Clinical trial NCT01980342
Conditions: Drug Interaction
Keywords: Long acting reversible contraception HIV
Sponsor: Johns Hopkins University
Start date: 2014-10-01; Completion date: 2018-04-04
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluates whether there is an interaction between etonogestrel, the progestin hormone released by the contraceptive implant Nexplanon, and efavirenz, a common medication used to treat HIV. The endpoints measured in this study will help determine if such an interaction leads to decreased contraceptive efficacy of the contraceptive implant.

Detailed description:
Women now make up nearly half of the world's HIV-infected population, and many of these women with HIV are of reproductive age. There is a growing need to provide effective contraception for those women who want or need to be protected against pregnancy. However, there is concern for decreased contraceptive efficacy in women on antiretroviral therapy who rely on hormonal contraception due to drug-drug interactions. Of particular concern is a possible interaction with etonogestrel, the active hormone in a long-acting reversible contraceptive implant. We propose a pilot study to evaluate the effect of efavirenz (EFV), a commonly used non-nucleoside reverse transcriptase inhibitor, on the pharmacokinetics of the etonogestrel implant. We will recruit 18 healthy women who have had the implant in place for 12 to 24 months. They will be asked to take a two-week course of efavirenz. During these two weeks and for four additional weeks, we will monitor semi-weekly etonogestrel concentrations, and serum, ultrasound, and cervical mucus markers of ovulation. We will also assess efavirenz concentration at baseline and at the end of the two-week treatment course. We will derive pharmacokinetic parameters and compare concentrations across time points. Results will help to inform the design of larger studies, and of similar studies with different antiretroviral medications. We hypothesize that taking efavirenz while using the etonogestrel contraceptive implant will not result in an increased incidence of ovulation.

Arms: arm 1: Healthy, reproductive-age women using the etonogestrel contraceptive implant who will take a two-week course of efavirenz 400 mg orally each night.
Interventions: intervention 1: Efavirenz
Intervention descriptions: intervention 1: Healthy women who are using Nexplanon will be asked to take a 2-week course of reduced-dose efavirenz (400 mg daily).

Protocol documents:
Prot_SAP_000.pdf: 
 
 
TITLE: Pharmacokinetics and pharmacodynamics of the etonogestrel contraceptive implant when co-
administered with efavirenz 
NCT:  NCT01980342 
DATE: January 5th 2017 
PI: Jennifer Robinson, MD, MPH 


Date: January 5th, 2017 
Principal Investigator: Jennifer Robinson, MD, MPH 
Application Number: NA_00087585 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 1 of 15 
 
 
JHM IRB - eForm A – Protocol 
 
*************************************************************************************************** 
 
 
1. 
Abstract 
Women of reproductive age who are living with HIV have to navigate complex decisions regarding 
fertility, contraception, and managing their HIV diagnosis. One consideration for HIV-infected women who 
want or need to prevent pregnancy is whether the medications used to treat HIV could reduce the efficacy 
of a contraceptive method through drug-drug interactions. Efavirenz (EFV) is a non-nucleoside reverse 
transcriptase inhibitor (NNRTI) that is an important component of first-line antiretroviral therapy 
worldwide.  However, in addition to having a side effect profile that leads some to discontinue therapy, 
EFV has been associated with failures of a highly effective hormonal contraceptive, the etonogestrel (ENG) 
implant.  A recent multi-center trial suggests that a lower EFV dose retains efficacy against HIV while 
reducing the incidence of side effects. We propose a pilot study to evaluate the effect of reduced dose EFV 
on the pharmacokinetics of the ENG implant. We will recruit 18 HIV-negative healthy women who have 
had the implant in place for 6 to 30 months. They will be asked to take a two-week course of reduced dose 
efavirenz. During these two weeks and for four additional weeks, we will monitor semi-weekly ENG 
concentrations, and serum, ultrasound, and cervical mucus markers of ovulation. We will also assess EFV 
concentration at baseline, the end of the two-week treatment course, and at the end of the study.  We will 
derive pharmacokinetic parameters and compare concentrations across time points. Results will help 
determine whether the ENG implant can be used safely by HIV-positive women taking EFV, and will help 
to inform the design of similar larger studies with different antiretroviral medications. 
 
2. 
Objectives  
 
The primary objective of this study is to determine whether etonogestrel (ENG) pharmacokinetics in users 
of the ENG contraceptive implant (Nexplanon®/Implanon®) are affected by concomitant administration of 
a reduced dose of oral efavirenz (EFV). 
 
Secondary objectives are: 
- 
To determine if co-administration of reduced-dose efavirenz with the ENG contraceptive implant 
results in pharmacodynamic changes that suggest increased risk of ovulation and consequently 
decreased contraceptive efficacy. 
- 
To determine if co-administration of reduced-dose efavirenz with the ENG contraceptive implant 
affects pharmacokinetic parameters of efavirenz, compared to expected levels based on historical 
controls. 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with procedures, 
drug or device, and any other relevant information to justify the research) 
 
The hormones used in most forms of birth control, and the major classes of antiretroviral drugs, are 
metabolized by the same hepatic enzyme system – the P450 family, particularly CYP3A4[1].  Protease 
inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) are the classes of antiretroviral 
drugs (ARVs) that interact most significantly with the P450 enzymes, and individual drugs can induce or 
inhibit these enzymes, or both.  This raises concern for interactions with contraceptive hormones that could 
result in decreased contraceptive efficacy.  A 2011 review concluded that there may be reduced 
contraceptive efficacy when combined oral contraceptives (COCs) are taken simultaneously with highly-


Date: January 5th, 2017 
Principal Investigator: Jennifer Robinson, MD, MPH 
Application Number: NA_00087585 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 2 of 15 
 
active antiretroviral therapy (HAART), but that the efficacy of intermediate- and long-acting reversible 
methods (such as injectable, implantable, and intrauterine contraceptives) appears to be maintained[2]. 
 
