the AUC ratio of 2.18 under the non-induced condition, despite the 
lower absolute AUC values in the CYP enzyme induced cohort13. For fluvastatin (at 
clinical doses), it is expected that this AUCIVrif:AUCnoIVrif  will be closer to 1, and it 
is desired to compare these ratios between induced and uninduced states as has 
previously been done for glyburide. 
 
references  
 
1. Giacomini, K.M. et al. Membrane transporters in drug development. Nat 
Rev Drug Discov 9, 215-236 (2010). 
2. Niemi, M. Role of OATP transporters in the disposition of drugs. 
Pharmacogenomics 8, 787-802 (2007). 
3. Kalliokoski, A. & Niemi, M. Impact of OATP transporters on 
pharmacokinetics. Br. J. Pharmacol 158, 693-705 (2009). 
4. Wu, CY. & Benet, L. Pharm Res (2005) 22: 11. 
https://doi.org/10.1007/s11095-004-9004-4 
5. Fong CW. Statins in therapy: Understanding their hydrophilicity, 
lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability 
to cross the blood brain barrier and metabolic stability based on electrostatic 


Protocol Number or PI name 
Confidential 
 
 
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Page 12 of 35 
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molecular orbital studies. European Journal of Medicinal Chemistry. 
2014;85:661-674. 
6. Benet LZ. The role of BCS (biopharmaceutics classification system) and 
BDDCS (biopharmaceutics drug disposition classification system) in drug 
development. Journal of Pharmaceutical Sciences. 2013;102:34-42. 
7. Xun Zhang, et al. Detection of Statin Cytotoxicity Is Increased in Cells 
Expressing the OATP1B1 Transporter. Toxicol. Sci. 134, 73-82 (2013).  
8. Bergman E, et al. The effect of acute administration of rifampicin and 
imatinib on the enterohepatic transport of rosuvastatin in vivo. Xenobiotica 
40, 558-68 (2010). 
9. Lam JL, Shugarts SB, Okochi H, Benet LZ. Elucidating the Effect of Final-
Day Dosing of Rifampin in Induction Studies on Hepatic Drug Disposition 
and Metabolism. Journal of Pharmacology and Experimental Therapeutics. 
2006;319:864-870. 
10. Lau Y, et al. Pharmacokinetics of Atorvastatin and its Hydroxy Metabolites 
in Rats and the Effects of Concomitant Rifampicin Single doses: Relevance 
of First-Pass Effect from Hepatic Uptake Transporters, and Intestinal and 
Hepatic Metabolism. DMD 34, 1175-1181, (2006). 
11. Lau Y et al. Effect of OATP1B Transporter Inhibition on the 
Pharmacokinetics of Atorvastatin in Healthy Volunteers. Clin Pharm& 
Therapeutics 81, 194-204, (2007). 
12. Wu H, Hristeva N, Chang J, et al. Rosuvastatin Pharmacokinetics in Asian 
and White Subjects Wild Type for Both OATP1B1 and BCRP Under 
Control and Inhibited Conditions. JOURNAL OF PHARMACEUTICAL 
SCIENCES. 2017;106:2751-2757. 
13. Zheng H, Huang Y, Frassetto L, Benet L. Elucidating Rifampin's Inducing 
and Inhibiting Effects on Glyburide Pharmacokinetics and Blood Glucose in 
Healthy Volunteers: Unmasking the Differential Effects of Enzyme 
Induction and Transporter Inhibition for a Drug and Its Primary Metabolite. 
Clinical Pharmacology & Therapeutics. 2009;85:78-85. 
14. Takehara I, Yoshikado T, Ishigame K, et al. Comparative Study of the 
Dose-Dependence of OATP1B Inhibition by Rifampicin Using Probe Drugs 
and Endogenous Substrates in Healthy Volunteers. Pharmaceutical 
Research. 2018;35:1-13. 
15. Lescol [package insert]. (Novartis Pharmaceuticals Corporation, 2017). 
2.  STUDY RATIONALE 
To our knowledge, the effect of OATP1B1 transporter inhibition after a rifampin 
pre-induction regimen on fluvastatin, a BDDCS class 1 drug, has not been studied 
to date. A preinduction regimen of rifampin followed by a single IV infusion of 


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rifampin can be used to evaluate the combined effects of enzyme induction and 
OATP1B1 transporter inhibition on fluvastatin disposition. 
 
 
2.1 Risk / Benefit Assessment 
There is minimum risk  involved in this study. Only approved doses of FDA 
approved medications are being used in this study. As outlined by the Data and 
Safety Management Plan for the study all precautions are being considered to 
uphold the safety and best interest of all participants. The subject may stop the 
study at any time for any reason. 
There is no direct benefit for subjects to participate in the study. . 
3. STUDY OBJECTIVES 
3.1 Primary Objective 
The primary objective is to determine whether or not inhibition of OATP1B1-
mediated drug transport of fluvastatin will be clinically significant when hepatic 
enzymes are induced.  
4.  STUDY DESIGN 
4.1  Study Overview 
The effect of rifampin on the pharmacokinetics of fluvastatin under a hepatic 
enzyme induced state will be studied in healthy volunteers in a two-period, 
randomized, unblinded, crossover clinical trial. For the first 5 days of the trial, the 
patients will be pretreated with 600mg oral  rifampin (two 300mg rifadin capsule) 
once daily to induce hepatic enzymes (and transporters).  For study period 1, 
subjects will be randomized to one of two treatment groups:  
 
(i) one oral dose of fluvastatin (Lescol®) 20mg capsule   
(ii) one oral dose of fluvastatin (Lescol®) 20mg capsule immediately following a 
30-min intravenous infusion of rifampin 600mg in 10ml Normal Saline 
 
The two study periods will ideally be on a Tuesday and Thursday, separated by one 
day of fluvastatin washout.The oral food intake will be standardized and subjects 
will be instructed to fast overnight the day before study period 1 and period 2, and 
for 3h post-dosing. In both treatments, venous blood samples (8ml each) will be 
drawn at 0, 0.33, 0.67, 1,1.5, 2, 2.5, 3, 4, 6, 9, 12h after fluvastatin dosing. During 
the 1 day of fluvastatin washout, patients will continue pretreatment with one 
600mg dose of oral rifampin. Period 2 will begin after 1 day of fluvastatin wash 
out, when subjects will receive the second treatment, followed by blood draws at 
the same time points after fluvastatin dosing.  If study period two does not follow 
one day after study period one, it will most likely be conducted on Tuesday or 


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Thursday of the following week. In this case, the subjects would be maintained in a 
state of induction of hepatic enzymes by the same preinduction regimen with 600 
mg of oral rifampin for 5 days before study period 2. 
 
 
Period 1 
Period 2 
Group 1 
A 
B 
Group 2 
B 
A 
A= fluvastatin; B =rifampin +fluvastatin 
 
5. CRITERIA FOR EVALUATION 
5.1 Primary Efficacy Endpoint 
Primary Outcome: The primary outcome will be fluvastatin AUC(0-12h) and AUC(0-
∞). 
5.2 Secondary Efficacy Endpoints 
Secondary outcomes will include fluvastatin  maximum plasma concentration 
(Cmax) and time to Cmax (Tmax) 
5.3 Safety Evaluations 
Subjects will be monitored on an ongoing basis while involved with the study by 
study personnel. Subjects will be screened with a medical history and physical 
examination by the study physician and have screening hematology, chemistries, 
liver, renal and coagulation laboratories. Subjects must have normal function of all 
major organs. At study completion, subjects will have repeat physical examination 
and repeat hematology, chemistries, liver, renal and coagulation laboratories for 
safety monitoring. The safety evaluations include change in clinical laboratory 
finding(Creatinine, phosphokinase) and also the Incidence of adverse events 
 
6. SUBJECT SELECTION 
6.1 Study Population 
Subjects who meet the inclusion and exclusion criteria will be eligible for 
participation in this study.   


