Pharmacokinetic and Pharmacodynamic Evaluation of Etonogestrel Dose Escalation With Efavirenz-based Antiretroviral Therapy in HIV-infected Ugandan
Phase: PHASE2
Conditions: HIV/AIDS, Contraception
Sponsor: Catherine Anne Chappell

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PHARMACOLOGIC STRATEGIES FOR ETONOGESTREL IMPLANTS IN 
HIV-INFECTED WOMEN 
 
Subtitle (descriptive): Pharmacokinetic and pharmacodynamic evaluation of etonogestrel 
dose escalation with efavirenz-based antiretroviral therapy in HIV-infected Ugandan 
women  
Area:  
HIV 
Type: 
Phase II  
 
Consortium Principal Investigator: University of Pittsburgh 
Catherine A. Chappell, MD, MSc 
Assistant Professor 
University of Pittsburgh 
Department of Obstetrics, Gynecology, and Reproductive Sciences 
300 Halket Street 
Pittsburgh, PA 15213-3180 
Phone: +1.412.641-1403 
Fax: +1.412.641-1133 
E-mail:  chappellca@upmc.edu 
 
Consortium Principal Investigator: University of Nebraska Medical Center 
Kimberly Scarsi, PharmD, MSc 
Associate Professor 
University of Nebraska Medical Center 
College of Pharmacy, Rm 4045 
986045 Nebraska Medical Center 
Omaha, NE 68198-6045 
Ph. +1.402.559.5390 
Fax +1.402.559.5673 
E-mail:  kim.scarsi@unmc.edu 
 
Consortium Principal Investigator: Infectious Disease Institute 
Mohammed Lamorde, MRCP, PhD 
Head, Prevention Care and Treatment 
Infectious Diseases Institute, Makerere University College of Health Sciences 
Mulago Hospital Complex 
Kampala, Uganda 
Phone: +256414307291 
E-mail: mlamorde@idi.co.ug  
 
Co-investigators:  
Kristin M. Darin, PharmD 
Research Assistant Professor 
Center for Global Health 
Feinberg School of Medicine 

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Northwestern University  
645 N. Michigan Ave. Suite 1058 
Chicago, IL 60611  
Ph +1.228.327.3844 
E-mail: k-hurt@northwestern.edu  
 
Pauline Byakika-Kibwika, MBChB, MSc, MMed, PhD 
Associate Professor, Department of Medicine, School of Medicine 
Makerere University College of Health Sciences 
P.O. Box 7072, Kampala 
Phone: +256414307291 
Email: pbyakika@idi.co.ug 
 
Susan E. Cohn, MD, MPH 
Professor of Medicine 
Northwestern University Feinberg School of Medicine 
Division of Infectious Diseases 
645 N. Michigan Ave, Ste. 900 
Chicago, IL 60611 
Phone: +1.312.926.3693 
E-mail: susan-cohn@northwestern.edu 
 
Sharon A. Riddler, MD, MPH 
Professor of Medicine 
University of Pittsburgh  
Division of Infectious Diseases  
Keystone Building, Suite 510 
3520 Fifth Avenue 
Pittsburgh, PA 15213  
Phone:  +1.412.383.1741 
E-mail:  riddler@pitt.edu 
 
Shadia Nakalema, MBChB, DTMH 
Infectious Diseases Institute, Makerere University College of Health Sciences 
Kampala, Uganda 
Phone: +256414307238 
Email: snakalema@idi.co.ug 
 
Funding: Merck Immunology Investigator Initiated Studies Program #55906 
 
Clinical Trials Registration number: NCT03282799 
 
 
 
 

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Document History 
 
Document 
Version Date 
Summary of Changes 
Version 1.1 
3 Nov 2017 
 
Version 2.0 
 
Responses to NDA comments with the following 
additions: 
-Appendix 1 (WHO Medical Eligibility Criteria for 
IUDs and Implants) 
-Clarified Inclusion criteria #8 regarding menstural 
bleeding pattern 
-QRISK®2 Score, hemoglobin A1c and lipid 
assessment added to screening procedure  
-QRISK® Score added to exclusion criteria #11 
-Screening window extended to 90 days to allow 
for IUD placement and return of regular menses 
-Allowance for participant re-screen  
-Added HIV/Family Planning Counseling added to 
each visits 
-Contraceptive Satisfaction and Condom Use 
Surveys removed from visits when they occur more 
frequently than every month 
-Flexibility added in the scheduling of weekly 
assessments for serum progesterone and cervical 
mucus testing 
-Clarified management in the case of efavirenz non-
adherence or discontinuation 
-Clarified serious adverse event reporting 
requirements  
Version 3.0 
16 Oct 2020 
Ugandan National Antiretroviral Guidance Change 
-Efavirenz 600 mg no longer recommended 
-All participants will be transitioned to either 
efavirenz 400 mg or dolutegravir-based 
antiretroviral therapy (ART)  
-Those participants on double-dose etonogestrel 
(two implants) who switch to dolutegravir-based 
ART will have one implant removed to return to 
standard dose etonogestrel 
-Four optional blood draws added at the time of 
ART switch to characterize the pharmacokinetics of 
efavirenz and etonogestrel after ART switch 
-Discontinuation of the cervical mucus collection 
and scoring due to futility 
Version 4.0 
26 May 2021 
-Allows for continued participation for participants 
that switch from efavirenz 400mg to dolutegravir-
based ART with that same study procedures as 

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those who switched from efavirenz 600 mg to 
dolutegravir-based ART in version 3.0 
-Provides counseling guidance for the removal of 
the copper IUD after switching to dolutegravir-
based ART 
 
 
Study Location and IRB of 
Record 
Date of Initial Approval 
Date of Revised Protocol 
Approvals 
University of Pittsburgh 
3 Nov 2017 
 
Infectious Diseases Institute; 
Joint Clinical Research Center 
IRB  
5 Dec 2017 
 

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PROTOCOL SUMMARY  
 
Title 
Pharmacokinetic and pharmacodynamic evaluation of etonogestrel 
dose escalation with efavirenz-based antiretroviral therapy in HIV-
infected Ugandan women (DoublET) 
Short Title 
Evaluation of the etonogestrel implant in HIV-infected women 
 
Protocol Number 
PK-20 
 
Phase 
II 
 
Methodology 
A randomized, open-label, longitudinal pharmacodynamic study to 
compare frequency of ovulation between a control group of HIV-
infected women on efavirenz (EFV)-based antiretroviral therapy 
receiving standard dose etonogestrel (ENG) implant and a 
treatment group receiving increased dose ENG implant. The overall 
goal is to assess the pharmacodynamic significance of the known 
drug-drug interaction between EFV and ENG and to determine if 
the increased dose will overcome this interaction.  Overall, this 
study will improve long-acting reversible contraceptive treatment 
options for women living with HIV and prevent unintended 
pregnancy. 
 
Study Duration 
48 weeks; if all safety measures are met, will extend to 144 weeks 
 
Study Center(s) 
Infectious Diseases Institute; Kampala, Uganda 
 

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Objectives 
Primary objective: 
To compare the rate of ovulation (by weekly endogenous 
progesterone at months 3, 6, and 12) when women receive two 68 
mg ENG implants (dose-escalated) compared to one 68 mg ENG 
implant (standard dose) in combination with EFV-based ART. 
 
Secondary objectives: 
1. To determine cervical mucus quality (by collecting weekly 
WHO cervical mucus scores at months 3, 6, and 12) when 
women receive two 68 mg ENG implants (dose-escalated) 
compared to one 68 mg ENG implant (standard dose) in 
combination with EFV-based ART.  
2. To compare the PK parameters of two ENG implants (136 
mg total) with combined EFV use versus the standard dose 
68 mg ENG implant with no ART (historical controls in the 
same population using the same laboratory1) over 6 months 
of combined use.   
3. To evaluate the safety and tolerability of two ENG implants 
with combined EFV-based ART use. 
4. To describe the relationship between ENG concentrations 
and participant specific variables, specifically body weight, 
albumin, sex hormone binding globulin, pharmacogenetic 
polymorphisms, and ART concentrations. 
5. To describe the long term feasibility and tolerability of 
increased dose ENG (136mg) subdermal implant use in 
HIV-infected women receiving EFV-based ART after 
weeks 96 and 144 of combined use. 
6. To describe the change in EFV trough concentrations and 
ENG steady state concentrations after switching from EFV 
600mg to either dolutegravir (DTG)- or EFV 400mg-based 
ART and after switching from EFV 400mg to dolutegravir 
(DTG)-based ART. 
 