Long-acting reversible contraceptive (LARC) methods are widely available in the US and around the 
world, and are highly effective in terms of both pregnancy prevention and cost.  They are also safe for use 
by women with various medical comorbidities, including HIV[3].  Several studies have demonstrated the 
safety of the intrauterine device (IUD) and depot medroxyprogesterone acetate (DMPA, a 3-month 
injectable contraceptive) in women with HIV[4-6] .  There is very limited data regarding another LARC 
method available in the United States and elsewhere: Nexplanon® (previously named Implanon®), an 
implantable rod that releases the progesterone etonogestrel (ENG) and prevents pregnancy for up to three 
years[7].   The implant contains 68 mg of ENG that is released slowly, maintaining a serum concentration 
greater than the 90 pg/ml needed for reliable ovulation suppression[8].  The package labeling for 
Nexplanon®/Implanon® raises concerns for potential drug interactions and decreased efficacy in HAART 
users; however, this is based on data regarding interactions between combined oral contraceptives (COCs) 
and antiretroviral drugs.  There are several case reports that suggest there may be decreased contraceptive 
efficacy in HIV-infected women who are using the ENG implant while taking HAART[9-12]. In all six 
reported cases, an unintended pregnancy occurred when the implant had been in place for at least 18 
months, and all women who experienced contraceptive failure were taking EFV.  Two studies investigating 
the effects of EFV on the ENG contraceptive implant have shown large, statistically significant decreases 
in ENG pharmacokinetic parameters compared to women not taking EFV[13, 14]. Even more concerning 
are results from a similar study investigating the effects of antiretroviral regimens, including an efavirenz-
based regimen, on a levonorgestrel (LNG) contraceptive implant.  The investigators found not only 
decreased LNG concentrations in women taking EFV, but three unintended pregnancies occurred in the 
EFV group[15]. 
 
 
 
4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
 
This will be a prospective, single arm pilot pharmacokinetic (PK) study. We will recruit 18 healthy, HIV-
negative women aged 18 to 40 years who are using Nexplanon®/Implanon® for contraception and who are 
willing to take a reduced dose of EFV for 2 weeks.  We will limit enrollment to women who have had the 
ENG implant in place 12 to 24 months to avoid the initial burst release of ENG after implant placement, 
and to target the time frame of concern based on case studies of contraceptive failures among women on 
HAART. Performing the study in women without HIV infection will allow us to evaluate any interactions 
between ENG and EFV without having to contend with the effects of other drugs that make up typical 
HAART regimens.  A two-week course of EFV will be sufficient for EFV to reach steady-state 
concentration while minimizing exposure in these healthy volunteers.  By using the reduced dose of EFV 
(400 mg daily instead of the standard 600 mg daily dose) 
 
Over 6 weeks from study entry, we will perform twice-weekly (see visit schedule) quantitative assessments 
of serum ENG as well as serum hormone concentration analysis, pelvic ultrasound for markers of 
ovulation, and cervical mucus testing, as described below.  Given the slow apparent clearance of ENG and 
based on previous PK studies, we estimate that sparse sampling will be adequate to assess changes in ENG 
clearance during EFV administration. EFV will be administered for 14 days from the beginning of the 
study, after collection of baseline samples for ENG concentration determination. All study procedures will 
take place at the Johns Hopkins Bayview Medical Center’s Clinical Research Unit (CRU).  All blood tests 
will be performed locally except for ENG concentrations, which will be performed at Columbia University 


Date: January 5th, 2017 
Principal Investigator: Jennifer Robinson, MD, MPH 
Application Number: NA_00087585 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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in New York City. ENG samples will be collected, frozen, and batch-shipped. The subject population will 
be healthy, HIV-negative women using Nexplanon®/Implanon®, with the anticipation that the findings 
will be applicable to HIV-infected women.  There is limited data regarding the use of the etonogestrel 
implant in obese women.  While two small studies found lower etonogestrel concentrations in obese 
women than normal weight women, the differences were not statistically significant[16, 17].  Overweight 
and obese women using the etonogestrel implant do not experience contraceptive failures more frequently 
than overweight or obese women using an intrauterine device[18].  We will limit enrollment to women with 
a BMI <30 kg/m2 so as to limit any effect morbid obesity may have on etonogestrel concentrations. We 
expect that the study will take a total of 12 months to complete. A screening visit to confirm eligibility will 
occur prior to initiation of study visits. 
 