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6.2 Inclusion Criteria 
1. Healthy male or female, ages 18-65 years old, with no current medical 
conditions or active diagnoses as determined by the study doctor based on 
history, physical exam, and laboratory evaluations. 
2.  Subjects who take no other medications two weeks prior to the study and 
during the time course of the study including prescription medications, over-
the-counter medications, dietary supplements, or drugs of abuse. 
3. Subjects able to maintain adequate birth control during the study 
independent of hormonal contraceptive use (use of condoms). 
4. Subjects able to abstain from grapefruit, grapefruit juice, oranges, orange 
juice, caffeinated beverages and/or alcoholic beverages from 7am the day 
before the study to completion of that study day.  
5. Participants determined to have normal liver and kidney function as 
measured at baseline (ALT: ≤ 2x upper level of normal (ULN), AST: ≤ 2x 
ULN, SCr: ≤ 1.5x ULN, T. Bili: 0.1-1.2mg/dL, Albumin: 3.4 – 4.7 mg/dL).  
6. BMI between 18.0 - 30 kg/m2 o Subjects capable of fasting from food and 
beverages at least 8 hours prior to medication dosing. 
 
7. Be able to read, speak, and understand English.  
8. Subjects capable of providing informed consent and completing the 
requirements of the study. 
6.3 Exclusion Criteria 
1. Subjects with active medical problems  
2.  Subjects on chronic prescription or OTC medication that cannot be stopped 
2 weeks prior to and during the study.  
3. Subjects incapable of multiple blood draws (HCT < 30mg/dL)  
4. Subjects with a history of rhabdomyolysis  
5. Subjects with a history of drug-related myalgias  
6. Subjects with a history or diagnosis of hemorrhagic tendencies or blood 
dyscrasias 
7. Subjects with a history of GI bleed or peptic ulcer disease  
8. Subjects who smoke tobacco or have ongoing alcohol or illegal drug use  
9.  Subjects who are pregnant, lactating, or trying to conceive during the study 
period   
10.  Subjects allergic to fluvastatin or rifampin or any known component of the  
medications  
11. Anyone who in the opinion of the study investigators is unable to do the 
study 
 
 
 


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7. CONCURRENT MEDICATIONS 
All subjects should not take any other concurrent medication  
7.1 Allowed Medications and Treatments 
Subjects will take no other medications two weeks prior to the study and during 
the time course of the study including prescription medications, over-the-
counter medications, dietary supplements, or drugs of abuse. 
7.2 Prohibited Medications and Treatments 
No other medications besides study medications are allowed. 
8. STUDY TREATMENTS 
8.1 Method of Assigning Subjects to Treatment Groups 
Once included in the study, patients will be randomized using computer-generated 
random numbers, corresponding to each treatment. This will be performed by 
someone other than the investigator and will ensure equal number of patients in 
each treatment sequence. 
8.2 Blinding 
The study is not blinded  
8.3 Formulation of Test and Control Products 
Formulation of Test and Control Product 
Fluvastatin sodium is a white to pale yellow, hygroscopic powder soluble in water, 
ethanol and methanol. LESCOL is supplied as capsules containing fluvastatin 
sodium, equivalent to 20 mg or 40 mg of fluvastatin.  
 
Trade Drug Name  
Lescol  
Generic Drug name  
Fluvastatin sodium  (capsules) 
Investigational Drug Name  
 
Identify the name of the 
manufacturer or source of 
investigational drug/biologic: 
 
 
Novartis Pharmaceuticals 
Corporation  
Active ingredient  
fluvastatin sodium  
Inactive  ingredient  
calcium carbonate, gelatin, 


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magnesium stearate, microcrystalline 
cellulose, pregelatinized starch 
(corn), red iron oxide, sodium 
bicarbonate, talc, titanium dioxide, 
yellow iron oxide, and other 
ingredients.  
 
PH  
4.5  
 
Rifampin is used only to treat or prevent infections that are proven or strongly 
suspected to be caused by bacteria. Rifampin is a red-brown crystalline powder 
very slightly soluble in water at neutral pH, freely soluble in chloroform, 
soluble in ethyl acetate and in methanol. 
Trade Drug Name: 
RIFADIN IV 
Generic Drug Name: 
RIFAMPIN  
Identify the name of the 
manufacturer or source of 
investigational drug/biologic: 
Sanofi-Aventis 
Active Ingredient  
rifampin 600 mg 
Inactivate Ingredient  
sodium formaldehyde sulfoxylate 10 
mg, and sodium hydroxide to adjust 
pH 
PH  
7.8–8.8 
 
 
Trade Drug Name: 
RIFADIN capsules 
Generic Drug Name: 
RIFAMPIN  
Identify the name of the 
manufacturer or source of 
investigational drug/biologic: 
Sanofi-Aventis 
Active Ingredient  
rifampin 300 mg 
Inactivate Ingredient  
 corn starch, D&C Red No. 28, 
FD&C Blue No. 1, FD&C Red No. 
40, gelatin, magnesium stearate, and 


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titanium dioxide. 
PH  
7.8–8.8 
8.4 Supply of Study Drug at the Site 
The Sponsor (or designee) will supplies Study Drug to the investigational sites 
through hospital pharmacy.   
Dosage/Dosage Regimen 
● fluvastatin 20 mg by mouth as a 20 mg Lescol® capsule 
● 30-min intravenous infusion of rifampin (Rifadin®, Sanofi-Aventis, 
Bridgewater, NJ) 600 mg in 10 ml sterile normal saline 
● rifampin 600 mg oral by mouth as two 300mg rifadin capsules for 5 days in 
the morning  
Dispensing 
The investigator has authority to dispense the drug  
8.41 Administration Instructions  
Patient will take two 300 mg rifampin capsules by mouth for the 5 days  prior to the 
study period 1 and another two 300 mg  rifampin capsules during fluvastatin 
washout day (between study periods 1 and 2). During study periods 1 and 2, 
subjects will take fluvastatin 20 mg by mouth as a 20mg lescol capsule. Subjects 
will also receive 30-min intravenous infusion of rifampin (Rifadin®, Sanofi-
Aventis, Bridgewater, NJ) 600 mg in 10 ml sterile normal saline at a rate of 20 
mg/min, administered immediately prior to oral fluvastatin dosing on one of the 
study periods. All subjects will be asked to abstain from caffeinated beverages, 
alcoholic beverages, all fruit juices, oranges, and grapefruits from 7am the day 
before each study period until the study is complete 
 
8.5 Supply of Study Drug at the Site 
The investigator will supply study drug to the investigational sites. 
 
Storage 
Study drugs should be stored by the study site at controlled room temperature, 15 to 
30ºC (59 to 86ºF). If the temperature of study drug storage in the clinic/pharmacy 
exceeds or falls below this range, this should be reported to the Sponsor or designee 
and captured as a deviation. It is important store the medication in original 
packaging (foil pouch and protected from light) at room temperature.  
8.5 Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for 
each subject will be maintained on an ongoing basis by a member of the study site 


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staff.  The number of study drugs dispensed and returned by the subject will be 
recorded on the Investigational Drug Accountability Record.  The study monitor 
will verify these documents throughout the course of the study. 
8.6 Measures of Treatment Compliance 
Subject’s daily rifampin dose will be verified by online video chat every morning 
during the 5 days prior to study, and on the one day washout period.   
During study periods 1 and 2, the investigator will monitor the subjects when they 
take fluvastatin and when they undergo the 30-min intravenous infusion of rifampin 
(Rifadin®, Sanofi-Aventis, Bridgewater, NJ) 600 mg in 10 ml sterile normal saline 
at a rate of 20 mg/min. 
 
9. STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed 
for the duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the 
Health Insurance Portability and Accountability Act (HIPAA) authorization must 
be signed and dated by the subject.  If appropriate, consent must also be obtained 
prior to conducting any study-related activities. 
9.1 Clinical Assessments: 
Concomitant Medications 
Only subjects who take no other medications two weeks prior to the study and 
during the time course of the study including prescription medications, over-
the-counter medications, dietary supplements, or drugs of abuse will be 
allowed to participate in the trial. 
 
Demographics  
A descriptive analysis of the demographic characteristics of the study subjects 
will be performed. Demographic characteristics of interest are age, race, 
height, weight and gender will be recorded at screening. 
 
Medical History  
Relevant medical history, including history of current disease, other pertinent 
respiratory history, and information regarding underlying diseases will be 
recorded at screening  
 
Physical Examination 
A complete physical examination will be performed by either the investigator 
who is a physician at screening visit.  Qualified staff (MD) may complete the 


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abbreviated physical exam at all other visits.  New abnormal physical exam 
findings must be documented and will be followed by a physician or other 
qualified staff at the next scheduled visit. 
 
Vital Signs 
Body temperature, blood pressure, pulse and respirations will be performed 
after resting for 5 minutes at the screening. 
  
Adverse Events 
Information regarding occurrence of adverse events will be captured 
throughout the study. Duration (start and stop dates and times), 
severity/grade, outcome, treatment and relation to study drug will be recorded 
on the case report form (CRF). 
 
9.2 Clinical Laboratory Measurements 
 
Hematology 
Blood will be obtained and sent to each site’s clinical hematology lab for a 
complete blood count (hemoglobin, hematocrit, red blood cell count, white 
blood cell count, white blood cell differential, and platelet count), erythrocyte 
sedimentation rate (ESR), and serum C-reactive protein (CRP) determinations 
for assessment of systemic evidence for infection and/or inflammation. 
 
Blood Chemistry Profile 
Blood will be obtained and sent to  site’s clinical chemistry lab forHgb, HCT, 
RBC, Plt, WBC with differential, Ca++, Na+, K+, Cl-, CO2, glucose, serum 
creatinine, BUN, phosphorus, AST,ALT, alkaline phosphatase, CPK, total 
bilirubin, albumin, total protein, cholesterol, and triglycerides. 
  
Pregnancy Test 
A urine or serum pregnancy test will be obtained from female subjects who 
are of childbearing age prior to their participation in the study. 
 
Urinalysis 
Urine will be obtained and sent to each site’s clinical laboratory for 
determination of (list as applicable) color, specific gravity, pH, protein, 
glucose, ketones, and blood. 
 
9.3 Pharmacokinetic Measurements 
Blood for determination of serum concentrations of fluvastatin will be       collected  
0, 0.33, 0.67, 1,1.5, 2, 2.5, 3,4, 6, 9, and 12h after fluvastatin dosing.Plasma will be 
separated and stored at –80°C until analysis of drug levels.   


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Plasma concentrations of fluvastatin and rifampin in all collected plasma samples 
will be measured via a previously validated tandem liquid chromatography mass 
spectrometry (LC-MS/MS) method. Determined plasma concentrations of 
fluvastatin will then be modeled using pharmacokinetic modeling software to 
calculate the corresponding AUC, oral clearance, and oral volume of distribution of 
fluvastatin in the treatment groups. 
 
9.4 Research Laboratory Measurements 
Cell Count and Differential blood sample (30mL) for determination of Hgb, HCT, 
RBC, Plt, WBC with differential will be collected during the screening visit. 
10 EVALUATIONS BY VISIT 
10.1 Screening Visit (at least one week prior to study period 1)  
1. Written informed consent will be obtained.  
2. A medical history and a physical exam including vital signs (oral 
temperature, heart rate, blood pressure, and respiratory rate), height, and 
weight will be performed. Subjects will also be asked about prescriptions, 
dietary supplements, and illegal drug use. 
3. Blood (30 ml) and urine tests (Hgb, HCT, RBC, Plt, WBC with differential, 
Ca++, Na+, K+, Cl-, CO2, glucose, serum creatinine, BUN, phosphorus, 
AST,ALT, alkaline phosphatase, CPK, total bilirubin, albumin, total protein, 
cholesterol, triglycerides, urinalysis.  
4. For female subjects, a urine pregnancy test will be obtained.  
10.2 Study period 1 (Tuesday of the Week): 
1. For female subjects, a urine pregnancy test will be performed. 
2. For the purpose of administering rifampin and drawing blood samples, two 
indwelling peripheral venous catheters will be inserted aseptically into the 
forearm vein by a nurse in the CRC immediately prior to medication 
administration. The rifampin catheter will be removed immediately after 
rifampin administration, the second catheter will be removed after the final 
blood draw. If the catheter malfunctions and needs to be removed prior to 
the last blood draw, a subject may choose to have remaining blood draws 
via peripheral venous needle sticks or have a new catheter placed. 
3. Dose study medications- Subjects will receive the pre-treatment dose two 
300mg Rifampin Capsules as 300mg Rifadin® caspsules for the 5 days 
prior to the study period 1. Subjects will receive one of  the following dose 
of medications:  
a. Dose fluvastatin 20 mg by mouth as a 20 mg Lescol® capsule  
b. Dose rifampin 600mg IV infusion over 30 minutes (t = -30 minutes)    
followed by a dose fluvastatin 20 mg by mouth as a 20 mg Lescol® capsule  
(t = 0 minutes) 
The order in which subjects receive the above treatments will be 
randomized via random number generator. 


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4. Serial blood sampling- Venous blood samples (8 mL) will be drawn at 0, 
0.33, 0.67, 1,1.5, 2, 2.5, 3,4, 6, 9, and 12h after fluvastatin dosing.Plasma 
will be separated and stored at –80°C until analysis of drug levels.   
10.3 Visit 3 (Thursday of the week ) 
1.  Admit to Clinical Research Center (CRC) at UCSF - 
During each study period, subjects will be admitted to the Clinical Research 
Center (CRC) at UCSF (12th Floor Moffitt Hospital). Subjects will be 
discharged after the 12 hour blood sample. 
 
2. Urine Pregnancy Test - For female subjects, a urine pregnancy test will 
be performed. 
 
3. Catheter placement- For the purpose of administering rifampin and 
drawing blood samples, two indwelling peripheral venous catheter will be 
inserted aseptically into the forearm vein by a nurse in the CRC immediately 
prior to medication administration. The rifampin catheter will be removed 
immediately after rifampin administration, the second catheter will be 
removed after the final blood draw. If the catheter malfunctions and needs to 
be removed prior to the last blood draw, a subject may choose to have 
remaining blood draws via peripheral venous needle sticks or have a new 
catheter placed. 
 
