Clinical trial NCT04463680
Conditions: Contraception Tuberculosis
Sponsor: University of Colorado, Denver
Start date: 2020-09-23; Completion date: 2022-02-22
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
It is important for women taking rifampin to be aware if they are at greater risk of an unintended pregnancy while on the implant. An unintended pregnancy has many social, emotional, and financial impacts on women and society. Rifampin is also a Class C medication for pregnancy and could have potential negative effects on a developing fetus. Additionally, women considering rifampin for treatment of LTBI face additional risks with an unintended pregnancy, making the reliability of contraception even more important for these women. The results of this study can directly inform counseling on a national and international basis for women who use the contraceptive implant and are considering their treatment options for LTBI.

Detailed description:
Rifampin is an antibiotic historically prescribed as part of a treatment regimen for active tuberculosis (TB) infection. Though active TB infections have become rarer over time in the US, it is estimated that up to 13 million people in the US may have latent TB infections (LTBIs), with even greater numbers of LTBIs worldwide1. In efforts to combat the persistent rate of LTBI, the US Centers for Disease Control and Prevention (CDC) released updated treatment guidelines for LTBI in 20181. This recommended treatment guideline consists of four treatment regimens, varying in duration from 3 to 9 months. The CDC recommends utilization of the shorter regimens when possible to achieve higher patient compliance and infection clear rates. The second shortest duration treatment regimen (4 months) consists of daily rifampin only1.

In addition to its antitubercular properties, rifampin is a known strong cytochrome P-450 (CYP) 3A4 enzyme inducer2. Similar to other strong CYP3A4 enzyme inducers (e.g. carbamazepine), rifampin can affect the serum concentrations of exogenous steroid hormones found in hormonal contraception2. The only published literature on the interaction between rifampin and hormonal contraception has focused on combined oral contraceptives3. Five studies that investigated the pharmacokinetics of combined oral contraceptives all found significant reductions in serum ethinyl estradiol and progestin concentrations with rifampin co-administration3. This pharmacokinetic effect is significant enough to warrant a category 3 recommendation (theoretical or proven risks usually outweigh the advantages) from the CDC Medical Eligibility Criteria (MEC) for Contraceptive Use for concomitant rifampin and combined hormonal contraceptive methods4. This pharmacokinetic effect is large enough to raise concerns for combined hormonal contraceptive method efficacy and recommendation of alternative methods. One of those alternative methods is the etonogestrel (ENG) implant (Nexplanon®), which has a category 2 recommendation in the CDC MEC for concomitant rifampin use4. However, in the clarifications for this recommendation, the CDC MEC warns that rifampin is "likely to reduce the effectiveness" of the ENG implant, with no supporting evidence provided4.

Prior work found that a strong CYP3A4 inducer (carbamazepine) caused clinically significant reductions in serum etonogestrel concentrations among contraceptive implant users5. The investigators found a median decrease in serum ENG of 61% (range 25-87) with 8/10 participants having serum ENG concentrations \<90pg/mL after concomitant carbamazepine5. Though there is currently no published data on the pharmacokinetic interaction between rifampin and the ENG implant, given its similar enzyme induction properties, there is concern that the CDC MEC recommendation for rifampin and the ENG implant may underestimate the potential risk for contraceptive failure.

Given the social, financial, and healthcare costs of unintended pregnancies, it is imperative that the investigators better understand the drug-drug interaction between rifampin and the ENG implant. Especially in light of the contradictory category 2 recommendation and clarification in the CDC MEC4, more data are needed to determine if rifampin has a significant enough pharmacokinetic effect on the ENG implant to potentially cause contraceptive failure. This information would allow healthcare providers around the world the ability to provide improved counseling to patients needing treatment for LTBI in regards to both their TB treatment regimen and their concurrent contraceptive options.