Screening:  Potential subjects will be identified by their treating providers as meeting basic eligibility 
criteria (appropriate age and currently using Nexplanon®/Implanon®).  Each candidate will be informed of 
the study purpose and design, and will be given contact information for study personnel if she is interested 
in enrolling.  With her permission, the potential subject’s contact information will also be forwarded to 
study personnel, who will then contact her by phone.  During a phone interview, details of the study will be 
discussed with her, after which she will be asked to come to the Bayview CRU for an in-person interview.  
During this visit, she will be asked to read and sign the approved consent form, undergo a history and 
physical exam, and have baseline laboratory tests performed (hematologic and metabolic panels as 
described in Inclusion Criteria, serum HIV, urine pregnancy test), as well as a baseline ultrasound to ensure 
her ovaries are detectable.  Study personnel will review the results of the laboratory tests, and if all results 
are in the specified ranges, the subject will be contacted to schedule the start of the study protocol. 
 
Data collection:  After successful screening, women will be asked to take 14 days of EFV in a once-
nightly 400 mg regimen. We will collect blood samples for baseline ENG concentration on the day 
participants begin taking EFV, before the first dose (Day 1, times 0 hour, 1 hour, and 2 hours).  The first 
dose of EFV will be taken in the evening of Day 1, and the next blood sample for ENG concentration will 
be drawn twelve to twenty hours after the first dose of EFV. (For example, if a participant takes her first 
dose of EFV at 10 PM on Day 1, she will be asked to return to the CRU between 10 AM and 6 PM on Day 
2.) We will then obtain subsequent samples every 3 to 4 days (+/- 1 day) for the remainder of the two week 
EFV course and for 4 additional weeks (through Week 6 of study participation). This is a total of 14 
outpatient visits, including screening.   All serum samples will be analyzed for concentrations of ENG, 
which will be used to derive the ENG area under the concentration-time curve (AUC), the maximum and 
minimum observed serum drug concentration (Cmax, Cmin), and the apparent average serum concentration at 
steady-state (Cssavg) using WinNonlin®. EFV concentrations will be determined from plasma samples 
obtained at 2 timepoints during EFV administration, and measured using a validated LC/MS/MS assay in 
the Clinical Pharmacology Analytical Laboratory of the Johns Hopkins Hospital. 
 
Table 1: Participant Visit Schedule and Timing of Study Assessments 
Visit 
Screening 
Study Entry
Week 1
Week 2
Week 3
Week 4 
Week 5
Week 6
Day # 
 
1 
2 
7 
11 
14 
18 
21 
25 
28 
32 
35 
39 
42 
Serum Tests 
 
0 hr 
1 hr 
2 hr 
 
 
 
 
 
 
 
 
 
 
 
 
ENG 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EFV 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
  
FSH 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LH 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Estradiol 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Progesterone 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Labs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
UPT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
TVUS 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CM 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Date: January 5th, 2017 
Principal Investigator: Jennifer Robinson, MD, MPH 
Application Number: NA_00087585 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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Secondary endpoints will be serum markers of ovulation (estradiol [E2], progesterone [P], follicle 
stimulating hormone [FSH], and luteinizing hormone [LH]), as well as evidence of ovulation on cervical 
mucus exam and transvaginal ultrasound (presence and subsequent disappearance of a dominant follicle 
>15 mm diameter)[19].  Blood for hormone assays will be drawn at the Bayview CRU at the same time as 
samples for ENG and EFV.  During these visits participants will also undergo a pelvic exam for cervical 
mucus assessment, and a pelvic ultrasound to look for ovarian follicular activity.  Monitoring throughout 
the study will allow us to compare ovarian activity across time points through both ultrasound visualization 
and ovarian hormone testing (E2 and P).  Changes in cervical mucus quality secondary to the progestin 
activity of ENG provide secondary contraceptive effects that may be maintained even if ovulation occurs.  
Continued monitoring for several weeks after cessation of EFV will allow us to follow subjects for the 
equivalent of a normal menstrual cycle, to ascertain whether either contraceptive effect (ovulation 
suppression or cervical mucus quality) was altered.  Urine pregnancy tests may be repeated throughout the 
duration of the study as needed. 
 
Ultrasounds and venipuncture for LH, FSH, E2 and P levels will occur in the CRU. A total of 20 mL of 
venous blood will be collected for each outpatient visit. FSH, LH, E2, and P assays will be performed by 
the CRU at JHU.  FSH and LH will be measured using the automated immunoradiometric assay (IRMA) 
system. Assay sensitivity of LH assays is 0.07 mIU/ml; assay sensitivity of FSH assays is 0.2 mIU/ml. P 
will be measured using an automated immulite chemiluminescent assay system. Assay sensitivity of the P 
assay is 0.05 ng/ml.  E2 will be measured via an ultra-sensitive competitive binding radioimmunoassay with 
sensitivity of 2.2 pg/ml. The EFV assay will be performed through the Johns Hopkins Hospital Clinical 
Pharmacology Analytical Lab, and will be measured via LC-MS/MS assay with a lower limit of 
quantification of 0.5 ng/ml. 
 
An assay for ENG is not commercially available, but the Irving Institute for Clinical and Translational 
Research at the Columbia University Medical Center in New York has developed a validated assay.  ENG 
concentrations will be measured by LC-MS/MS, and the assay has a lower limit of quantification of 50 
pg/ml. 
 