4. Dose study medications- Subjects will receive the pre-treatment dose two 
300mg Rifampin Capsules as 300mg Rifadin® caspsules during one day 
washout of fluvastatin. Subjects will receive one of  the following dose of 
medications:  
a. Dose fluvastatin 20 mg by mouth as a 20 mg Lescol® capsule  
b. Dose rifampin 600mg IV infusion over 30 minutes (t = -30 minutes)    
followed by a dose fluvastatin 20 mg by mouth as a 20 mg Lescol® capsule  
(t = 0 minutes) 
The order in which subjects receive the above treatments will be randomized 
via random number generators. 
 
5. Serial blood sampling- Venous blood samples (8 mL) will be drawn at 0, 
0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 9 and 12h after fluvastatin dosing.Plasma 
will be separated and stored at –80°C until analysis of drug levels. 
  
6. Safety Monitoring- At study completion, subjects will have repeat 
physical examination and repeat hematology, chemistries, liver, renal and 
coagulation laboratories for safety monitoring. 
 
11. ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 


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11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical 
investigation of a patient administered a pharmaceutical product and that does not 
necessarily have a causal relationship with the treatment.  An AE is therefore any 
unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom or disease temporally associated with the administration of an 
investigational product, whether or not related to that investigational product.  An 
unexpected AE is one of a type not identified in nature, severity, or frequency in the 
current Investigator’s Brochure or of greater severity or frequency than expected 
based on the information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of 
AEs during each subject visit and record the information in the site’s source 
documents.  Adverse events will be recorded in the patient CRF.  Adverse events 
will be described by duration (start and stop dates and times), severity, outcome, 
treatment and relation to study drug, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria 
can be found in the study manual.  If the experience is not covered in the modified 
criteria, the guidelines shown in Table 1 below should be used to grade severity.  It 
should be pointed out that the term “severe” is a measure of intensity and that a 
severe AE is not necessarily serious. 
 
 
 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no 
medical intervention or therapy required. The subject may be 
aware of the sign or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required, hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 


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AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following 
the guidelines in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or 
expected response pattern to the suspected drug; that is confirmed by stopping 
or reducing the dosage of the drug; and that is not explained by any other 
reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to the suspected 
drug; that is confirmed by stopping or reducing the dosage of the drug; and 
that is unlikely to be explained by the known characteristics of the subject’s 
clinical state or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to that suspected 
drug; but that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the 
study drug. 
 
11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the 
following outcomes: 
● death 
● a life-threatening adverse experience 
● inpatient hospitalization or prolongation of existing hospitalization 
● a persistent or significant disability/incapacity 
● a congenital anomaly/birth defect  
● Other important medical events may also be considered an SAE when, 
based on appropriate medical judgment, they jeopardize the subject or 
require intervention to prevent one of the outcomes listed.  
 
Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) 
per UCSF CHR Guidelines.  The collection period for all SAEs will begin after 


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informed consent is obtained and end after procedures for the final study visit have 
been completed. 
 
In accordance with the standard operating procedures and policies of the local 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC), the site 
investigator will report SAEs to the IRB/IEC.   
   
12. DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to 
continue.  The following is a list of possible reasons for study treatment 
discontinuation: 
● Subject withdrawal of consent (or assent) 
● Subject is not compliant with study procedures 
● Adverse event that in the opinion of the investigator would be in the best 
interest of the subject to discontinue study treatment 
● Protocol violation requiring discontinuation of study treatment 
● Lost to follow-up 
● Sponsor request for early termination of study 
● Positive pregnancy test (females) 
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom 
has resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early 
discontinuation visit as soon as possible and then should be encouraged to complete 
all remaining scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, 
specified or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for 
subject withdrawals.  The reason for the subject’s withdrawal from the study will be 
specified in the subject’s source documents Refer to Section 10 for early 
termination procedures. 
 12.2 Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to 
continue.   


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All subjects are free to withdraw from participation at any time, for any reason, 
specified or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for 
subject withdrawals.  The reason for the subject’s withdrawal from the study will be 
specified in the subject’s source documents.  Subjects who withdraw after study 
period 1 but prior to study period 2 should be encouraged to come in for a final visit 
(and the procedures to be followed would include those for their next scheduled 
visit).   
12.3 Replacement of Subjects 
Subjects who withdraw from the study treatment will be replaced.   
Subjects who withdraw from the study will be replaced.  
 
13. PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigator, or sponsor fails to 
adhere to significant protocol requirements affecting the inclusion, exclusion, 
subject safety and primary endpoint criteria.  Protocol violations for this study 
include, but are not limited to, the following: 
Failure to meet inclusion/exclusion criteria 
Use of a concomitant medication 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The sponsor will determine if a protocol violation will result in 
withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a 
Protocol Violation Form detailing the violation will be generated. This form will be 
signed by a Sponsor representative and the Investigator. A copy of the form will be 
filed in the site’s regulatory binder and in the Sponsor’s files. 
14. DATA SAFETY MONITORING 
The study does not required a Data and Safety Monitoring Board 
15. STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan 
(SAP) will be written describing all analyses that will be performed.  The SAP will 
contain any modifications to the analysis plan described below.   
15.1 Data Sets Analyzed 
All eligible patients who are randomized into the study will be included in the data 
analysis. 


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15.2 Demographic and Baseline Characteristics 
A descriptive analysis of the demographic characteristics of the study subjects will 
be performed. Demographic characteristics of interest are age, race, height, weight 
and gender.   
15.3 Analysis of Primary Endpoint 
AUC0-∞ will be calculated using the trapezoidal rule from time 0 to Clast + 
Clast/ke. Log-transformed pharmacokinetic parameters will be compared across 
treatments with analysis of variance for repeated measures. Differences will be 
regarded as statistically significant if p< 0.05. Data will be presented as mean 
values with standard deviations. Each subject will serve as his/her own control. 
Differences in pharmacokinetic parameters between treatments will be calculated 
using student’s paired t-test. Statistical calculations will be done using STATA 10.0 
(StataCorporation, College Station, TX). 
15.4 Analysis of Secondary Endpoints 
Parameters such as maximum plasma concentration (Cmax) and time to Cmax 
(Tmax) will be determined from the observed data. The terminal elimination rate 
constant (ke) will be obtained using linear regression of log transformed 
concentrations over the terminal log-linear decline phase. Oral clearance (CL/F) 
will be calculated using Dose/AUC0-∞. Other estimated pharmacokinetic 
parameters will be calculated using non-compartmental methods with WinNonlin 
Professional software (Pharsight, Inc., Mountain View, CA). 
 
15.5 Interim analysis  
There is no scheduled interim analysis, as the trial is short in duration, but serious 
adverse events will be monitored by the committee on an ongoing basis throughout 
the study. 
15.6 Sample Size and Randomization 
Using a paired t-test and prior data, a sample size of n=10 in each group is needed 
to detect a 50% difference in AUC0-12 between the two study regimens with a 
statistical power of 80% (two sided alpha = 0.05) and standard deviation of 50%. 
Due to the lesser effects of rifampin on fluvastatin AUC, the within subject 
variability can affect the sample size. We plan to enroll sample size of 12 subjects 
to maintain an adequate sample size in case of potential attrition.  
Once included in the study, patients will be randomized using computer-generated 
random numbers, corresponding to each treatment. This will be performed by 
someone other than the investigator and will ensure equal number of patients in 
each treatment sequence. 