Number of Participants 
HIV-infected women receiving EFV-based ART, n=72 
 
Diagnosis and Main 
Inclusion Criteria 
Consenting HIV-infected women receiving EFV-based ART for at 
least 3 months, who are medically eligible for the use of an ENG 
subdermal implant as a contraceptive method.   
 
Study Product(s), Dose, 
Route, Regimen 
Increased dose ENG implant (two implants, total 136mg) placed 
subdermally on study day 0 after baseline evaluations.  

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Duration of 
administration 
Planned study duration will be at least 48 weeks if all safety 
measures are met, but may extend up to 144 weeks to assess long 
term safety  
 
The ENG implant system is approved for 3 years of use. 
Participants may continue to use the ENG implant as part of 
standard of care after the study period. 
 
Reference therapy 
For pharmacodynamic outcomes:  Standard dose ENG implant (one 
implant, total 68mg) placed subdermally on study day 0 after 
baseline evaluations. 
 
For pharmacokinetic outcomes: Standard dose ENG implant 
without ART from a historical group of participants (N=20) from 
the same research site (IDI) and ENG assays performed in the same 
laboratory (University of Pittsburgh) followed for 6 months 
Statistical Methodology 
The ovulatory rate and the number of WHO mucus scores greater 
than 10 will be compared between the groups (standard-dose vs. 
dose escalated implant groups) at month 3, 6 and 12 of implant use 
using mixed-effects logistic regression.   
 
Between-group comparisons will evaluate changes in ENG PK 
parameters between the historical standard dose ENG implant 
without ART vs. dose-escalated ENG implant group with 
concurrent EFV-based ART use for 6 months. Geometric mean 
ENG will be compared at each time point (weeks 1, 4, 12, and 24) 
between the historical control group and two ENG implants (dose-
escalated on EFV-based ART group using a Wilcoxon rank sum 
test. Drug concentrations will be summarized descriptively 
(geometric mean, minimum, maximum, standard deviation) by 
study visit.  The ENG concentration-time curve will be evaluated 
using standard non-compartmental analysis (Phoenix, Pharsight®).  
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE 
Adverse events 
ALT 
Alanine transaminase 
ART 
Antiretroviral therapy 
AUC 
Area under the concentration-time curve 
CRF 
Case report form 
CYP 
Cytochrome P450 
D 
Day 
DAIDS 
National Institute of Health Division of AIDS 
DDI 
drug-drug interactions 
DTG 
dolutegravir 
EFV 
efavirenz 
ENG 
Etonogestrel  
GCP 
Good Clinical Practices 
GMR 
Geometric mean ratio 
HIV 
Human Immunodeficiency Virus 
HPLC 
High performance liquid chromatography 
IDI 
Infectious Diseases Institute 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
LC-MS/MS HPLC linked to mass spectrometry  
LMIC 
Low and middle income country 
ENG 
Etonogestrel 
MU-JHU 
Makerere University – Johns Hopkins University Core Laboratory 
NDA 
National Drug Authority 
NVP 
Nevirapine  
OCP 
Oral Contraceptive Pill 
PK 
Pharmacokinetic 
SAE 
Serious Adverse Event 
SMC 
Safety Monitoring Committee 
UNCST 
Uganda National Council of Science and Technology 
UNMC 
University of Nebraska Medical Center 
W 
Week 
WHO 
World Health Organization 
 
 
 

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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...................................................................8 
INTRODUCTION ........................................................................................................................................................ 11 
1.1. DISEASE SETTING/PATIENT POPULATION ................................................................................. 11 
1.2. BACKGROUND AND RATIONALE .............................................................................................. 11 
1.2.1. ENG Pharmacokinetics........................................................................................................................... 12 
1.2.2. Pharmacokinetics of ENG alone, and in combination with NVP or EFV-based ART .......... 12 
1.2.3. Clinical outcomes of the ENG-EFV drug-drug interaction .......................................................... 14 
1.2.4. Relationship between ART exposure and ENG .............................................................................. 15 
1.2.5. Study rationale builds upon prior dose adjustment strategies to overcome DDIs............. 16 
1.2.6. Concentrations achieved with the ENG implant are lower than what is achieved with a 
daily oral contraceptive pill ............................................................................................................................. 16 
1.2.7. Frequent interim measures of ENG efficacy and safety based on PK exposure and 
reported side effects .......................................................................................................................................... 17 
1.2.8. Influence of pharmacogenetics on ENG PK ............................Error! Bookmark not defined. 
1.3. INTENDED STUDY OUTCOME AND SUMMARY ........................................................................... 17 
2. STUDY OBJECTIVES AND ENDPOINTS ................................................................................................... 18 
2.1. OBJECTIVES ........................................................................................................................... 18 
2.2. STUDY ENDPOINTS ................................................................................................................. 19 
2.3. STUDY HYPOTHESIS ............................................................................................................... 20 
3. STUDY DESIGN ..................................................................................................................................................... 20 
4. PARTICIPANT SELECTION ............................................................................................................................ 21 
4.1. INCLUSION CRITERIA .............................................................................................................. 21 
4.2. EXCLUSION CRITERIA ............................................................................................................. 22 
5. TREATMENTS OF PARTICIPANTS............................................................................................................. 23 
5.1. ALLOCATION TO TREATMENT/GROUP ...................................................................................... 23 
5.2. DRUG SUPPLIES ...................................................................................................................... 23 
5.2.1. Administration ........................................................................................................................................... 23 
5.2.2. Drug Storage and Drug Accountability ................................................................................................ 24 
5.3. CONCOMITANT MEDICATION(S) .............................................................................................. 24 
6. STUDY PROCEDURES ....................................................................................................................................... 24 
6.1. SCREENING ............................................................................................................................ 26 
6.2. STUDY PERIOD ....................................................................................................................... 26 
6.3. FOLLOW-UP VISIT................................................................................................................... 30 
6.4. PARTICIPANT WITHDRAWAL ................................................................................................... 33 
7. ASSESSMENTS ....................................................................................................................................................... 34 
7.1. SAFETY.................................................................................................................................. 34 
7.1.1. Physical assessments ................................................................................................................................ 34 
7.1.2. Contraceptive Questionnaires................................................................................................................. 34 
7.1.3. Concomitant medications and ART medication adherence ............................................................. 34 
7.1.4. Safety laboratory evaluations ................................................................................................................. 34 
7.1.5. Phone calls to assess ART adherence and ENG related AEs .......................................................... 35 
7.2. PREGNANCY TESTING ............................................................................................................. 35 
7.3. PHARMACOKINETICS ASSESSMENTS ........................................................................................ 35 
7.3.1. Blood for PK analysis of ENG or efavirenz ........................................................................................ 35 

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7.3.2. Sample Handling ....................................................................................................................................... 36 
7.3.3. Justification for PK shipment ................................................................................................................. 36 
7.4. OTHER MEASUREMENTS.......................................................................................................... 36 
7.4.1. Patient characteristics that may influence pharmacokinetic properties......................................... 36 
8. ADVERSE EVENT REPORTING .................................................................................................................... 37 
8.1. ADVERSE EVENTS .................................................................................................................. 37 
8.2. SERIOUS ADVERSE EVENTS ..................................................................................................... 37 
8.3. SEVERITY ASSESSMENT .......................................................................................................... 38 
8.4. CAUSALITY ASSESSMENT........................................................................................................ 38 
8.5. REPORTING REQUIREMENTS .................................................................................................... 38 
8.6. POST-RECRUITMENT ILLNESS.................................................................................................. 39 
9. DATA ANALYSIS/STATISTICAL METHODS .......................................................................................... 39 
9.1. SAMPLE SIZE DETERMINATION................................................................................................ 39 
9.2. ANALYSIS OF ENDPOINTS........................................................................................................ 40 
9.2.1. Analysis of ENG concentrations............................................................................................................ 40 
9.2.2. Analysis of EFV concentrations ............................................................................................................ 40 
9.3. ANALYSIS OF OTHER ENDPOINTS ............................................................................................ 40 
9.4. SAFETY ANALYSIS.................................................................................................................. 41 
9.5. INTERIM ANALYSIS................................................................................................................. 41 
9.6. DATA SAFETY AND MONITORING COMMITTEE (IF APPLICABLE) ................................................ 42 
10. QUALITY CONTROL AND QUALITY ASSURANCE......................................................................... 42 
11. DATA HANDLING/RECORD RETENTION ............................................................................................ 42 
11.1. CASE REPORT FORMS (CRF)/ELECTRONIC DATA RECORD ...................................................... 42 
11.2. RECORD RETENTION ............................................................................................................. 43 
11.3. CONFIDENTIALITY ................................................................................................................ 43 
11.4. MISSING DATA ..................................................................................................................... 43 
12. ETHICS.................................................................................................................................................................... 43 
12.1. INSTITUTIONAL REVIEW BOARD (IRB)................................................................................... 43 
12.2. ETHICAL CONDUCT OF THE STUDY ........................................................................................ 43 
12.3. PARTICIPANT INFORMATION AND CONSENT ........................................................................... 43 
12.4. RISKS AND BENEFITS............................................................................................................. 44 
13. DEFINITION OF END OF TRIAL................................................................................................................ 45 
14. PUBLICATION OF STUDY RESULTS ...................................................................................................... 45 
15. FUNDING................................................................................................................................................................ 45 
16. REFERENCES ...................................................................................................................................................... 46 
 