Specific Aim:

* To evaluate the pharmacokinetic effect of rifampin on serum etonogestrel concentrations in contraceptive implant users at the dose of rifampin used for latent tuberculosis infection (LTBI) treatment (600mg per day)
* Exploratory Aim - to evaluate the effect of rifampin on serologic measures of ovulatory suppression (estradiol and progesterone) in contraceptive implant users

Hypothesis:

· The investigators hypothesize that rifampin will have a significant pharmacokinetic effect on participants' etonogestrel levels resulting in etonogestrel concentrations at least 35% decreased from baseline measurements.

Methods:

The investigators propose a prospective, pre and post study to evaluate the pharmacokinetic effect of rifampin on serum ENG levels in contraceptive implant users. The investigators will enroll healthy women using an ENG implant for at least 12 months and no greater than 36 months.

Participants will then begin a 2 week regimen of rifampin at 600mg per day. This dose is the recommended dose for treatment of LTBI and duration of 2 weeks will achieve steady state rifampin levels with adequate time for liver enzyme induction. All participants will then return at the end of the second week for a repeat blood draw. The investigators will again obtain serum as described above for planned measurement of serum ENG concentrations. The investigators will also obtain blood samples for repeat measurements of serum estradiol and progesterone. The investigators will also measure a serum rifampin level at the time of the second ENG blood draw to confirm compliance. Serum estradiol, serum progesterone, and serum rifampin levels will all be measured at the UCH Clinical Laboratory. At the conclusion of enrollment, all stored serum samples will be de-identified and shipped to a Merck® laboratory for serum ENG concentration measurement. Batch analysis will be performed using a liquid chromatography mass-spectrometry method that has been previously validated. Participants will serve as their own controls for this study.

All participants will be required to use either a back-up non-hormonal method of birth control or abstain from intercourse during the study and for 2 weeks after the last dose of rifampin. Rifampin has a half-life of 3-4 hours, and thus, will be eliminated within 1-2 days of the last dose, but the investigators will allow a full 2 weeks of buffer to ensure that the contraceptive effect of the implant has reinitiated before recommending resuming unprotected intercourse.

All study visits will occur at the Comprehensive Women's Health Clinic in Lowry.

Arms: arm 1: Will receive 2 week regimen of rifampin 600mg per day
Interventions: intervention 1: Rifampin 600 MG
Intervention descriptions: intervention 1: Administered daily for 2 weeks

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: The effect of rifampin on etonogestrel concentrations in contraceptive 
implant users 
NCT Number: NCT04463680 
Document date: 5/8/2020 
Principal Investigators: Stephanie Teal, MD and Jeanelle Sheeder, PhD 


Proposal Narrative 
 
 
 
  
 
I. Hypotheses and Specific Aims:  
 
Specific Aim: 
• To evaluate the pharmacokinetic effect of rifampin on serum etonogestrel 
concentrations in contraceptive implant users at the dose of rifampin used for latent 
tuberculosis infection (LTBI) treatment (600mg per day)  
 
• Exploratory Aim – to evaluate the effect of rifampin on serologic measures of 
ovulatory suppression (estradiol and progesterone) in contraceptive implant users 
 
Hypothesis: 
• We hypothesize that rifampin will have a significant pharmacokinetic 
effect on participants’ etonogestrel levels resulting in etonogestrel 
concentrations at least 35% decreased from baseline measurements. 
 