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16. DATA COLLECTION, RETENTION AND MONITORING 
16.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated 
with the study drug. The investigator will enter data from source documents 
corresponding to a subject’s visit into the protocol-specific electronic Case Report 
Form (eCRF) when the information corresponding to that visit is available.   
The Investigator is responsible for all information collected on subjects enrolled in 
this study.  All data collected during the course of this study must be reviewed and 
verified for completeness and accuracy by the Investigator.  A copy of the CRF will 
remain at the Investigator’s site at the completion of the study. 
16.2 Data Management Procedures 
The data will be entered into a validated database.  The Data Management group 
will be responsible for data processing, in accordance with procedural 
documentation.  Database lock will occur once quality assurance procedures have 
been completed. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data 
for clinical trials. 
16.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular 
basis. The study database will be updated in accordance with the resolved queries.  
All changes to the study database will be documented. 
16.4 Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files 
will be maintained.  Databases are backed up by the database administrator in 
conjunction with any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final 
reports), data for analysis is locked and cleaned per established procedures. 
16.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency 
(e.g., FDA) inspectors upon request.  A file for each subject must be maintained 
that includes the signed Informed Consent, HIPAA Authorization and Assent Form 
and copies of all source documentation related to that subject.  The Investigator 


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must ensure the reliability and availability of source documents from which the 
information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, 
Study File Notebook, etc.) must be kept secured for a period of two years following 
marketing of the investigational product or for two years after centers have been 
notified that the IND has been discontinued.  There may be other circumstances for 
which the Sponsor is required to maintain study records and, therefore, the Sponsor 
should be contacted prior to removing study records for any reason. 
16.6 Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor according to 
the U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).    
By signing this protocol, the Investigator grants permission to the Sponsor (or 
designee), and appropriate regulatory authorities to conduct on-site monitoring 
and/or auditing of all appropriate study documentation. 
16.7 Subject Confidentiality 
Only the investigators listed on this application and research personnel directly 
involved in the study will have access to personal information. All personal and 
medical data will be considered confidential. All subject information will be kept 
confidential as possible under the law. 
17. ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and 
other records will be identified by a coded number and initials only.  All study 
records will be kept in a locked file cabinet and code sheets linking a patient’s name 
to a patient identification number will be stored separately in another locked file 
cabinet.  Clinical information will not be released without written permission of the 
subject, except as necessary for monitoring by the FDA.  The Investigator must also 
comply with all applicable privacy regulations (e.g., Health Insurance Portability 
and Accountability Act of 1996, EU Data Protection Directive 95/46/EC).The study 
will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations 
of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and 
other records will be identified by a coded number and initials only.  All study 
records will be kept in a locked file cabinet and code sheets linking a patient’s name 
to a patient identification number will be stored separately in another locked file 
cabinet.  Clinical information will not be released without written permission of the 
subject, except as necessary for monitoring by the FDA.  The Investigator must also 


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comply with all applicable privacy regulations (e.g., Health Insurance Portability 
and Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
17.1 Protocol Amendments 
Any amendment to the protocol will be written by investigator.  Protocol 
amendments cannot be implemented without prior written IRB/IEC approval except 
as necessary to eliminate immediate safety hazards to patients.  A protocol 
amendment intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, provided the IRBs are notified within five working days. 
17.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of 
each participating center prior to study initiation.  Serious adverse experiences 
regardless of causality will be reported to the IRB/IEC in accordance with the 
standard operating procedures and policies of the IRB/IEC, and the Investigator will 
keep the IRB/IEC informed as to the progress of the study.  The Investigator will 
obtain assurance of IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as 
protocol, protocol amendments, Investigator’s Brochure, consent forms, 
information concerning patient recruitment, payment or compensation procedures, 
or other pertinent information) will be submitted to the IRB/IEC.  The IRB/IECs 
written unconditional approval of the study protocol and the informed consent form 
will be in the possession of the Investigator before the study is initiated.  The 
IRB/IECs unconditional approval statement will be transmitted by the Investigator 
prior to the shipment of study supplies to the site.  This approval must refer to the 
study by exact protocol title and number and should identify the documents 
reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated 
without prior written IRB/IEC approval except when necessary to eliminate 
immediate hazards to the patients or when the change(s) involves only logistical or 
administrative aspects of the study.  Such modifications will be submitted to the 
IRB/IEC and written verification that the modification was submitted and 
subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally 
submitted for review; serious and/or unexpected adverse experiences occurring 
during the study in accordance with the standard operating procedures and policies 
of the IRB; new information that may affect adversely the safety of the patients of 
the conduct of the study; an annual update and/or request for re-approval; and when 
the study has been completed. 
17.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, 
ICH GCP, US Code of Federal Regulations for Protection of Human Subjects (21 


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CFR 50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance 
Portability and Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA 
authorization and provide the documents to the Sponsor or designee for approval 
prior to submission to the IRB/IEC.  The consent form generated by the Investigator 
must be acceptable to the Sponsor and be approved by the IRB/IEC.  The written 
consent document will embody the elements of informed consent as described in 
the International Conference on Harmonisation and will also comply with local 
regulations. The Investigator will send an IRB/IEC-approved copy of the Informed 
Consent Form to the Sponsor (or designee) for the study file. 
A properly executed, written, informed consent will be obtained from each subject 
prior to entering the subject into the trial.  Information should be given in both oral 
and written form and subjects (or their legal representatives) must be given ample 
opportunity to inquire about details of the study.  If appropriate and required by the 
local IRB/IEC, assent from the subject will also be obtained.  If a subject is unable 
to sign the informed consent form (ICF) and the HIPAA authorization, a legal 
representative may sign for the subject.   A copy of the signed consent form (and 
assent) will be given to the subject or legal representative of the subject and the 
original will be maintained with the subject’s records. 
17.4 Publications  
The preparation and submittal for publication of manuscripts containing the study 
results shall be in accordance with a process determined by mutual written 
agreement among the study Sponsor and participating institutions.  The publication 
or presentation of any study results shall comply with all applicable privacy laws, 
including, but not limited to, the Health Insurance Portability and Accountability 
Act of 1996.  
17.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or 
welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB 
review and approval meet federal guidelines, as stated in § 21 CFR, parts 50 
and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the 
study, in accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations in meeting the above 
commitments. 


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6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 
and to make those records available for inspection with the Sponsor (or 
designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 
will be responsible for initial and continuing review and approval of the 
clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the 
research activity and all unanticipated problems involving risks to subjects or 
others (to include amendments and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except 
when necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical 
investigators and all other pertinent requirements listed in § 21 CFR part 312. 
 