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INTRODUCTION 
Family planning options including hormonal contraceptives are essential to improving womens’ 
reproductive health. Each year, effective contraception prevents 188 million unintended 
pregnancies worldwide, thereby averting 1.1 million newborn and 150,000 maternal deaths, as 
well as preventing 112 million abortions2,3. While the problem is global, the burden of unintended 
pregnancies lies in low- and middle-income countries (LMIC) where over 222 million women face 
an unmet need for effective contraception4. This carries an even greater risk for the over 16 million 
HIV-infected women worldwide5, for whom contraceptives decrease the risk of mother-to-child 
HIV transmission6,7.  
 
Despite the benefits of hormonal contraceptives, significant drug-drug interactions (DDIs) with 
some antiretroviral therapies (ART) represent a critical barrier to effective family planning 
methods for HIV-infected women. Our research team recently demonstrated that combined use of 
efavirenz- (EFV) based ART, the only World Health Organization (WHO)-preferred first-line 
ART regimen for adults living with HIV8, with the etonogestrel (ENG)-releasing subdermal 
implant, also a WHO-recommended form of long-acting, reversible contraception and the easiest 
to insert9, caused a 63% reduction in ENG serum concentrations in Brazilian women10 and a 84% 
reduction of ENG plasma concentrations in Ugandan women1, which in turn, jeopardized 
contraceptive efficacy. There are 6 case reports of etonogestrel contraceptive failures11-13, as well 
as a reported pregnancy rate of 3.0 (95% CI 1·4–4·7) per 100 woman-years, in women using EFV-
based ART with the ENG implant14.  This is in significant contrast to the reported <1% pregnancy 
rate in women using the contraceptive implant without a coadministered interacting drug15.  
Therefore, it is of critical public health importance to identify a safe and effective treatment 
strategy that allows for combined use of these preferred family planning and ART strategies in 
HIV-infected women. This protocol investigates one practical approach to this patient care 
challenge. 
 
1.1. Disease Setting/Patient Population 
The public health burden of unintended pregnancies lies in LMIC where maternal mortality is 
highest. The magnitude of this public health burden is well illustrated in the Uganda, where 
approximately 800,000 women are living with HIV, 40% of pregnancies are unplanned; and 220 
neonatal and 310 maternal deaths occur per 100,000 live births16,17.  
 
At the onset of this study, the WHO  recommended EFV-containing ART as the only preferred 
initial regimen for HIV-1-infected adults, a recommendation recently expanded to include women 
of reproductive ages8. WHO and Uganda guidelines for ART were updated during the conduct of 
the trial, discussed further in section 1.4.18  
 
This study will include HIV-infected women who are receiving EFV-based ART and who request 
female controlled contraception options for family planning at the Infectious Diseases Institute 
(IDI), Kampala, Uganda.  
 
1.2. Background and Rationale 
Long-acting reversible contraception methods, such as subdermal hormone implants, are 
recommended by the WHO, are widely used, and provide women with a safe and effective option 
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subdermal implants offer women convenient control of their fertility without concern for frequent 
oral pill refills or injections. In addition, the subdermal implant insertion is quick, nearly painless 
and the return to fertility is almost immediate after its removal22-24. Contraceptive implants are the 
fastest growing method of contraception in sub-Saharan Africa; which includes a 9-fold increase 
in use from 2008 to 2012, and 9 million implants shipped to sub-Saharan Africa in 201525.    
 
Despite increasing use of both EFV-based ART and subdermal hormone implants, three recent 
clinical studies have reported a pregnancy rate of 4.2% to 15% in women using levonorgestrel 
contraceptive implants while taking EFV-based ART14,26,27. For women using the ENG implant 
while on EFV-based ART reported a pregnancy rate of 3.0 (95% CI 1·4–4·7) per 100 woman-
years14.  All of these reports are in significant contrast to the reported <1% pregnancy rate in 
women using the contraceptive implant without a coadministered interacting drug.  From these 
very limited data it appears that for women on EFV-based ART the ENG implant could be more 
effective in preventing pregnancy than the levonorgestrel implant.  This could be due to the 
increased potency of etonogestrel compared to levonorgestrel with regards to ovulation 
suppression.  Rice and colleagues demonstrated that only one ovulation out of 59 cycles were 
ovulatory with oral desogestrel and 16 ovulations out of 59 cycles for levonorgestrel28.  
Additionally, etonogestrel could be a preferred candidate for dose escalation because it the single 
rod system allows for easy insertion. 
 
1.2.1. ENG Pharmacokinetics 
The pharmacokinetic (PK), safety, and efficacy of the ENG implant (68mg) have been clearly 
established in clinical trials22,29-32. Following subdermal insertion into the upper arm, ENG is 
released from the implant into the interstitial fluids at a rate of 60-70 mcg/day at one-month post-
insertion, decreasing to 40 mcg/day within one-year and to 25-30 mcg/day within three-years22. 
Serum ENG concentrations reaching peak concentrations of 1145 (±577) within one and thirteen 
days post-insertion and a median four days post-insertion and then slowly decline over the three 
years of intended use29.  ENG is tightly protein-bound to sex hormone-binding globulin (32%) 
and albumin (66%)15. This, in addition to an inverse association between ENG concentrations 
and bodyweight33, contribute to its interpatient variability. However, ENG concentrations are 
less variable then levonorgestrel concentrations likely due to ENG being more bound to albumin 
rather than sex hormone binding globulin34. 
 
ENG clearance and metabolism are via the cytochrome P450 (CYP) enzyme system, specifically 
the CYP3A4 isoenzyme, and co-administration of medications that induce or inhibit CYP3A4 are 
known to impact ENG concentrations15.  
 
1.2.2. Pharmacokinetics of ENG alone, and in combination with either NVP or EFV-based 
ART  
Our team recently completed a 24-week PK evaluation of the ENG implant in HIV-infected 
women not receiving ART (control group, n=20) compared to women receiving EFV-based ART 
(EFV group, n=20) or nevirapine (NVP)-based ART (NVP group=20)35. After providing informed 
consent, each participant had one 68mg ENG implant (standard dose) placed subdermally at 
enrollment (Day 0); PK sampling for ENG plasma concentrations were performed at 1, 4, 12, and 
24 weeks. As shown in Table 1, the EFV group showed a significant reduction in ENG 

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concentrations compared to the control group. The interaction was observed by week 1, and 
remained relatively stable throughout weeks 4-24 (Figure 1). 
 
In the EFV group, ENG concentrations were significantly lower at each visit compared to the 
ART-naïve group [Week 24 GMR: 0.18 (0.17-0.20)]. In contrast, there were no significant 
differences in the ENG concentrations in the NVP group at each study visit compared to the ART-
naïve group [Week 24 GMR: 0.94 (0.90-1.01)]. The ENG GM AUC0-24 was 11.12, 10.47, and 1.80 
ng*wk/mL in the ART-naïve, NVP, and EFV groups, respectively [AUC0-24 GMR: NVP:ART-
naïve 0.94 (0.94-0.94); EFV:ART-naïve 0.16 (0.16-0.16)].  The number of participants in the EFV 
group with ENG concentrations below 90 pg/mL (the reported threshold for ovulation 
suppression36) was 9 (47%), 16 (84%), and 18 (95%) at weeks 4, 12 and 24, respectively.  In 
contrast, all participants in the ART-naïve and the NVP groups had ENG concentrations above 90 
pg/mL throughout the 6 month study duration. 
 