Transvaginal ultrasound (TVUS) will be performed using high-resolution machines (Sonosite Edge, 
SonoSite, Inc., Bothell, WA) in our clinic to monitor follicular development. Follicular diameter will be 
calculated by averaging the mean of the length and width in both the sagittal and transverse plane.  Follicles 
measuring > 10 mm will be considered dominant preovulatory follicles, and only follicles measuring >10 
mm will be recorded[20]. Ovulation will be defined as the disappearance of a follicle > 15 mm in diameter 
that was observed the visit before.  We will collect cervical mucus using an endocervical aspirator, and 
evaluate the sample for consistency, ferning, Spinnbarkeit, and cellularity. Each variable will be scored on 
a 0 to 3 point scale according to WHO guidelines.  A total score of 9 to 12 will indicate mucus conditions 
favorable to sperm penetration[21]. 
 
Recruitment: Subjects will be recruited from the general gynecology office in JHOC and practices 
affiliated with JHBMC.  We will recruit patients known to be using Nexplanon®/Implanon®.  Written 
notices advertising the study will be placed in the gynecology offices as well as in other affiliated primary 
care offices.  We will also place advertising notices throughout Johns Hopkins institutions including the 
School of Nursing and the School of Public Health. 
 
b. Study duration and number of study visits required of research participants. 
 


Date: January 5th, 2017 
Principal Investigator: Jennifer Robinson, MD, MPH 
Application Number: NA_00087585 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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We anticipate that the study will take 12 months to complete.  Participants will be enrolled for a total of 6 
weeks (2 weeks taking EFV, and 4 weeks additional follow-up), during which time they will complete 14 
visits including a screening visit.  After enrollment, visits will occur twice weekly. 
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
Not applicable in this pilot pharmacokinetic study 
 
d. Justification of why participants will not receive routine care or will have current therapy 
stopped. 
 
Not applicable. 
 
e. Justification for inclusion of a placebo or non-treatment group. 
 
Not applicable. 
 
f. Definition of treatment failure or participant removal criteria. 
 
Treatment failure is not applicable to this study as efavirenz is being given to healthy volunteers and not 
part of an HIV treatment regimen.  A participant will be removed from the study under the following 
circumstances: 
- 
She misses more than three study visits 
- 
She becomes pregnant 
- 
She experiences a serious adverse event 
- 
She requests to stop the study 
 
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
 
If a participant leaves the study prior to its completion, there will be no effect on her general medical care.  
At the conclusion of the study, participants will not receive any additional study medications and will 
return to their routine care providers for ongoing care as needed. 
 
5. 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria: 
- 
Healthy women aged 18-40 years who have a Nexplanon®/Implanon® in place that is palpable on 
exam, had the device placed between 12 and 24 months prior to enrollment, and can provide 
documentation of when the implant was placed 
- 
Able to speak and read English 
- 
Documented HIV-negative status within 30 days of enrollment 
- 
BMI between 18.5 and 29.9 kg/m2 
- 
Willingness to take a two-week course of reduced-dose efavirenz 
- 
Willingness to comply with study visit schedule (as described below), including blood sampling, 
transvaginal ultrasounds, and cervical mucus assessment 
- 
Negative urine hCG pregnancy test at study entry 
- 
Normal laboratory values within 30 days of study entry, as specified below: 
o White blood cell count ≥ 4500 and ≤ 11000 cells/mm3 
o Platelet count ≥ 100,000 platelets/mm3 


Date: January 5th, 2017 
Principal Investigator: Jennifer Robinson, MD, MPH 
Application Number: NA_00087585 
 
 
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Version 3 Dated:   06/2007 
 
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o Hemoglobin ≥ 8.0 g/dL 
o International normalized ratio (INR) ≤ 1.8 
o Aspartate transaminase (SGOT) and alanine aminotransferase (SGPT) ≤ 3 times the upper 
limit of normal (ULN) (upper limit of normal) 
o Creatinine ≤ 1.5 x ULN 
o Serum amylase ≤ 1.5 x ULN 
o Total bilirubin ≤ 2.0 x ULN 
- 
Agree to use an additional reliable method of contraception while participating in the study.  
Acceptable methods include: 
o Abstinence 
o Condoms (male or female) with or without spermicide 
o Pre-existing sterilization of subject or her male partner 
- 
Willingness to abstain from alcohol consumption during the study period 
- 
Willingness to abstain from any grapefruit product or supplement for the duration of the study. 
 
Exclusion Criteria: 
‐ 
Breastfeeding 
‐ 
Hypersensitivity to efavirenz 
‐ 
History of seizure disorder 
‐ 
History of significant psychiatric illness 
‐ 
Initiated, discontinued, or changed doses of drugs that are CYP3A4 inducers or inhibitors within 30 
days of study entry. 
 