II. Background and Significance:  
 
Rifampin is an antibiotic historically prescribed as part of a treatment regimen for 
active tuberculosis (TB) infection. Though active TB infections have become rarer over 
time in the US, it is estimated that up to 13 million people in the US may have latent TB 
infections (LTBIs), with even greater numbers of LTBIs worldwide1. In efforts to combat 
the persistent rate of LTBI, the US Centers for Disease Control and Prevention (CDC) 
released updated treatment guidelines for LTBI in 20181. This recommended treatment 
guideline consists of four treatment regimens, varying in duration from 3 to 9 months. The 
CDC recommends utilization of the shorter regimens when possible to achieve higher 
patient compliance and infection clear rates. The second shortest duration treatment 
regimen (4 months) consists of daily rifampin only1. 
In addition to its antitubercular properties, rifampin is a known strong cytochrome 
P-450 (CYP) 3A4 enzyme inducer2. Similar to other strong CYP3A4 enzyme inducers 
(e.g. carbamazepine), rifampin can affect the serum concentrations of exogenous steroid 
hormones found in hormonal contraception2. The only published literature on the 
interaction between rifampin and hormonal contraception has focused on combined oral 
contraceptives3. Five studies that investigated the pharmacokinetics of combined oral 
contraceptives all found significant reductions in serum ethinyl estradiol and progestin 
concentrations with rifampin co-administration3. This pharmacokinetic effect is significant 
enough to warrant a category 3 recommendation (theoretical or proven risks usually 
outweigh the advantages) from the CDC Medical Eligibility Criteria (MEC) for 
Contraceptive Use for concomitant rifampin and combined hormonal contraceptive 
methods4. This pharmacokinetic effect is large enough to raise concerns for combined 
hormonal contraceptive method efficacy and recommendation of alternative methods. One 
of those alternative methods is the etonogestrel (ENG) implant (Nexplanon®), which has a 
category 2 recommendation in the CDC MEC for concomitant rifampin use4. However, in 


the clarifications for this recommendation, the CDC MEC warns that rifampin is “likely to 
reduce the effectiveness” of the ENG implant, with no supporting evidence provided4. 
Our prior work found that a strong CYP3A4 inducer (carbamazepine) caused 
clinically significant reductions in serum etonogestrel concentrations among contraceptive 
implant users5. We found a median decrease in serum ENG of 61% (range 25-87) with 
8/10 participants having serum ENG concentrations <90pg/mL after concomitant 
carbamazepine5. Though there is currently no published data on the pharmacokinetic 
interaction between rifampin and the ENG implant, given its similar enzyme induction 
properties, there is concern that the CDC MEC recommendation for rifampin and the ENG 
implant may underestimate the potential risk for contraceptive failure. In further support of 
this, our Family Planning listserv recently discussed the case of a patient with an ENG 
implant in place that became pregnant shortly after starting rifampin for LTBI treatment.  
Given the social, financial, and healthcare costs of unintended pregnancies, it is imperative 
that we better understand the drug-drug interaction between rifampin and the ENG 
implant. Especially in light of the contradictory category 2 recommendation and 
clarification in the CDC MEC4, more data are needed to determine if rifampin has a 
significant enough pharmacokinetic effect on the ENG implant to potentially cause 
contraceptive failure. This information would allow healthcare providers around the world 
the ability to provide improved counseling to patients needing treatment for LTBI in 
regards to both their TB treatment regimen and their concurrent contraceptive options. 
 
III. Preliminary Studies/Progress Report: There are no preliminary studies 
for this protocol. 
 
IV. Research Methods 
A.  Outcome Measure(s):   
Primary outcome:  
• Serum etonogestrel concentrations measured before and after concomitant rifampin 
therapy 
 
Secondary outcomes: 
• Serum estradiol (E2) and serum progesteron (P4) concentrations measured before 
and after concomitant rifampin therapy 
 
B. Description of Population to be Enrolled:   
 
We aim to enroll up to 15 reproductive age (18-45 years) women in this study based on the 
following criteria: 
• Inclusion Criteria:  Healthy women, who have had an ENG implant for 12-36 
months at the time of enrollment and will maintain their implant during the study 
without modifications. 
• Exclusion Criteria (at baseline):   
o We will exclude women who are taking any known cytochrome P-450 3A4 
enzyme inducers or inhibitors.  
o We will exclude women with a known allergy or insensitivity to rifampin. 