Table 1. Etonogestrel Plasma Concentrations over 24 weeks (pg/mL) 
 
Weeks from 
Implant 
Insertion 
ART-Naïve 
Group 
(N=20)1 
NVP  
Group 
(N=19)1 
EFV  
Group 
(N=19)1 
GMR 
NVP:ART-
Naive2 
GMR 
EFV:ART-
Naive2 
1 
831  
(738, 924) 
647  
(548, 746) 
137  
(118, 156) 
0.78 
(0.74-0.81) 
0.16 
(0.16-0.17) 
4 
507  
(445, 568) 
457  
(394, 521) 
87  
(74, 99) 
0.90 
(0.88-0.91) 
0.17 
(0.17-0.17) 
12 
441 
(382,500) 
453  
(398, 509) 
63  
(55, 71) 
1.03 
(1.02-1.04) 
0.14 
(0.14-0.14) 
24 
362  
(308, 415) 
341  
(310, 373) 
66  
(60, 72) 
0.94 
(0.90-1.01) 
0.18 
(0.17-0.20) 
1Geometric mean with 90% confidence intervals 
2Geometric mean ratio (GMR) with 90% confidence intervals 
ART= Antiretroviral Therapy, NVP=Nevirapine, EFV=efavirenz 
 
 
 
 
 
 

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Figure 1. Etonogestrel (ENG) geometric mean concentrations (pg/mL) with 90% 
confidence intervals over 24 weeks 
 
1.2.3. Clinical outcomes of the ENG-EFV drug-drug interaction  
High quality clinical data regarding the clinical outcome of women using the contraceptive implant 
while on EFV-based ART are limited to retrospective secondary analyses of observational cohort 
studies, small prospective PK studies and 6 case reports of contraceptive failures11-13,37. In a PK 
study of the levonorgestrel implant, which was designed similarly to that described in Section 
1.2.2, our team observed three (15%) unintended pregnancies among women receiving EFV-based 
ART with the levonorgestrel implant, all occurring between study weeks 36 and 48; no pregnancies 
were observed in the NVP or control groups27.  In our subsequent PK study of the ENG implant, 
the women on EFV-based ART were required to use the copper intrauterine device (IUD) to avoid 
the life-altering event of an unplanned pregnancy; therefore we did not observe any pregnancies 
with the ENG implant in the EFV group35.   
 
There are 3 retrospective cohort studies published that explore pregnancy outcomes among women 
using ART and hormone implants.  First, a retrospective study of 570 HIV-infected women in 
Swaziland reported pregnancy in 12.4% of women using the levonorgestrel implant and EFV-
based ART, but no pregnancies with other ART regimens26.  Secondly, a study combined data 
from three longitudinal studies and found that among women using implants, the calculated 
incident pregnancy rate was 6.0 vs. 1.4 pregnancies/100 women-years in women using EFV-based 
ART vs. no ART, respectively38. Finally, a three-year retrospective cohort study from Kenya 
examined pregnancy rates among nearly 25,000 HIV-infected women using various combinations 
of contraceptive methods and ART regimens. They observed a 3-fold higher pregnancy risk in 
implant users (either ENG or levonorgestrel-containing) receiving EFV-based ART compared to 
0
100
200
300
400
500
600
700
800
900
1000
0
4
8
12
16
20
24
Weeks Post-Implant Insertion
ENG pg/mL 
        ART-Naïve Group 
        NVP Group 
        EFV Group 
        Ovulation Threshold 

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NVP-based ART (adjusted rate ratio: 3.0 [1.3-4.6])14. Importantly, they also showed that among 
EFV-based ART users, women reporting oral and injectable contraceptive use were up to three 
times more likely to become pregnant than those women reporting use of implants. This 
retrospective study had several limitations, including self-reported use of contraceptive methods 
and lack of initiation or discontinuation dates for the methods.  Nonetheless, it demonstrated that 
despite drug-drug interactions between implants and EFV, implants remain one of the most 
effective contraceptive methods for HIV-infected women. 
 
Based upon the cumulative data, the WHO recently released an updated statement on the use of 
progestin containing implants in HIV-infected women. Given the high effectiveness of implants 
compared to other methods of contraception, even in the presence of a drug-drug-interaction, the 
WHO confirmed the 2014 consolidated HIV/contraception guidelines and advises that HIV-
infected women should have the opportunity to use all types of contraception, including implants19. 
In light of this WHO recommendation, combined use of implants and EFV-based ART is certain; 
thus, strategies to optimize their combined use are desperately needed, specifically, strategies to 
improve the implant’s effectiveness to <1% risk of pregnancy, as is observed in women not using 
an interacting co-medication.  
 
1.2.4. Relationship between ENG exposure and contraceptive effect 
There are two primary mechanisms of action for contraceptive implants.  First, the progestin 
suppresses the luteinizing hormone surge necessary for ovulation.  Second, the progestin causes 
decreased cervical mucus formation and increases cervical mucus thickening, therefore making 
the mucus impenetrable to sperm.  Progestin pharmacokinetics has been used as a broad marker of 
contraceptive effect due to easy assertainment, as compared to pharmacodynamic markers of 
contraceptive effectiveness.  Clinical studies have shown that individual women may require 
differing concentations of progestins to prevent pregnancy.  For example, previous studies have 
shown that for etonogestrel, the threshold for ovulation suppression was 90pg/mL36, however a 
later study reported ovulation occuring in one woman with etonogestrel concentrations of 
120pg/mL29.  Furthermore, we reported that there was an 84% decrease in ENG exposure with 
95% of women having ENG concentrations below 90pg/mL at 24 weeks of use.     
 
In this study, we will evaluate the impact of standard dose and dose escalated ENG implant on the 
ovulation and cervical mucus in women on EFV-based ART, while preventing unplanned 
pregnancies with the placement of the copper IUD in all women.  After ovulation the corpus luteum 
cyst secretes progesterone and measurement of serum progesterone at day 21 of the menstural 
cycle is commonly assessed in clinical care as a marker of ovulation. However, due to the 
unpredictability of ovulation during contraceptive implant use, we will collect serum enogenous 
progesterone weekly at specified months of use.  In infertility assessment, the WHO cervical 
mucus score is used to evaluate the potential sperm-mucus interaction.  A score of greater than 10 
considered indicative of cervical mucus favoring sperm penetration39.  By simultaneously 
assessing ovulation, cervical mucus and ENG plasma concentrations, we will address the 
knowledge gap of at what ENG concentration threshold will there be a contraceptive effect and 
how that threshold varies between women.  Furthermore, we will be able to more accurately know 
the risk of pregnancy for women using the ENG implant and EFV-based ART, and whether two 
ENG implants (136mg – dose escalated) will improve contraceptive effectiveness for women on 
EFV-based ART.   

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1.2.5. Study rationale builds upon prior dose adjustment strategies to overcome DDIs 
The premise of our study is to evaluate if the DDI between the ENG implant and EFV-based ART 
can be safely and adequately overcome by using an adjusted dose of the ENG implant, specifically 
increasing the ENG dose from 68mg to 136mg in combination with EFV-based ART. Dose 
adjustment is a well-accepted strategy to overcome DDIs and there are examples of this strategy 
being used with other medications. For example, when rifampicin, an antituberculous medication, 
is given concomitantly with raltegravir, an antiretroviral medication, raltegravir plasma exposure 
is decreased 40%; this interaction can be overcome by doubling the raltegravir standard dose, from 
400mg twice daily to 800mg twice daily40. Additionally, a recent investigation evaluated using an 
increased dose of an oral contraceptive pill (OCP) containing levonorgestrel plus ethinyl estradiol 
to overcome the decrease in hormone PK exposure observed in obese women41,42. Fifteen women 
in this study received levonorgestrel 100mcg/day during one menstrual cycle, followed by a 50% 
increased levonorgestrel dose (150mcg/day) during a subsequent cycle. This dose adjustment 
resulted in a 42% increase in levonorgestrel AUC, with no reported adverse events (AE), 
demonstrating the success of dose adjustment to effectively increase exposure43.  
 