Disallowed Drugs 
Antibiotics and other anti-infectives 
Artemether 
Atovaquone 
Bedaquiline 
Clarithromycin 
Lumefantrine 
Proguanil 
Rifabutin 
Rifampin 
Anticoagulants and Antiplatelet Drugs 
Apixaban 
Clopidogrel 
Rivaroxiban 
Ticagrelor 
Warfarin 
Anticonvulsants 
Carbamazepine 
Felbamate 
Fosphenytoin 
Lamotrigine 
Oxcarbazepine 
Perampanel 
Phenobarbital 
Phenytoin 
Topiramate 
Antidepressants, Antipsychotics 
Aripiprazole 
Bupropion 
Citalopram 


Date: January 5th, 2017 
Principal Investigator: Jennifer Robinson, MD, MPH 
Application Number: NA_00087585 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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Clobazam 
Clozapine 
Lurasidone 
Mirtazapine 
Pimozide 
Quetiapine 
Sertraline 
Vilazodone 
Vortioxetine 
Antifungals 
Caspofungin 
Griseofulvin 
Itraconazole 
Posaconazole 
Voriconazole 
Antihistamines 
Astemizole 
Azelastine 
Cisapride 
Doxylamine 
Hydroxyzine 
Antihypertensive and Cardiac Drugs 
Bepridil 
Carvedilol 
Diltiazem 
Dofetilide 
Dronedarone 
Eplerenone 
Guanfacine 
Metyrosine 
Nifedipine 
Nisoldipine 
Propafenone 
Ranolazine 
Timozide 
Antineoplastic Agents 
Abiraterone acetate 
Axitinib 
Bortezomib 
Bosutinib 
Bretuximab vedotin 
Cabozantinib 
Crizotinib 
Dabrafenib 
Dasatinib 
Everolimus 
Ifosfamide 
Imatinib 
Lapatinib 
Nilotinib 
Paclitaxel 
Pazopanib 
Ponatinib 


Date: January 5th, 2017 
Principal Investigator: Jennifer Robinson, MD, MPH 
Application Number: NA_00087585 
 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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Regorafenib 
Romidepsin 
Sorafenib 
Sunitinib 
Vandetanib 
Vemurafenib 
Vincristine 
Cholesterol-lowering agents 
Atorvastatin 
Lovastatin 
Pravastatin 
Simvastatin 
Ergot derivatives 
Dihydroergotamine 
Ergotamine 
Ergonovine 
Methylergonovine 
Immunomodulators and immunosuppressants 
Cyclosporine 
Mycophenolate 
Pomalidomide 
Sirolimus 
Tacrolimus 
Tocilizumab 
Tofacitinib 
Sedative hypnotics, Sleep aid 
Midazolam 
Quazepam 
Triazolam 
Zolpidem 
Herbal products 
St. John’s Wort 
Bloodroot 
Chasteberry 
Oregano 
Grapefruit juice 
Gingko biloba 
Opiate agonists and antagonists 
Buprenorphine 
Fentanyl 
Methadone 
Tapentadol 
Hypoglycemic agents 
Exenatide 
Linagliptin 
Saxagliptin 
Anti-Parkinson’s Agents 
Pramipexole 
Ropinirole 
Rotigotine 
Antiemetics 
Aprepitant 
Fosaprepitant 
Antiretroviral drugs 
Atazanavir 
Boceprevir 
Cobicistat 
Darunavir 
Dolutegravir 


Date: January 5th, 2017 
Principal Investigator: Jennifer Robinson, MD, MPH 
Application Number: NA_00087585 
 
 
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6. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 
Nexplanon®/Implanon® is the only contraceptive implant currently available in the United States, and is 
the most effective reversible contraceptive method with a failure rate of less than 0.05%[22].  As it is a 
progestin-only method, it is safe for use in women with a variety of medical comorbidities who are unable 
to take estrogen-containing methods.  The World Health Organization Medical Eligibility Criteria (WHO 
MEC) rates Nexplanon®/Implanon® as category 1 (no restriction for use) for women with HIV/AIDS, and 
category 2 (advantages of use generally outweigh theoretical or proven risks) for women taking NNRTIs 
and PIs, due to theoretical concerns about decreased contraceptive efficacy related to drug interactions[23].  
Case reports of 7 pregnancies occurring in 6 HIV-positive women taking efavirenz and 
Nexplanon®/Implanon® simultaneously suggest the concern about drug interactions between these two 
compounds may be more than theoretical[9-12]. Two recent clinical studies have demonstrated significant 
reductions in serum etonogestrel concentrations when women using Nexplanon® were treated for HIV 
infection using standard doses of efavirenz[13, 14].  Another study evaluating the concurrent use of a 
levonorgestrel contraceptive implant and either efavirenz- or nevirapine-based antiretroviral regimens for 
treatment of HIV found that women taking efavirenz experienced not only decreased levonorgestrel 
concentrations, but unplanned pregnancies as a result of contraceptive implant failures[15]. 
 
Accumulating evidence suggests a significant effect of efavirenz on systemic concentrations of etonogestrel 
when the two medications are taken together.  Published studies have focused on changes in serum 
concentrations of etonogestrel and serum progesterone concentrations as a marker of ovulation, but they 
have not evaluated the other ways the etonogestrel implant likely prevents pregnancy (i.e. changes in 
endometrium and cervical mucus).  It remains unclear whether a lower dose of efavirenz will lead to a 
similar decrease in etongestrel concentrations. We propose this study to formally evaluate the interactions 
that may exist between these two drugs.  Among the antiretroviral drugs that could affect the activity of 
ENG, we selected EFV for this study because of the case reports mentioned above as well as its widespread 
use as part of first-line antiretroviral regimens.  We will use a lower dose than that currently used in clinical 
practice (400 mg orally each night, instead of the standard dose of 600 mg). 
 
b. Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or participant populations are 
changed. 
 