o We will also exclude women with a body mass index (BMI) <18.5, as 
underweight women may have altered metabolism. We will not have an 
upper BMI cut-off as studies have shown that overweight and obese women 
have equivalent metabolism and efficacy with the ENG contraceptive 
implant6,7. 
• Exclusions Criteria (screening laboratory testing) 
o We will also exclude women with any hepatic or renal dysfunction as 
determined by a comprehensive metabolic panel. For purposes of this study, 
liver function tests will be evaluated and evidence of hepatic dysfunction 
will be defined as an ALT >52 or AST >39, which are beyond the reference 
range of normal values used by the University of Colorado clinical 
laboratory. Renal function will be assessed by a serum creatinine and a 
value >1.2 will be evidence of renal dysfunction as this is greater than the 
reference range used by the University of Colorado clinical laboratory. 
o We will also exclude women with any abnormal hematology as determined 
by a complete blood count. For purposes of this study, abnormal 
hematology will be defined as a WBC, RBC, or PLT value beyond the 
reference range of normal values used by the University of Colorado 
clinical laboratory. 
o We will also exclude women with abnormal coagulation factors as 
determined by coagulation factor tests (PT/INR, PTT). For purposes of this 
study, abnormal coagulation factors will be defined as any test value 
beyond the reference range of normal values used by the University of 
Colorado clinical laboratory. 
 
C. Study Design and Research Methods   
 
We propose a prospective, pre and post study to evaluate the pharmacokinetic 
effect of rifampin on serum ENG levels in contraceptive implant users. We will enroll 
healthy women using an ENG implant for at least 12 months and no greater than 36 
months. Our exclusion and inclusion criteria are detailed as above. Interested participants 
will undergo a phone screening prior to scheduling an enrollment visit. At the enrollment 
visit, potential participants will have their vital signs checked in the form of a pulse and 
blood pressure and will have their height and weight measured for purposes of calculating 
a body mass index. We will review each potential participants past medical history and 
current medications to ensure study eligibility. If interested participants meet our non-
laboratory inclusion and exclusion criteria, then they will undergo informed consent in a 
private clinic room. 
After the participant has been consented, we will perform a blood draw to obtain 
whole blood and serum. Appropriate blood samples will be sent to the University of 
Colorado Clinical Laboratory for a comprehensive metabolic panel, complete blood count, 
and coagulation factor testing (PT/INR, PTT). We will also obtain additional blood tubes 
for measurement of serum estradiol and progesterone. These tubes will be sent to the UCH 
Clinical Laboratory for analysis if the participant’s screening laboratory testing is normal. 
A blood sample for serum will be centrifuged on location and the serum collected for 


storage in our -80°F freezer. For participants that meet our laboratory exclusion criteria, we 
will ultimately measure a serum baseline ENG concentration from the serum collected at 
the enrollment visit. The research team will then follow-up the screening laboratory tests to 
determine final eligibility based on the criteria discussed above. Eligible participants will 
then be given the options of either returning to our clinic to pick up the study medication or 
have the study medication mailed to them via FedEx. 
Participants will then begin a 2 week regimen of rifampin at 600mg per day. This 
dose is the recommended dose for treatment of LTBI and duration of 2 weeks will achieve 
steady state rifampin levels with adequate time for liver enzyme induction. All participants 
will then return at the end of the second week for a repeat blood draw. We will again 
obtain serum as described above for planned measurement of serum ENG concentrations. 
We also obtain blood samples for repeat measurements of serum estradiol and 
progesterone. We will also measure a serum rifampin level at the time of the second ENG 
blood draw to confirm compliance. Serum estradiol, serum progesterone, and serum 
rifampin levels will all be measured at the UCH Clinical Laboratory. At the conclusion of 
enrollment, all stored serum samples will be de-identified and shipped to a Merck® 
laboratory for serum ENG concentration measurement. Batch analysis will be performed 
using a liquid chromatography mass-spectrometry method that has been previously 
validated. Participants will serve as their own controls for this study. 
All participants will be required to use either a back-up non-hormonal method of 
birth control or abstain from intercourse during the study and for 2 weeks after the last 
dose of rifampin. Rifampin has a half-life of 3-4 hours, and thus, will be eliminated within 
1-2 days of the last dose, but we will allow a full 2 weeks of buffer to ensure that the 
contraceptive effect of the implant has reinitiated before recommending resuming 
unprotected intercourse. 
All study visits will occur at the Comprehensive Women's Health Clinic in Lowry. 
This is our Family Planning site for both clinical and research visits. All consent and 
enrollment processes will be conducted in a private clinic room and interested participants 
will be allowed as much time as needed to review the consent and ask any questions 
regarding the consent and study procedure. 
 