1.2.6. Concentrations achieved with the ENG implant are lower than what is achieved with 
a etonogestrel vaginal ring 
As previously mentioned, the ENG implant releases variable rates of ENG over the approved 3 
year duration of use (60-70 mcg/day at one-month post-insertion, 40 mcg/day within one-year and 
to 25-30 mcg/day within three-years). Placement of two implants (136mg total) would likely result 
in 140 mcg/day for only the first month, followed by 80mcg/day within one year and 50 mcg/day 
within 3 years.  Without an interacting drug, a doubling of the dose might result in an ENG Cmax 
of 2400pg/mL (single dose ENG Cmax=1200pg/mL) occurring in the first 2 weeks, declining to 
approximately mean serum ENG concentration of 600pg/mL (300pg/mL for single dose at 6 
months) and 400pg/mL at 12 month (200pg/mL for single dose at 12 months).  However, in the 
setting of the significant drug-drug interaction with EFV, a conservative estimate reported in 
Brazilian women of 63% decrease in serum concentrations, therefore we anticipate that the actual 
ENG serum concentrations would be approximately 888pg/mL (Cmax), 222pg/mL (at 6 months) 
and 148pg/mL (at 12 months).  In comparison, the Nuvaring® (a vaginal ring containing 11.7mg 
of etonogestrel and 2.7 mg of ethinyl estradiol), like the implant is 100% bioavailable and releases 
120mcg/day of etonogestrel, a very similar dose to the first month placement of 2 ENG implants 
(136mg total). The NuvaRing® results in significantly higher serum ENG concentration than 
expected with 2 ENG implants and EFV-based ART: 1578 pg/mL mean serum ENG at 1 week of 
use44. Therefore, even if ENG concentrations resulting from the increased dose (136mg) of the 
ENG implant in the setting of a conservative estimate of the resultant ENG-EFV drug-drug 
interaction, ENG concentrations would still be 40% lower than the ENG concentrations achieved 
with NuvaRing® use. Given this, ENG dose related AEs are not expected in this study. However, 
to ensure patient safety, strict monitoring will be conducted at regular intervals for both the efficacy 
and safety of increased dose ENG. 
 
AEs that were possibly related to the ENG implant in our prior study are described in Table 2. 
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intensity (Grade 2).  The one adverse event of moderate intensity was due to menorrhagia in the 
NVP group.  Importantly, no drug-related AE was severe or resulted in implant discontinuation.  
 
Table 2.  Cumulative Adverse Events Reported Over 24 Weeks of ENG Implant Use  
 
Adverse Event 
ART-naïve  
Group 
(n=100) 
NVP 
Group 
 (n=124) 
EFV 
Group 
(n=74) 
Menorrhagia  
13 (13%) 
17 (14%) 
13 (17%) 
Metrorrhagia  
17 (17%) 
12 (10%) 
6 (8%) 
Amenorrhea  
18 (18%) 
20 (16%) 
14 (19%) 
Headache  
18 (18%) 
31 (25%) 
15 (20%) 
Weight Gain 
23 (23%) 
18 (14%) 
19 (26%) 
Breast tenderness 
3 (3%) 
5 (4%) 
2 (3%) 
Nausea 
4 (4%) 
17 (14%) 
2 (3%) 
Implant site discomfort 
4 (4%) 
4 (3%) 
3 (4%) 
Grade 1  
100 
123 
74 
Grade 2 
0 
1 (menorrhagia) 
0 
 
1.2.7. Frequent interim measures of ENG efficacy and safety based on PK exposure and 
reported side effects 
To ensure participants are not at excess risk of pregnancy, all participants will have a copper 
intrauterine device (IUD) placed to ensure adequate contraceptive efficacy. In addition, to ensure 
subjects do not receive long-term, suboptimal or supratherapeutic hormonal contraception, we will 
assess the futility of the ENG implant (standard and increased dose) + EFV-based ART after 24 
weeks of combined use, then every 24 weeks thereafter. The first interim analysis of the ENG 
concentrations will occur as soon as 20 participants (at least 10 in each group) completes 24 weeks 
of combined ENG implant and EFV use. This assessment will be based upon lack of contraceptive 
effect as evidence by either ENG <90pg/mL, progesterone concentration >3ng/mL or WHO 
cervical mucus scores >10. See section 9.4 for the defined measures of safety monitoring, and 
section 9.6 for external study monitoring plans.  
 
1.3. Intended Study Outcome and Summary 
With the evidence outlined above, it is highly plausible that increasing the dose of the ENG implant 
to 136mg, by inserting two 68mg ENG implants, can safely and effectively overcome suboptimal 
ENG concentrations when combined with EFV-based ART.  
 
Given the public health importance of preventing unplanned pregnancies in HIV-infected women, 
coupled with the growing use of EFV-based ART and ENG subdermal implants in this population, 
there is an urgent need to determine the clinical significance of the EFV-ENG interaction and to 
identify alternative dosing strategies for the ENG implant in women using EFV-based ART that 
will allow for safe and effective concomitant use of these preferred therapies. This study will 
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the known PK interaction with EFV-based ART in a clinically meaningful way. This study will be 
the first to evaluate an alternate strategy for the use of the ENG implant among women receiving 
EFV-based ART. In doing so, we will inform and improve clinical practice by providing sound 
data upon which healthcare providers and policy makers can make evidence-based decision to 
guide the safe and effective use of ENG implants in HIV-infected women receiving EFV-based 
ART.  
 
1.4 Updated Ugandan ART Guidelines in 2020: implications for study participants 
 
In 2020, the Ugandan Ministry of Health (MoH) published new guidelines on the prevention and 
treatment of HIV and AIDS45.  MoH selected first-line regimens based on reduced toxicity, pill 
burden, efficacy, sequencing, harmonization across populations, and lower costs based on the most 
recent data.  Dolutegravir (DTG) is now recommended as the “anchor” ARV in the preferred first 
and second-line treatment regimens for all persons living with HIV.  The rationale for the inclusion 
of DTG-based therapy recommendations include a high level of circulating resistance to NNRTIs 
in Uganda, DTG is more effective, better tolerated and has a higher genetic barrier to resistance. 
DTG has been associated with hyperglycemia, therefore persons living with HIV and that have 
diabetes or are at high risk of diabetes will be continued on EFV based ART.  However, EFV will 
be given at a dose of 400 mg because this dose is non-inferior to 600 mg, is better tolerated, and 
can be co-administered with rifampicin-containing anti-TB treatment.  
 
It is unclear if the reduction in the dose of EFV will have any impact on the DDI between EFV 
and ENG.  However, there does not appear to be a clinically significant DDI between DTG and 
ENG based on cross-sectional data46.  
 
Given that the Uganda ART guidance is consistent with WHO guidance, it is anticipated that many 
women across the world using EFV 600mg will be transitioned to DTG- or EFV 400mg-based 
ART while using the ENG implant.  Therefore, it is important to characterized both the ART and 
ENG concentrations around the time of the ART switch. 
 
 
2. STUDY OBJECTIVES AND ENDPOINTS 
 
2.1. Objectives 
 
Primary objective: 
To compare the rate of ovulation (by weekly endogenous progesterone measured at months 3, 6, 
and 12) when women receive two 68 mg ENG implants (dose-escalated) compared to a standard 
dose 68 mg ENG implant in combination with EFV-based ART. 
 
Secondary objectives: 
1. To determine cervical mucus quality (by collecting weekly WHO cervical mucus scores 
at months 3, 6, and 12) when women receive two 68 mg ENG implants (dose-escalated) 
compared to a standard dose 68 mg ENG implant in combination with EFV-based ART.  

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2. To compare the PK parameters of two ENG implants (136 mg total) when combined with 
EFV-based ART versus the standard dose 68 mg ENG implant with no ART (historical 
controls in the same population using the same laboratory) over 6 months of implant use.   
3. To evaluate the safety and tolerability of two ENG implants (dose-escalated) in HIV-
infected women receiving EFV-based ART over 12 months of combined use. 
4. To describe the relationship between ENG concentrations and participant specific 
variables, specifically body weight, albumin, sex hormone binding globulin, 
pharmacogenetic polymorphisms, and EFV concentrations. 
5. To describe the long term feasibility and tolerability of increased dose ENG (136mg) 
subdermal implant use in HIV-infected women receiving EFV-based ART after weeks 96 
and 144 of combined use. 
6. To describe the change in EFV trough concentrations and ENG steady state 
concentrations after switching from EFV 600mg to DTG- or EFV 400mg-based ART and 
from EFV 400mg to DTG-based ART. 
 

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2.2. Study Endpoints 
Primary endpoint 
1. 
Frequency of ovulation at months 3, 6, and 12, defined as a single serum progesterone 
concentration above 3ng/mL, collected at weeks 9-12 (month 3), 21-24 (month 6), and 45-
48 (month 12) after implant insertion from participants on EFV-based ART using dose-
escalated ENG implant (136mg) compared to standard-dose ENG implant (68mg).  
 