This pilot study is being conducted to determine if reduced-dose EFV decreases the efficacy of ENG 
delivered by the contraceptive implant to the point where HIV-positive women taking reduced-dose EFV 
Etraverine 
Fosamprenavir 
Indinavir 
Lopinavir 
Maraviroc 
Nevirapine 
Raltegravir 
Ritonavir 
Saquinavir 
Telaprevir 


Date: January 5th, 2017 
Principal Investigator: Jennifer Robinson, MD, MPH 
Application Number: NA_00087585 
 
 
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who are also relying on this contraceptive are at increased risk of unintended pregnancy.  The use of EFV 
in this protocol is therefore off-label in that EFV will be given to HIV-uninfected women.  EFV is indicated 
only for use in combination with other antiretroviral drugs in the treatment of HIV.  Consequently, it would 
be very difficult to isolate the effects of EFV on ENG in women taking combination antiretroviral therapy 
due to the potential other drug interactions that may be present. 
 
EFV was chosen for this study because it is the backbone of one of the preferred antiretroviral regimens 
recommended by the NIH[24].  As such, it is commonly taken by women of reproductive age.  There is 
some concern that EFV increases the risk of neural-tube defects when exposure occurs during the first 5-6 
weeks of pregnancy[21].  For this reason, it is particularly important to avoid unintended pregnancy in 
women taking EFV.  Determining whether the ENG implant retains its high level of contraceptive efficacy 
in women taking EFV is important so that HIV-positive women and their healthcare providers can make 
the most informed decisions regarding antiretroviral regimens and contraception. 
 
The dose of EFV that is used in clinical practice is 600 mg given orally once per day, typically at bedtime, 
and it is generally well tolerated[25].  Recent data suggest that a lower daily dose of EFV (400 mg) is as 
effective as the standard 600 mg dose in suppressing HIV, with lower incidence of drug-related side 
effects. As the criteria for starting ART continue to broaden, there is considerable concern about the costs 
of providing treatment to more individuals, and reducing the accepted dose of EFV is one strategy to make 
ART available to as many people as possible[26].  
 
Certain drugs are contraindicated or not recommended for use with EFV, including ergot derivatives, 
benzodiazepines, calcium channel blockers, cisapride, pimozide, and St. John’s wort.  Women taking these 
drugs will be excluded from the study due to potential adverse drug interactions.  While the 400 mg daily 
dose of EFV has been associated with a lower incidence of drug-related adverse events, participants will be 
informed of potential adverse reactions to EFV prior to enrolling in the study, and will be counseled 
regarding when and how to inform study personnel of any potential adverse reactions.  The adverse 
reactions that have been identified in studies comparing EFV-based antiretroviral regimens to control 
regimens include: 
‐ 
Psychiatric symptoms: depression (19% with EFV-based regimen vs. 16% with control), anxiety 
(13% vs. 9%), nervousness (7% vs. 2%) 
‐ 
Nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal 
dreaming, euphoria, confusion, agitation, amnesia, hallucinations, stupor, abnormal thinking, 
depersonalization.  Mild symptoms occurred in 33.3% of patients taking EFV compared to 15.6% of 
patients in control groups; moderate symptoms occurred in 17.4% of patients taking EFV compared 
to 7.7% of controls; and severe symptoms occurred in 2% of patients taking EFV compared to 1.3% 
of controls. 
‐ 
Rash: 26% of patients taking EFV developed a rash compared to 17% of patients in control groups.  
A grade 4 rash (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, 
necrosis requiring surgery, exfoliative dermatitis) was seen in 0.1% of patients treated with EFV 
and no patients in control groups.  Rashes usually occur during the first two weeks of treatment, and 
are mild-to-moderate maculopapular skin eruptions.  The rash typically resolves within one month 
in patients who continue EFV. 
‐ 
Hepatotoxicity: it is recommended that liver enzymes be evaluated before and during treatment with 
EFV, as EFV can cause elevated liver enzymes even in patients without underlying hepatic disease. 
‐ 
Convulsions: Convulsions have been noted in patients treated with EFV, typically in the setting of a 
known seizure disorder. 
‐ 
Lipid elevations: EFV can lead to increased concentrations of total cholesterol and triglycerides.  
Some HIV-uninfected volunteers who received EFV were noted to have 10-20% increases in total 
cholesterol from baseline. 


Date: January 5th, 2017 
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‐ 
Fat redistribution: Body fat may redistribute or accumulate in certain regions of the body, including 
central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, 
breast enlargement, and “cushingoid appearance.”  This phenomenon has been noted among 
patients taking antiretroviral therapy in general, and while it has not been specifically linked to 
EFV, it is a potential adverse reaction to this drug. 
 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.  
 
Not applicable 
 
7. 
Study Statistics 
a. Primary outcome variable. 
 
Primary Outcome: Serum concentrations of ENG before and after two weeks of reduced-dose EFV 
 
b. Secondary outcome variables. 
 
Secondary Outcomes: 
- 
Serum concentrations of EFV at the start and end of the study period 
- 
Serum hormonal markers of ovulation (P, E2, LH, FSH) 
- 
Presence of dominant follicle(s) on transvaginal ultrasound during and after EFV dosing 
- 
Change in cervical mucus quality suggesting ovulation during and after EFV dosing 
 
c. Statistical plan including sample size justification and interim data analysis. 
 