 
 


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APPENDIX 1.  SCHEDULE OF STUDY VISITS 
 
SCREENING 
VISIT  
 
STUDY PERIOD 
1 
STUDY PERIOD   
Informed Consent 
X 
 
 
Medical History 
X 
 
 
Complete Physical Exam 
X 
 
 
Abbreviated Physical Exam 
 
X 
X 
Height  
X 
X 
X 
Weight  
X 
X 
X 
Vital Signs  
X 
X 
X 
Pharmacokinetics 
 
X 
 
Chemistry 
X 
 
 
Pregnancy Test (Urine or 
Serum)  
X 
 
 
Hematology 
X 
 
 
ESR 
X 
 
 
C-Reactive Protein 
X 
 
 
Urinalysis 
X 
 
 
Randomization 
X 
 
 
Dispensing or 
Administration of Study 
Drug 
X 
X 
X 
Counting of Returned Study 
Drug 
 
X 
X 
Initiate Subject Diary 
X 
 
 
Concomitant Medication 
Review 
X 
X 
X 
Adverse Experiences 
 
 
 
a  
±2 days 
 


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APPENDIX 2. DIAGRAM OF STUDY PLAN  
All patient w
monitor fo
medication
S
1 Day of 
Fluvastatin 
PK parameter 
modeling in WinNolin  
All subjects will fast from 
midnight the night prior to 
each treatment and until 3h 
post Fluvastatin dosing. All 
subjects will avoid eating 
grapefruit and oranges and 
drinking alcoholic beverages, 
caffeinated beverages, 
grapefruit juice, and orange 
juice from 7am the day before 
each study period.  and until 
3h post rosuvastatin 
Dosing  All subjects will 
avoid all fruit juices from 7am 
h d
b f
il h
d f
Serial of the blood 
Sample will be performed 
at  0, 0.33, 0.67, 1, 
 1.5, 2, 2.5, 3, 
4, 6, 9, 12h 
ft
Fl
t ti d
i
The Effect of Rifampin on Pharmacokinetics of Fluvastatin 
in Healthy Volunteers (induced)  
Telephone screening to determined the 
eligibility 
Admit to CRC at UCSF, Pregnancy Test for female
First 5 days Pretreated with 600mg 
rifampin PO QD
Period 1, Group 1: 
fluvastatin 20mg PO X1
Pretreated with 600mg rifampin 
for one day  and wash out 
fluvastatin for 1 day 
Period 2, Group 1: 
30-min intravenous infusion of
rifampin 600mg in 10ml
Normal Saline  
+
fluvastatin 20mg PO x 1
Period 1, Group 2: 
30-min intravenous infusion of
rifampin 600mg in 10ml
Normal Saline 
+
fluvastatin 20mg PO x 1
Pretreated with 600mg rifampin PO 
for one day  and wash out 
fluvastatin for 1 day 
Period 2, Group 2:
fluvastatin 20mg PO x1 

ICF_002.pdf: 
Official Title: The Effects of Single Dose Rifampin on Pharmacokinetics of Fluvastatin in 
Uninduced and Hepatically Induced Healthy Volunteers 
 
NCT number: NCT04029584 
 
Document date: 12/26/2018 


DATE 12/26/2018                        FLUVASTATIN AND PO RIFAMPIN STUDY 
PAGE 1 OF 10 
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
 
Study Title 
THE EFFECTS OF SINGLE DOSE RIFAMPIN ON THE PHARMACOKINETICS OF 
FLUVASTATIN IN HEALTHY VOLUNTEERS 
 
This is a medical research study.  Your study doctors, Leslie Benet, Ph.D., Professor of 
Bioengineering & Therapeutic Sciences, Lynda Frassetto, M.D., Professor of Medicine, and/or 
study coordinators Yue Xiang, Doctor of Pharmacy Candidate and Ivan Kozachenko, Doctor of 
Pharmacy Candidate will explain this study to you. 
 
Medical research studies include only people who choose to take part.  Take your time to make your 
decision about participating.  You may discuss your decision with your family and friends and with 
your health care team.  If you have any questions, you may ask your study doctors. 
 
You are being asked to take part in this study because you are a nonsmoking person with no active 
medical problems, taking no medications between the ages of 18-65 years old. If you are 
determined to be eligible for participation in this study, you may be asked to consider to participate 
in another similar clinical study (study number: 18-27007). Participation in both studies is not a 
requirement.  
 
Why is this study being done? 
 
The purpose of this study is to look into the interaction between Fluvastatin (Lescol®) and rifampin 
when the two drugs are taken together.  Fluvastatin is a cholesterol-lowering medication used in 
combination with diet and exercise to treat high cholesterol and related conditions, and to prevent 
heart disease.  Rifampin is an antibiotic used to treat tuberculosis and a variety of other infections 
caused by certain germs called bacteria.  Both drugs affect a protein found in your liver cells called 
organic anion transporting polypeptides (OATPs).  This protein regulates drugs getting into and out 
of your body. We want to find out what effect taking the two drugs together has on the level of 
fluvastatin in the blood of patients.   
 
Who pays for this study? 
 
Private research funds of the primary investigator, Dr. Benet, will help pay for the conduct of this 
study.  This disclosure is made so that you can decide if this relationship will affect your 
willingness to participate in this study. 
 
How many people will take part in this study? 
About 10-12 healthy people will take part in this study. 
 
What will happen if I take part in this research study? 
Study location: All study procedures will take place in the Clinical Research Center (CRC) at 
UCSF (400 Parnassus Ave). 
Before you begin the main part of the study... 


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You will need to have the following “screening” medical history, physical exam and tests to find 
out if you can be in the main part of the study.  
 
• Medical History:  You will have a medical history taken, similar to those done for regular 
medical care. 
 
• Physical exam:  You will have a physical examination, similar to those done for regular 
medical care. 
 
• Urine sample:  You will be asked to give a urine sample for laboratory tests. 
 
• Blood drawing (venipuncture):  You will be asked to give a blood sample for laboratory tests.  
Approximately 2 tablepoons (30ml) blood will be drawn by inserting a needle into a vein in 
your arm for these tests. 
 
• Pregnancy testing:  Because the drugs in this study can affect a fetus, pregnant women may not 
participate in this study.  If you are a female and have had your first menstrual period, a urine 
test will be done at the screening visit to make sure you are not pregnant. If you know that you 
are pregnant or trying to become pregnant, you should tell the investigators now.  You will need 
to use a reliable form of birth control throughout study enrollment 1) abstinence, i.e. not 
participate in sexual intercourse or 2) condom AND spermicidal agent 3) copper intrauterine 
device (IUD).  Because hormonal contraceptives may interfere with the results of the study, the 
oral, ‘patch’, and ‘IUD’ ‘ring’ forms of hormonal contraceptives may not be used.  
During the main part of the study... 
If the screening history, exams and tests show that you can continue to be in the study, and you 
choose to take part, then you will return to the Clinical Research Center (CRC) at UCSF  for two 
study periods.  Each study period is approximately 13-14 hours in length. The two periods will be 
separated by at least one day. 
During both study periods, you will have the same tests and procedures done.  The only difference 
between periods is the medication(s) you receive.  
Period 1 and Period 2 Tests and Procedures 
Study period 1  
● You will avoid grapefruit, oranges, alcoholic beverages, caffeinated beverages, grapefruit 
juice, and orange juice from 7am the day before study period 1 and until completion of study 
period 2. 
● You will fast (no food or beverages except water) from midnight the night prior to study 
period 1 until 3 (three) hours after medication administration.  You are allowed and 
encouraged to drink water during this time.   
● You will arrive at the Clinical Research Center (CRC) at UCSF by 7:30 am. 
● One or two intravenous catheters (small tubes inserted in your vein for withdrawing or 
introducing fluids) will be placed in an arm vein for collection of blood and rifampin dosing.  
If you are receiving the rifampin infusion, you will have 2 IVs placed.  
● You will then receive one of the following treatment regimens: 


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a) Fluvastatin by mouth 
b) Rifampin infused through the vein (IV) for 30 minutes, then fluvastatin by mouth 
 