Secondary endpoints 
1. Frequency of WHO cervical mucus scores >10 at months 3, 6, and 12 collected at weeks 
9-12 (month 3), 21-24 (month 6), and 45-48 (month 12) after implant insertion from 
participants on EFV-based ART using dose-escalated ENG implant (136mg) compared to 
standard-dose ENG implant (68mg). 
2. ENG concentrations (in pg/mL) obtained at week 1, 4, 12 and 24 from participants in this 
study on EFV-based ART using dose-escalated ENG implant (136mg total) compared to 
historical controls (standard-dose ENG implant with no ART).  
3. Frequency of AEs and participant satisfaction related to ENG during the study period 
through week 48 in women on EFV-based ART using dose-escalated ENG implant 
(136mg) compared to standard-dose ENG implant (68mg).  
4. Differences in ENG concentrations as they relate to body weight, albumin, sex hormone 
binding globulin, pharmacogenetic polymorphisms, and EFV concentrations.  
5. ENG concentrations, ovulatory frequency, and signs and symptoms related to hormone 
exposure (i.e. potential AEs) evaluated at weeks 69-72, 93-96, 117-120, and 141-144. 
6. ENG and EFV concentrations at the time of ART switch to DTG- or EFV 400mg-based 
ART and two, four and six weeks after.  
 
2.3. Study Hypothesis  
Overall, we hypothesize that the rate of ovulation in the group of women using EFV-based ART 
with dose-escalated ENG implants will be lower than in the group of women using EFV-based 
ART with a standard dose ENG implant.    
 
3. STUDY DESIGN 
This is a randomized, open-label, parallel, two-group pharmacodynamic study to compare the 
rate of ovulation and WHO cervical mucus scores between standard (68mg) or dose-escalated 
(136mg) ENG implants in 72 HIV-infected Ugandan women who are on EFV-based ART.  
  
HIV-infected women between the ages of 18-40 years of age on EFV-based ART attending clinic 
at the Infectious Disease Institute will be offered study participation.  All participants will be 
randomized to either having a dose-escalated or standard-dose implant that will inserted at study 
entry (Day 0) using computer generated numbers in sealed opaque envelopes. A study schema is 
shown in Figure 2.  
 
 

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For the pharmacokinetic analysis of ENG, data from 20 historical control patients, comprised of 
Ugandan HIV-infected women receiving standard dose ENG implant will also be used in  analyzed 
in this study. The control group will be comprised of data from our previous control group of HIV-
infected women using a standard dose ENG (68mg) subdermal implant without concomitant ART 
(no ART, n=20) followed for 24 weeks. No additional data analysis will occur on historical 
participants than was performed in the original study.  
 
4. PARTICIPANT SELECTION 
The clinical study will be conducted at the IDI, Makerere University. Approximately 7,500 HIV-
infected adults, 60% of whom are women, receive care at the IDI. Integrated HIV care and family 
planning services began in 2010. At present, EFV is used in approximately 66% of first line 
antiretroviral regimens at IDI. The ENG implant is registered for use in Uganda and is a desirable 
form of contraception among HIV-infected women at the IDI (10% of women at IDI currently use 
the implant). 
   
All women receiving EFV-based ART and seeking family planning services at the IDI will receive 
information about this study involving the ENG implant, as well as information about all other 
family planning methods available to them. All family planning services at IDI are provided at no 
cost to the patient, including all contraceptive methods under investigation (implants and copper 
intrauterine device [IUD]). Condoms are provided at all visits, and will continue to be given to all 
participants at each study visit to prevent HIV transmission to uninfected partners. For women 
who are interested in the ENG implant and participation in this study, the following eligibility 
criteria are designed to select participants for whom protocol treatment is considered appropriate. 
 
4.1. Inclusion Criteria 
The inclusion and exclusion criteria are designed first to provide protections for research 
participants (informed consent, appropriateness of contraceptive choice, organ function, 
prevention of pregnancy, and safety of study procedures) and second to ensure the study’s ability 
to address the stated objectives (no external drug-drug interactions and likelihood to remain on 
study related medications and enrolling subject that are ovulating).  
 
Participants must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. Evidence of a personally signed and dated informed consent document indicating that the 
participant has been informed of all pertinent aspects of the study. 

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2. Participants who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures. 
3. Women age 18 years to 40 years 
4. Diagnosed with HIV infection 
5. Medically eligible for the ENG subdermal implant as a contraceptive method based on the 
WHO Medical Eligibility Criteria for Contraceptive Use, see appendix 120 
6. Receiving EFV-based ART for a minimum of 3 months prior to screening  
7. Must agree to have concurrent highly effective non-hormonal contraception with a copper 
IUD, if not previously medically sterilized.  
8. Participants must report regular menses (menstrual bleeding for 4-8 days at 21 to 35 day 
intervals) for the preceding 2 month (intermenstral spotting is allowable). 
9. Participants must have a negative urine pregnancy test at entry and report no unprotected 
sex since the last menstrual period or in the last two weeks.   
 
4.2. Exclusion Criteria 
Participants presenting with any of the following will not be included in the study: 
1. HIV RNA > 50 copies/mL at screening visit  
2. Serum hemoglobin < 10.0 g/dl 
3. Elevations in serum levels of alanine transaminase (ALT) above 5 times the upper limit of 
normal 
4. Elevations in serum creatinine above 2.5 times the upper limit of normal 
5. Use of drugs known to be contraindicated with ENG or EFV within 30 days of study entry. 
Due to the dynamic nature of drug interactions related to ART, the study team will review 
all concomitant medications at screening based on the US Department of Health and 
Human Services drug interaction table47 and the ENG implant product labeling15.  
6. Currently pregnant or postpartum <30 days at study entry. 
7. Breastfeeding women within 6 months of delivery. 
8. Use of hormonal contraception in the preceding 3 months prior to entry 
9. Participants determined to be ineligible for IUD placement by the WHO Medical Eligibility 
Criteria for Contraceptive Use48 
10. Patients with a history of hypersensitivity to ENG implant, undiagnosed vaginal bleeding, 
diagnosed or suspected sex hormone dependent neoplasia, benign or malignant liver tumor, 
or thromboembolic disease. 
11. Presence of any active clinically significant disease or life-threatening disease that, in the 
investigator’s opinion, would compromise the subject’s safety or outcome of the study, 
specifically including but not limited to QRISK®2 score (calculator located at: 
https://qrisk.org/2017/) that predicts a greater than 10% risk of heart attack in the next 10 
years, or severe depression. 

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5. TREATMENTS OF PARTICIPANTS 
5.1. Allocation to Treatment/Group 
This is a randomized, open-label, parallel, two-group pharmacodynamic study to compare standard 
(68mg) to dose-escalated (136mg) ENG implants in 72 HIV-infected women who are on EFV-
based ART.  The participants’ ART will not be determined by this research protocol and HIV care 
will remain at the discretion of the treating clinician.  
 
The participant’s ART at enrollment will determine eligibility for the study:  
- 
ENG subdermal implant, standard dose (68mg mg/1 rod) + EFV-based ART (control) 
- 
ENG subdermal implant, escalated dose (136 mg/2 rods) + EFV-based ART (treatment) 
 
At the enrollment visit, the participant will be randomized to either standard dose ENG implant or 
dose-escalated ENG implant.   
 
Participants will continue their current ART as directed by their primary HIV care provider 
throughout the study period.  No changes will occur as a result of study procedures. Participants 
will continue to receive HIV care and treatment through the standard IDI ART clinical treatment 
procedures and according to the Ugandan HIV treatment guidelines. 
 
5.2. Drug Supplies 
Active ingredients and dosage strength:  
Etonogestrel 1-rod implant (68mg/rod) 
Route of administration:  
 
 
Subdermal placement 
Dose:  
Control group: 1 rod (68mg) inserted subdermally 
into one arm 
Treatment group: 
2 
rods 
(136mg) 
inserted 
subdermally; 2 rods in one arm 
Duration of treatment:  
Clinically approved for 3 years of use. Study 
participation will be complete after up to 3 years. 
 
The study drug will be purchased from local suppliers. ENG implant is registered in Uganda. The 
supplier of the ENG implant will remain consistent throughout the study and will be certified 
through Good Manufacturing Practices or International Organization for Standardization. 
 