Sample size:  We hypothesize that during co-administration of the ENG implant and reduced-dose EFV, 
we will detect a decrease in serum ENG concentrations, but that overall contraceptive effect will be 
maintained.  We do not anticipate that any subjects will have a drop in ENG concentration below the 
threshold needed for ovulation suppression (90 pg/mL)[8].  Using a two-sided Wilcoxon test, a sample size 
of 15 will have 80% power (with an alpha of 0.05) to detect a 20% difference in ENG concentration 
between women taking EFV and historical controls. We plan to enroll 18 women to account for a potential 
20% drop-out rate. 
 
Data Analysis: We will calculate area under the curve (AUC) and maximum and minimum concentrations 
of each drug (Cmax and Cmin), as noted above.  For hormone markers (LH, FSH, E2, P) we will evaluate 
change over time as well as whether pertinent threshold levels are reached that could indicate that ovulation 
has occurred.  All serum tests will be evaluated through the Johns Hopkins Division of Clinical 
Pharmacology, with the exception of etonogestrel concentrations as this assay is not widely available.  
Serum samples will be frozen and shipped to the Irving Institute for Clinical and Translational Research at 
Columbia University Medical Center in New York City, which will perform the etonogestrel assay. 
 
Interpretation: If the pharmacokinetic parameters for etonogestrel that are seen in this interaction study 
are consistent with those published in the literature (less than 30% difference), we will conclude that there 
is no significant interaction between ENG and reduced-dose EFV.  This would support the assertion that 
Nexplanon®/Implanon® is a safe and effective option for HIV-infected women taking reduced-dose EFV 
who desire long-acting reversible contraception.  However, if two or more women out of a sample of 15 
breach the threshold concentration needed for ovulation suppression, it will indicate a statistically and 
clinically significant decrease in ENG concentration and potential for decreased contraceptive efficacy.   
 


Date: January 5th, 2017 
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d. Early stopping rules. 
 
Participants may be removed from the study under the following circumstances: 
- 
Participant requests to withdraw from the study 
- 
Participant requests that she have the ENG implant removed prior to conclusion of the study. (Of 
note, removal would be performed by the subject’s clinician and not performed as part of the study.) 
- 
Participant judged by the investigator to be at significant risk of failing to comply with the 
provisions of the protocol as to cause harm to self or seriously interfere with the validity of the 
study results. 
- 
Participant takes emergency contraception during the study 
 
8. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency. 
 
The medical risks related to participation in this study fall into two categories: medication side effects or 
adverse reactions, and possible contraceptive failure. 
 
Medication Adverse Reactions: 
The most common adverse reactions for EFV are: 
- 
Psychiatric symptoms – severe depression (2.4%), suicidal ideation (0.7%), nonfatal suicide 
attempts (0.5%), aggressive behavior (0.4%), paranoid reactions (0.4%), and manic reactions 
(0.2%) 
- 
Central nervous system symptoms (overall incidence 53%) – dizziness (28.1%), insomnia (16.3%), 
impaired concentration (8.3%), somnolence (7%), abnormal dreams (6.2%), and hallucinations 
(1.2%) (usually begin during the first 2 days of therapy and resolve after 2-4 weeks). 
- 
Rash (26%) – usually mild to moderate maculopapular skin eruptions that occur within the first 2 
weeks of initiating therapy and typically resolve within 1 month 
 
Additional adverse reactions to EFV include elevated liver enzymes, convulsions, elevated total cholesterol 
and triglycerides, and fat redistribution.  Adverse reactions attributed to EFV occurred less frequently with 
the 400 mg daily dose compared to 600 mg[27]. 
 
It is possible that any changes in ENG concentrations that occur during and after the course of EFV could 
lead to increased incidence of adverse reactions to ENG.  The most common adverse reactions leading to 
discontinuation of Nexplanon®/Implanon® are[7]Error! Bookmark not defined.: 
- 
Bleeding irregularities (11.1%) 
- 
Emotional lability (2.3%) 
- 
Weight increase (2.3%) 
- 
Headache (1.6%) 
- 
Acne (1.3%) 
- 
Depression (1.0%) 
 
Given that co-administration of EFV with the ENG implant may lead to decreased serum concentrations of 
ENG, participants may experience greater or lesser breakthrough bleeding than is typical with the ENG 
implant.  They could also experience an improvement in progestin-related side effects with lower ENG 
concentrations. 
 
Unintended Pregnancy 
Since the goal of the study is to determine whether reduced-dose EFV lowers the serum concentration of 
ENG to a level where ovulation might occur, there is the possibility that a participant could ovulate during 


Date: January 5th, 2017 
Principal Investigator: Jennifer Robinson, MD, MPH 
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or after taking reduced-dose efavirenz.  If she is sexually active during the study, this would put her at risk 
of an unintended pregnancy.  There is also some concern that EFV may cause neural tube defects when 
taken during the first trimester.  This risk was suggested by isolated case reports; however, larger reviews 
have found no increased risk in congenital anomalies with EFV. 
 
b. Steps taken to minimize the risks. 
 