● The exact order you receive the above treatments may not be in the order listed above, and the 
order will be determined by chance. After completing the study you will have received both 
treatment regimens listed (a and b). 
● The separate catheter for rifampin infusion will be removed at the end of the infusion (about 
30 minutes). The other catheter will be removed after the final blood sample (after about 12 
hours). 
● Blood samples (~2 teaspoons each) will be collected from the intravenous catheter before you 
are given each of the study medications and at 0, 0.33, 0.67, 1,1.5, 2, 2.5, 3,4, 6, 9, and 12 
hours after receiving fluvastatin. If the intravenous catheter falls out or fails during the study 
day, you may choose to have another intravenous catheter placed in an arm vein OR have the 
remaining blood samples drawn by inserting a needle into a vein in your arm. 
● Throughout the study visit you will have your blood pressure, heart rate and respiratory rate 
measured.   
● You will also be asked to report any side effects that you notice from the treatments and/or 
procedures. 
● After the 12 hour blood draw, you will be discharged from the CRC to home.  
Study Period 2 
The second period of the study will preferentially begin 48 hours after study period one. This will 
follow the same procedures as above. The only difference is you will receive the other treatment 
medication(s). 
Study Chart 
 The chart below shows what will happen to you during the entire study. The left-hand column 
shows the day in the cycle and the right-hand column tells you what to do on that day. 
 
Day  
What you do 
At least a week 
before starting 
the study 
● Get screening visit completed. 
Day before study 
period 1 
● All day: Avoid grapefruit, oranges, alcoholic beverages, caffeinated 
beverages, grapefruit juice, and orange juice. 
● Night before: Fast (no food or drink other than water) after midnight. 
Period 1  
● Check-in to CRC at 400 Parnassus Ave by 7:30 am. Leave the hospital 
after the 12 hour blood draw is completed. 
Day before study 
period  2 
● All day: Avoid grapefruit, oranges, alcoholic beverages, caffeinated 
beverages, grapefruit juice, and orange juice. 
● Night before: Fast (no food or drink other than water) after midnight. 


DATE 12/26/2018                        FLUVASTATIN AND PO RIFAMPIN STUDY 
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Period 2  
● Check-in to CRC at 400 Parnassus Ave by 7:30 am. Leave the hospital 
after the 12 hour blood draw is completed 
 
What amount of blood will I have collected in the study? 
The total amount of blood drawn during the entire study is about 1/2 pint (approximately 250 ml), 
which is less than the amount taken during a blood donation.  You will not be able to donate blood 
for 8 weeks after the study.  
How long will I be in the study? 
The required time for each option is estimated as follows: One 2-3 hour screening visit, and two 13-
14 hours stays in the CRC (separated by 1 day). The maximum total time required is approximately 
31  hours over a several week period.  
Can I stop being in the study? 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping or 
decide to stop.  He or she will tell you how to stop your participation safely.  
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped. 
 
 


DATE 12/26/2018                        FLUVASTATIN AND PO RIFAMPIN STUDY 
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What side effects or risks can I expect from being in the study? 
You may have side effects while in the study.  Everyone taking part in the study will be watched 
carefully for any side effects.  However, doctors don't know all the side effects that may happen.  
Side effects may be mild or very serious.  Your study doctors may give you medicines to help 
lessen side effects.  Most side effects go away soon after you stop taking fluvastatin and/or 
rifampin.  In extremely rare cases, side effects can be serious, long lasting, or may never go away. 
You should talk to your study doctor about any side effects you experience while taking part in the 
study. 
Fluvastatin: 
Fluvastatin is generally well-tolerated. Adverse events are usually mild, go away after the drug is 
stopped, and require no treatment. Risks and side effects related to fluvastatin include those which 
are: 
Less likely (1-10% chance) 
● Muscle pain and/or joint pain 
● General weakness 
● Headache 
● Insomnia   
● Gastrointestinal:  Dyspepsia, abdominal pain, diarrhea, nausea 
Rare but serious (< 1% chance) 
● Fluvastatin has been associated with altering certain laboratory blood tests including 
elevation of blood liver enzyme levels and increases in creatine phosphokinase (a muscle 
breakdown test). 
● Very rare cases of rhabdomyolysis (breakdown of muscle fibers) with kidney failure have 
been reported with fluvastatin. This usually occurs when taking this medication every day 
for months.  
Rifampin:  
Rifampin is generally well tolerated.  Adverse events are usually mild, go away after the drug is 
stopped, and require no treatment.  Since only a small number of doses of rifampin will be given, 
we anticipate side effects to be much less frequent than reported when rifampin is given for months 
or years. Risks and side effects related to rifampin include those which are: 
Likely 
● 
IV Rifampin produces a harmless reddish coloration of the urine, sweat, tears and sputum 
and may stain contact lenses. 
Less Likely (1-10% chance) 
● Nausea, vomiting, heartburn, abdominal pain, passing gas, cramps, diarrhea, elevation of blood 
liver enzyme levels. 
● Rash or itching 
Rare but serious (<1% chance) 
● Headache, drowsiness, dizziness, difficulty with concentration, fatigue 


DATE 12/26/2018                        FLUVASTATIN AND PO RIFAMPIN STUDY 
PAGE 6 OF 10 
● Decreases in blood cell counts, including decreases in red cells, white cells and platelets 
● Changes in menstrual cycles 
● Allergic reactions, including rash, itching, swelling, skin breakdown, and transient 
worsening of kidney function.  
Risk and side effects of other procedures include… 
● Blood drawing (venipuncture) risks:  Drawing blood may cause temporary discomfort from 
the needle stick, bruising, and infection. 
 
● Intravenous catheter placement and infusion risks: Placing the intravenous catheter may 
cause temporary discomfort from the needle stick, bruising, and infection.  The risk of rifampin 
infusion through the vein include pain at the infusion site, irritation of the vein and 
inflammation.  The infusion will be stopped if any discomfort occurs. 
 
● Reproductive risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed a baby 
while on this study.  It is important to understand that you need to use birth control while on this 
study.  Appropriate birth control is one of the following: 1) abstinence (i.e. not participate in 
sexual intercourse) or 2) condom AND spermicidal agent.  Because hormonal contraceptives 
may interfere with the results of the study, the oral, ‘patch’, and ‘ring’ forms of hormonal birth 
controls may not be used. 
 
● Inconvenience and boredom:  There is inconvenience and boredom from the time spent in the 
research unit and from eating the same diet on the study days. To decrease boredom, you may 
bring books, magazines, a radio with headphones, and/or a computer to the research unit. 
 
• 
Unknown risks: The experimental treatments may have side effects that no one knows about 
yet.  The researchers will let you know if they learn anything that might make you change your 
mind about participating in the study. 
 
• 
For more information about risks and side effects, ask your study doctor. 
 
Things to follow while in the study… 
● Avoid consuming alcoholic beverages, caffeinated beverages, orange juice, grapefruit juice, 
grapefruit, and oranges from 7am the day before a study day until completion of that study day. 
● Maintain adequate birth control throughout study participation without the use of hormonal 
contraceptives. 
Are there benefits to taking part in the study? 
There will be no direct benefit to you from participating in this study.  However, this study will help 
doctors learn more about fluvastatin and rifampin, and it is hoped that this information will help 
future patients treated with these medications.  
What other choices do I have if I do not take part in this study? 
Participation in this study is entirely voluntary and subjects can choose not to participate.  Subjects 
have the right to withdraw at any time. 