5.2.1. Administration 
Following completion of entry procedures (outlined below), The ENG implant systems will be 
placed subdermally in the upper arm by a trained clinician at the IDI clinic on study day 0. 
Participants will either have one implant or 2 implants placed into one arm. Placement of two rods 
will be performed similarly to the placement of the 2-rod levonorgestrel implant that is also 
commonly used in Uganda and at the Infectious Disease Institute49.  Specifically, 2 ENG implants 
will be placed in one arm at a V-orientation to facilitate easy of removal.   
 
Insertion of the implant will be according to standard procedures followed routinely in the clinic 
for long-acting subdermal implants, and inserted according to the product labeling. At every visit 
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5.2.2. Drug Storage and Drug Accountability  
The investigator will ensure that the ENG implant purchased with study grant funds will only be 
used in accordance with the protocol. Drug supplies will be kept in a secure, limited access storage 
area under the recommended storage conditions. A drug accountability log will be kept with the 
investigational supplies for reconciliation purposes. This should be used to record the identification 
of the participant to whom the investigational product was dispensed, the date and quantity of the 
investigational product dispensed. Storage conditions will be according to the ENG implant 
product labelling and individual product expiration date.  
 
5.3. Concomitant Medication(s) 
There are no restrictions to concurrent therapy, except those outlined in the exclusion criteria. 
Participants will be encouraged to avoid grapefruit juice, herbal or natural products during the 
course of the study due to the potential unknown PK interactions with those products. However, if 
a participant uses an herbal or natural product during the study period, she will be encouraged to 
report that use to study investigators.  Participants’ concomitant therapy will be documented at 
study screening and reviewed at each study visit. Any change in concomitant therapies must be 
recorded on the case report form (CRF).  
 
6. STUDY PROCEDURES   
Study visits will occur at screening, entry (day 0), and weeks 1, 4, 9, 10, 11, 12, 21, 22, 23, 24, 36, 
45, 46, 47 and 48 for all participants. Study personnel will call participants to assess any AEs on 
day 3 +/- 48 h. In all participants, a single blood sample will be drawn for a serum progesterone 
measurement and a speculum exam will be performed for the collection of cervical mucus for the 
WHO cervical mucus score measurement at weeks 9, 10, 11, 12, 21, 22, 23, 24, 36, 45, 46, 47 and 
48.   Cervical mucus collection was discontinued on October 19th, 2020, at which time 41 
participants had completed the week 48 follow-up. Additionally, in all participants, a blood sample 
will be drawn to measure ENG concentrations at the following study visits: day 0, and at weeks 1, 
4, 12, 24, 36, and 48. Participants will also have a timed, single blood sample for EFV 
concentrations at: Screening, day 0, and at weeks 1, 4, 12, 24, 36, and 48.  This sampling schedule, 
through week 48, follows the same schedule as that which was used in the historical control group.  
 
If all safety measures are met, participants will have additional visits will be evaluated every 6 
months for 4 consecutive weeks, specifically weeks 69-72, 93-96, 117-120, and 141-144. 
 
In order to facilitate flexibility for the participant’s schedule, if a participant misses the first visit 
among the 4 weekly consecutive visits (week 9-12, week 21-24, week 45-48, etc.), then the visit 
can be rescheduled to the week following when the fourth consecutive week was previous 
scheduled.  For example, if the participant misses the week 9 visit, then they can make up that visit 
on week 13 within 7 days (plus or minus 24 hours) of the week 12 visit.  If the participant misses 
both week 9 and 10 week visits, then they can make these visits on weeks 13 and 14.  If the 
participant misses weeks 9, 10 and 11 post-insertion visits, then these visits can be made up on 
weeks 13, 14 and 15 post-insertion. 
 

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To improve convenience for participants, the research visits will be scheduled with concurrent 
clinical visits to IDI for routine HIV care, when possible. All reasonable efforts should be made to 
ensure that the sampling schedule falls on the outlined days or within the window defined for each 
study visit.  All PK samples should be collected prior to ENG subdermal implant placement on 
day 0. Specific PK sampling considerations are as follows: 
 
• Because EFV is dosed once daily, typically in the evening, participants should have their 
PK sampling performed approximately 12-14 hours after their evening dose of EFV. The 
study nurse will confirm the time at which the participant took the EFV dose prior to PK 
sampling.  
 
Prior to all visits, the study staff will contact the participant by phone 3-7 days prior to the 
scheduled visit to confirm the visit time, review the ART dosing schedule, and remind the 
participant to remember the exact time at which the EFV dose prior to the study visit was actually 
taken. 
 
Clinical information obtained during the study period as part of standard of care, such as 
demographics, laboratory values (as indicated in the section 6.2 below), and medication related 
adherence toxicities may be abstracted from the participants’ medical records. 
 
Given the known risk of HIV transmission, family planning counselling will occur at each visit, 
including the importance of using barrier contraception. Given the increased concerns of 
contraceptive failures with combined standard dose ENG implant and EFV use, we will require 
women to have concurrent highly effective non-hormonal contraception with a copper T380A 
IUD, if not already sterilized prior to study entry. The copper IUD is a T-shaped device, measuring 
32 mm horizontally and 36 mm vertically with a 3 mm diameter bulb at the tip of the vertical stem. 
A monofilament polyethylene thread is tied through the tip, resulting in two threads to aid in 
detection and removal of the device. The T-frame is made of polyethylene, with barium sulfate to 
aid in detecting the device under x-ray. The Copper T 380A IUD has been FDA approved since 
1984 for contraceptive use. It is currently approved for use up to 10 years. All IUD insertions will 
be performed by a trained clinician. 
 
Following the Ugandan ART guidance change, participants already enrolled in the study will be 
switched to the new first line recommended therapies, either DTG- or EFV 400 mg-based ART, 
based on the discussion with a HIV clinician who is not affiliated with the study team.  If the 
participant decides to remain in the study after ART switch, then they will sign an informed 
consent document indicating their agreement to continue study follow-up.  If a participant in the 
double-dose ENG arm desires to remain in the study and switches from either EFV600mg or 
EFV400mg to DTG-based ART, then one of the contraceptive implants will be removed by a study 
clinician.  Any participant on DTG-based ART remaining in the study may have the Copper T 
380A IUD removed if she desires.  It is recommended that the IUD be removed  4 weeks after the 
discontinuation of EFV and to avoid the risk of pregnancy due to the drug interaction between 
ENG and EFV and the long half-life of EFV.  If the participant opts to remove the IUD prior to 4 
weeks from IUD discontinuation, then the study clinician recommend that condoms be used for 4 
weeks to prevent pregnancy. Participants that remain in the study will have the opportunity to 
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switch.  Participants will sign additional consent for these additional visits if they agree to these 
additional visits that are described in section 6.3.2. 
 
6.1. Screening 
Each participant must sign an Informed Consent Form prior to the conduct of any screening 
procedures. Participants will be given the opportunity to ask any questions. Consenting patients at 
the IDI will be screened for eligibility.  
 
Screening evaluations will be used to determine each candidate’s eligibility for study enrollment 
(refer to Exclusion Criteria section 4.2, above, for detail on eligibility).  
 
The screening visit procedures are outlined in the schedule of events (section 6.2). In addition,  
- 
Review of eligibility criteria for enrollment (including urine pregnancy test and review of 
concomitant medications) 
- 
Demographic details 
 
The screening procedures may occur over multiple visits within 90 days prior to enrollment as 
necessary.  The screening physical exam and laboratory examinations must occur within 30 days 
of enrollment.  A participant may rescreen for the study at the discretion of the study investigator, 
but will be reassigned a new study number.   
 