Participants will be advised to take EFV at bedtime and on an empty stomach in an effort to minimize the 
central nervous system effects.  They will also be counseled about the potential for psychiatric effects and 
rash as part of the informed consent process, and will be provided with contact information for study 
personnel should they experience any concerning symptoms. If needed, depending on the nature of the 
psychiatric symptoms or effects, participants will be referred for appropriate clinical care.  This may 
include the emergency department, a psychologist, or the participant’s primary care physician. 
 
Participants will also be encouraged to either abstain from intercourse during the study period, or to use an 
additional backup method such as male or female condoms.  They will be counseled about the potential for 
unintended pregnancy and teratogenic effects as part of the informed consent process.  Participants will 
also be counseled about the availability of emergency contraception (either over-the-counter or by 
prescription) if they ever feel at risk for unintended pregnancy during the study (i.e. in the event of condom 
breakage). 
 
c. Plan for reporting unanticipated problems or study deviations. 
 
If there is an emergency protocol deviation, it will be reported to the IRB by the study team as soon as 
possible, but no later than 5 business days after the occurrence.  The PI will submit a report through eIRB 
as a Further Study Action using the Problem/Event Report.  Any major, non-emergent protocol deviations 
will be submitted to the IRB as a Change in Research prior to the change being implemented.  Minor or 
administrative protocol deviations will be reported to the IRB as part of a continuing review application. 
 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
 
If there is a breach of confidentiality during the study, it could lead to disclosure of sensitive health 
information such as a participant’s sexual history or contraceptive use.  All specimens and study 
documentation will be labeled with a participant ID number to prevent identification of each participant.  
Identifiable participant information will be maintained in secure documents, either in a locked file cabinet 
or password protected computer files that are accessible only to study personnel.   
 
e. Financial risks to the participants. 
 
The risk of a drug-related adverse event occurring during the study is low, but if such an event occurs the 
study participant will be financially responsible for the evaluation and treatment of the adverse event. For 
example, if a participant experiences a rash related to efavirenz, she will be responsible for the costs of 
medication used to treat the rash. Such treatments may be covered by health insurance or paid for out of 
pocket. 
 
9. 
Benefits 
a. 
Description of the probable benefits for the participant and for society. 
 
The results of this pilot study will provide greater understanding of whether reduced-dose efavirenz, a 
commonly used NNRTI, affects etonogestrel concentrations in women using Nexplanon®/Implanon® such 


Date: January 5th, 2017 
Principal Investigator: Jennifer Robinson, MD, MPH 
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that contraceptive effect is compromised.  By investigating the effects of one component of HAART on 
Nexplanon®/Implanon® in a population of healthy volunteers, this preliminary data will help guide future 
studies of the efficacy of Nexplanon®/Implanon® in HIV-infected women on multi-agent therapy.  
Determining whether this highly-effective reversible contraceptive method is a safe and viable option for 
HIV-infected women on HAART will broaden these patients’ contraceptive options, particularly when they 
wish to avoid pregnancy for an extended period of time.  The knowledge gained from this study will also 
help determine whether the lifespan of Nexplanon®/Implanon® is reduced in women taking reduced-dose 
efavirenz.  After Nexplanon®/Implanon® is inserted, there is an initial burst release of etonogestrel, and 
peak serum concentration is reach at a mean of 4 days after placement[7].  Serum ENG concentrations 
decline slowly over the three-year lifespan of the implant, and this study will provide information as to 
whether ENG concentrations remain sufficient to reliably suppress ovulation when EFV is taken 
simultaneously.  If reduced-dose EFV causes ENG concentrations to decrease below the ovulation 
suppression threshold, the ENG implant may need to be replaced prior to the licensed three years. 
 
10. 
Payment and Remuneration 
a. 
Detail compensation for participants including possible total compensation, proposed bonus, 
and any proposed reductions or penalties for not completing the protocol. 
 
Participants will be compensated as follows:  
- 
Screening visit = $75 
- 
Enrollment visit = $45 
- 
Follow-up visits (total of 12) = $60 each = $720 total 
- 
Bonus payment for completion of study = $180 
- 
Parking/Bus tokens (total of 14) = $5 each = $70 total 
 
This comes to a total of $1090 for each participant at the end of the study.  The bonus payment at the 
completion of the study will be made if there have been no significant deviations from the study protocol.  
Participants will not be compensated for visits that are not completed, and they will not receive the bonus if 
they are missing data for three or more visits. 
 
11. 
Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify 
who will pay for them. 
There will be no costs incurred by the participants.  In order to be eligible for the study, participants must 
already be using Nexplanon®/Implanon® for contraception, so they will not be provided with the implant 
by the study.  The two-week course of reduced-dose efavirenz costs $285 per participant and will be 
provided by the study through the Johns Hopkins Bayview Medical Center Pharmacy Service for Clinical 
Investigations.  Phlebotomy for all blood samples will be performed at the Johns Hopkins Bayview 
Medical Center Clinical Research Unit and will not be charged to participants.  These costs will be paid for 
by the study. Members of the study team will be performing all transvaginal ultrasounds and cervical 
mucous assessments, so there is again no cost to participants. 
 
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3. 
Organization, W.H., Medical Eligibility Criteria for Contraceptive Use. 2010, World Health Organization: 
http://www.who.int/. 


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