F.   Data Analysis Plan:   
 
For this study, we aim to show a decrease in serum ENG concentrations of at least 
35% from baseline, which would be consistent with the effect of a moderate to strong 
CYP3A4 inducer based on FDA standard definitions2. Based on our previous cohort of 350 
ENG implant users8, we converted the median and range of serum ENG from that cohort to 
a mean of 137.4pg/mL with a SD of 106.6 based on Hozo et al’s (BMC Med Res 
Methodol, 2005) formula. We then determined the assumed standard deviation of the 
differences in serum ENG concentrations to be 53.3 for before and after rifampin exposure 
based on an assumed correlation of 0.875 between these measurements. In order to find at 
least a 35% decrease in serum ENG concentrations (at least 48.1pg/mL decrease) with 
alpha level of 0.05 and power of 0.9, we will need 13 study compliant participants. Given 
the non-normal distribution of serum ENG concentrations, we will plan for 15 study 
compliant participants. We expect the discontinuation rate to be low given the short period 


of treatment time (2 weeks), and so will plan for enrollment of 15 participants. If our 
discontinuation rate is higher than expected, then we will consider additional enrollment as 
needed. 
We will use a paired Wilcoxon signed rank test to compare pre and post exposure 
serum ENG concentrations with each participant serving as their own control. We use the 
same analytic test for comparing pre and post exposure estradiol and progesterone levels. 
We will use a p-value of <0.05 as a cut-off for statistical significance. As each participant 
serves as her own control, we do not need to incorporate demographic factors into our 
analyses. 
 
 H. References: 
 
References 
 
• 
1. 
Treatment Regimens for Latent TB Infection (LTBI).  
https://www.cdc.gov/tb/topic/treatment/ltbi.htm. Accessed July 17, 2019. 
• 
2. 
U.S. Food and Drug Administration. Drug Development and Drug 
Interactions: Table of Substrates, Inhibitors, and Inducers.  
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/dru
ginteractionslabeling/ucm093664.htm. Accessed 01/17/2017. 
• 
3. 
Simmons KB, Haddad LB, Nanda K, Curtis KM. Drug interactions between 
rifamycin antibiotics and hormonal contraception: a systematic review. BJOG. 
2018;125(7):804-811. 
• 
4. 
Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria 
for Contraceptive Use, 2016. MMWR Recomm Rep. 2016;65(3):1-103. 
• 
5. 
Lazorwitz A, Davis A, Swartz M, Guiahi M. The effect of carbamazepine 
on etonogestrel concentrations in contraceptive implant users. Contraception. 
2017;95(6):571-577. 
• 
6. 
McNicholas C, Swor E, Wan L, Peipert JF. Prolonged use of the 
etonogestrel implant and levonorgestrel intrauterine device: 2 years beyond Food 
and Drug Administration-approved duration. American journal of obstetrics and 
gynecology. 2017;216(6):586.e581-586.e586. 
• 
7. 
Xu H, Wade JA, Peipert JF, Zhao Q, Madden T, Secura GM. Contraceptive 
failure rates of etonogestrel subdermal implants in overweight and obese women. 
Obstet Gynecol. 2012;120(1):21-26. 
• 
8. 
Lazorwitz A, Aquilante CL, Sheeder J, Guiahi M, Teal S. Relationship 
between patient characteristics and serum etonogestrel concentrations in 
contraceptive implant users. Contraception. 2019;100(1):37-41.