DATE 12/26/2018                        FLUVASTATIN AND PO RIFAMPIN STUDY 
PAGE 7 OF 10 
Will my medical information be kept private? 
We will do our best to make sure that the personal information in your medical record is kept 
private.  A medical record will be created because of your participation in this study.  Your consent 
form and some of your research test results will be included in this record.  Therefore, your other 
doctors may become aware of your participation.  Hospital regulations require that all healthcare 
providers treat information in medical records with confidentiality. However, we cannot guarantee 
total privacy.  Your personal information may be given out if required by law.  If information from 
this study is published or presented at scientific meetings, your name and other personal information 
will not be used. 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• UCSF’s  Institutional Review Board and Clinical Research Center. 
What are the costs of taking part in this study? 
You will not be charged for any of the study activities or study medications.   
Will I be paid for taking part in this study? 
In return for your time, effort, and travel expenses, you will be paid a total of $350 for taking part in 
this study.  If you complete only the study period 1, you will receive $75. If you complete both 
study periods 1 and 2, you will receive another $75 for study period 2 and an additional $150 bonus.  
A check will be mailed to you about 4-6 weeks after your participation in the study has ended.   
You will receive $25 each study day for meals.  You will also receive parking vouchers to allow 
you to park in the UCSF parking garage. 
 
You will have to provide your name, address, and social security number in order to receive 
payment by check.  As payments for research participation in excess of $600 per calendar year are 
reportable to the IRS, you will have to pay taxes on payments if you receive more than $600 in the 
year by participating in other research studies. 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, Lynda Frassetto, M.D., Yue Xiang, or Ivan 
Kozachenko if you feel that you have been injured because of taking part in this study.  You can tell 
the doctor in person or call Lynda Frassetto, M.D. at 415-476-6143, Yue Xiang at 206-617-3735 or 
Ivan Kozachenko at 858-842-8529. 
• 
Treatment and Compensation for Injury:  If you are injured as a result of being in this 
study, the University of California will provide necessary medical treatment.  The costs of 
the treatment may be billed to you or your insurer just like any other medical costs, or 
covered by the University of California depending on a number of factors.  The University 
does not normally provide any other form of compensation for injury.  For further 
information about this, you may call the office of the Institutional Review Board at 415- 
476-1814. 
 
 


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PAGE 8 OF 10 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.  No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits.  Leaving the study will not affect your medical care.  
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form. 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions, concerns, or complaints you have about this 
study.  Contact your study doctors Lynda Frassetto, M.D. at 415-476-6143, Yue Xiang at 206-617-
3735 or Ivan Kozachenko at 858-842-8529. 
If you wish to ask questions about the study or your rights as a research participant to someone 
other than the researchers or if you wish to voice any problems or concerns you may have about the 
study, please call the Office of Institutional Review Board at 415-476-1814.   
ClinicalTrials.gov is a website that provides information about clinical trials.  A description of this 
clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law.  This Web 
site will not include information that can identify you.  At most, the Web site will include a 
summary of the results.  You can search this Web site at any time.  
************************************************************ 
OPTIONAL GENETIC TESTING AND STORAGE OF BLOOD FOR FUTURE 
RESEARCH 
Why is blood being stored? 
By storing a sample of your blood, the researchers will be able to perform future genetic research on 
your blood that may help them understand the results of this study.  The results of these genetic tests 
will not be put into your medical health record. 
What will be done if I agree to have my blood stored? 
If you agree to let researchers collect and store your blood for future research, the following will 
happen: 
 
● Two teaspoons of blood will be obtained at the same time as your routine blood draw at the 
screening visit. The blood sample will be frozen and stored at the study doctor’s laboratory 
(Dr. Leslie Benet, 533 Parnassus Ave, Room U-66, San Francisco, CA 94143).  Your 
specimen will be kept for up to 3 years from completion of the study.  
● The blood sample will be kept for research purposes only.  The blood may be used only by 
investigators in this study for future genetic research purposes.  You or your doctor will not 
be told the results of any genetic testing or any future research.  
 
What risks are involved with donating specimens for research? 
 


DATE 12/26/2018                        FLUVASTATIN AND PO RIFAMPIN STUDY 
PAGE 9 OF 10 
Confidentiality: Donating specimens may involve a loss of privacy, but information about you will 
be handled as confidentially as possible. Study data will be physically and electronically secured.  
As with any use of electronic means to store data, there is a risk of breach of data security. Your 
name will not be used in any published reports from research performed using your specimen. The 
researchers involved in this study will have access to information about you but they will not 
release any identifying information about you to researchers using your specimen. The UCSF  
Institutional Review Board and other University of California personnel also may see information 
about you to check on the stored blood specimens. Once your health information is disclosed to the 
research team it is not protected under the Health Information Portability and Accountability Act 
(HIPAA). The investigators of this study will continue to protect your personally identifiable health 
information as described in this consent form. The University of California complies with the 
requirements of HIPAA and its privacy regulations, and with all other applicable laws that protect 
the confidentiality of your health information. 
 
Genetic information that results from this study does not have medical or treatment importance at 
this time.  However, there is a risk that information about taking part in a genetic study may 
influence insurance companies and/or employers regarding your health. To further safeguard your 
privacy, genetic information obtained in this study will not be placed in your medical record. 
 
How do I have my blood specimen removed from storage at a later time? 
 
If you decide later that you do not want your specimens and information to be used for future 
research, you can notify the investigator in writing at (Dr. Leslie Benet, School of Pharmacy, 
Department of Bioengineering and Therapeutic Sciences, 533 Parnassus Ave, San Francisco, CA  
94143), and we will destroy any remaining identifiable specimens and information if they are no 
longer needed for your care. However, if any research has already been done using portions of your 
specimens, the data will be kept and analyzed as part of those research studies. 
What are the benefits of donating specimens for research? 
There will be no direct benefit to you from allowing your specimens to be kept and used for future 
research. However, we hope we will learn something that will contribute to the advancement of 
science and understanding of health and disease. 
What financial issues should I consider before donating? 
You will not be charged for donating and storing your specimen. You will not be paid for donating 
your specimen. If any new products, tests or discoveries that result from this research have potential 
commercial value, you will not share in any financial benefits. 
What other choices do I have if I do not donate blood for storage? 
Deciding to donate blood for storage is your choice.  You may choose either to take part or not to 
take part in this part of study.  No matter what decision you make, there will be no penalty to you 
and you will still be able to take part in the main study. 
 
 


DATE 12/26/2018                        FLUVASTATIN AND PO RIFAMPIN STUDY 
PAGE 10 OF 10 
Consent for Storage of Blood 
Please read the sentence below and think about your choice. After reading, put your initials in the 
"Yes" or "No" box. 
No matter what you decide to do, it will not affect your care. 
1. My blood may be taken and stored for genetic testing and for future research use.  
YES  
NO 
2. Someone may contact me in the future to ask me to take part in more research. 
YES  
NO 
************************************************************ 
CONSENT 
 
You have been given copies of this consent form and the Experimental Subject's Bill of Rights to 
keep. 
 
You will be asked to sign a separate form authorizing access, use, creation, or disclosure of health 
information about you. 
 
PARTICIPATION IN RESEARCH IS VOLUNTARY.  You have the right to decline to participate 
or to withdraw at any point in this study without penalty or loss of benefits to which you are 
otherwise entitled. 
 
If you wish to participate in this study, you should sign below. 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
Participant's Signature for Consent 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
Person Obtaining Consent