6.2. Study Period 
The schedule of events is summarized in the table below: 
 
 

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Protocol 
Activity 
SC 
D0 
D35 
W11 
W42 
W93 
W103 
W113 
W123 
W213 
W223 
W233 W243 
W362 
W453 
W463 
W473 
W483 
Early 
D/C4 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study 
registration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history and 
physical exam 
X 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
IUD insertion 
(if applicable) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ENG implant 
placement  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight + vital 
signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess for 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess for 
AEs 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess for 
ART 
adherence  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contraception 
use 
questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
symptoms 
questionnaire 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contraceptive 
satisfaction 
questionnaire  
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
X 
Condom use 
questionnaire 
X 
X 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
X 
HIV Risk and 
FP counseling 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QRISK®2 
Score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol 
Activity 
SC 
D0 
D35 
W11 
W42 
W93 
W103 
W113 
W123 
W213 
W223 
W233 W243 
W362 
W453 
W463 
W473 
W483 
Early 
D/C4 
Laboratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
test (urine) 
X 
X 
 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
X 
Hemoglobin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
Creatinine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cholesterol/ 
LDL 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Glycosylated 
hemoglobin 
(HbA1c) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
HIV-RNA 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X6 
CD4 cell count  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X6 
SHBG 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Albumin 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
EFV PK 
sample 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
X 
ENG PK 
sample 
 
X 
O 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
X 
Endogenous 
progesterone 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Cervical 
mucus 
assessment7 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
PG sample 
(with optional 
consent) 
 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: SC – Screening; X – All participants; O – Optional procedures, for consenting participants; A – As needed; D0 – Day 0, study entry; D1 – Day 1 
after implant placement; D2 - Day 2 after implant placement; D3 - Day 3 after implant placement; D4 - Day 4 after implant placement; W1 – 1 week after implant 
placement; W4 - 4 weeks after implant placement; W9 - 9 weeks after implant placement; W12 - 12 weeks after implant placement; W21 - 21 weeks after implant 
placement; W24 - 24 weeks after implant placement; W36 - 36 weeks after implant placement; W48 - 48 weeks after implant placement; PG – pharmacogenomic; 
FP – Family Planning. 
1. Visit date +/- 3 days 
2. Visit date +/- 1 week 
3. Visit date +/- 24 hours 
4. For any participant who discontinues study procedures prior to the week 48 visit. Do not complete if the participant withdraws consent to perform study 
procedures. 

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5. Visit date +/- 48 hours. 
6. Only if visit is occurring after week 24. 
7. Cervical mucus assessments were stopped on October 19, 2020 due to stock outs. 
 

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7.3.1 Follow-up Visit 
The primary comparison between these participants and the historical control group will be complete at week 48. If all safety thresholds 
have been met, participants in will have follow-up visits during years 2 and 3 post-implant placement to ensure long-term tolerability 
and PK stability of the increased ENG dose strategy in combination with EFV-based ART, as follows: 
 
Protocol 
Activity 
W691 
W701 
W711 
W721 
W931 
W941 W951 
W961 
W1171 
W1181 
W1191 
W1201 
W1411 
W1421 
W1431 
W1441 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
and PE 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
Weight + VS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess for 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess for AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess for ART 
adherence 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contraceptive 
satisfaction 
questionnaire  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Condom use 
questionnaire 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
HIV Risk and 
FP counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(urine) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
HIV-RNA  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CD4 cell count 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Cholesterol/ 
LDL 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 HbA1c 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
EFV PK sample  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
ENG PK 
sample 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Endogenous 
progesterone 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Cervical mucus 
assessment3 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: X – All participants; O – Optional procedures, for consenting participants; A – As needed. If not available in clinical record, draw as 
part of study visit procedures; PE – physical exam; VS – vital signs. 
1. Visit date +/- 24 hours 
2. No discontinuation visit is required if participants choose to leave the study after week 48. 
3. Cervical mucus assessments were stopped on October 19, 2020 due to stock outs. 
 
 
 
 

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7.3.2 Follow-up Visits after ART Switch 
 
Participants who switch from EFV600 mg-based ART to either DTG-based ART or EFV 400mg-based ART will have an 
opportunity to participate in optional visits, as described in section 6.  All participants that desire to remain in the study after ART 
switch and agree to the additional PK visits will have the following visit schedule, which can occur on their regularly scheduled visit if 
possible:  
 
 
Day of Switch1 
2 Weeks2 
4 Weeks2 
6 Weeks2 
EFV PK Sample 
X 
X 
X 
X 
ENG PK sample 
X 
X 
X 
X 
Removal of 
second implant3 
X 
 
 
 
1. Visit date +/- 24 hours 
2. Visit date +/- 7 days 
3. For participants in the double dose arm who are switching to DTG-based ART 
 
 
 

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7.3.3 Participant Withdrawal 
Participants may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the participant to comply with the protocol required schedule of study 
visits or procedures. 
 
If a participant does not return for a scheduled visit, every effort should be made to contact the 
participant. The participant will be contacted by telephone and if this is unsuccessful, a home visit 
will be arranged. In any circumstance, every effort should be made to document participant 
outcome, if possible.  The investigator should inquire about the reason for withdrawal and follow-
up with the participant regarding any unresolved AEs. Reason for withdrawal will be documented 
on the CRFs. 
 
If a participant needs to switch ART to a regimen that is not based on EFV or DTG, the participant 
will discontinue study follow up. Participants who switch to alternative ART options will be 
counseled by the IDI Family Planning clinicians regarding effective contraceptive options and will 
have one or both ENG implants removed after this consultation. 
 
If a participant chooses to remove the IUD before week 48, they will discontinue study follow-up. 
After 48 weeks, information from the study regarding the effectiveness of increasing the dose of 
ENG implant in combination with EFV-based ART will be available. If successful, the study will 
continue through week 144 and participants will have the option to remove the IUD in consultation 
with the IDI family planning caregivers. If the participant switches to DTG-based ART in the 
course of follow-up, those participants may have the IUD removed in consultation with the IDI 
family planning providers.  Due to the long half-life of EFV, it is recommended that the IUD 
remain in place for 4 weeks after EFV discontinuation to avoid the risk of pregnancy. The 
participant may have the IUD removed sooner if desired and will be counseled to use condoms to 
avoid the risk of pregnancy.  
 
If the participant desires implant and/or IUD removal upon study exit, the implant and/or IUD will 
be removed by a study clinician.   
 
Participants will be considered adherent to their drug regimen if they take at least 90% of the 
EFV/DTG as prescribed. Non-adherence to DTG/EFV-based ART may make the study results un-
interpretable, given the removal of the DDI. Subject to Institutional Review Board (IRB) approval, 
participants withdrawn for not adhering to study procedures may be rescheduled and/or withdrawn 
and replaced by the investigators. 
 
Participants to be withdrawn prior to week 48 should be invited to attend an early discontinuation 
(early D/C) visit (refer to Schedule of events, Section 6.2). Participants who complete study 
procedures through week 24 will contribute data to the primary objective analysis. If the participant 
withdraws from the study and also withdraws consent for disclosure of future information, no 
further evaluations should be performed, and no additional data should be collected.  The 
investigator may retain and continue to use any data collected before such withdrawal of consent. 
 

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8. ASSESSMENTS 
 
8.3 Safety 
 
8.3.1 Physical assessments 
Full physical examinations will be performed at the screening visit and as needed during follow-
up based on clinical judgment by the local investigators. 
 
Adverse events will be assessed at each visit and documented following the procedures outlined 
in section 8.0. 
 
8.3.2 Contraceptive Questionnaires 
Contraception use questionnaire: Brief questionnaire (1 page) of prior contraceptive use and about 
the participant’s rationale for desiring the use of the ENG implant. This questionnaire is completed 
at entry only. 
 
Baseline symptoms questionnaire: Brief questionnaire that the participants will complete at 
enrolment. Questions will objectively address signs and symptoms of hormone related toxicity at 
baseline (prior to implant insertion). 
 
Contraceptive satisfaction questionnaire: Brief questionnaire that the participants will complete 
following implant insertion, according to the Schedule of Events. Questions will objectively 
address signs and symptoms of hormone related toxicity, as well as the participant’s satisfaction 
with the ENG implant as a contraceptive method. 
 
Condom use questionnaire: Brief questionnaire that the participants will complete at baseline and 
according to the Schedule of Events. The condom use questionnaire will assess ongoing condom 
use among participants. 
 
8.3.3 Concomitant medications and ART medication adherence 
A completed medication list will be documented at screening to assess eligibility requirements 
(see Concomitant medications in Schedule of Events). This list will be reviewed at each study visit 
and any changes to concomitant medications will be documented in the CRFs. 
Adherence to ART will be evaluated at all study visits and phone calls by study staff. Methods of 
assessment will include direct questioning of dosing schedules, missed or late doses in the past 30 
days or since the last visit, using a standardized questionnaire administered and each visit. 
Specifically, participants will be asked to make note of the exact time at which they took their last 
dose of EFV prior to the study visit, which will be documented during the study visit by the study 
staff. Any participant found to be nonadherent to EFV will be counselled regarding the concern 
regarding increased ENG exposure.  Any participant that completely discontinues EFV by their 
primary care provider or due to nonadherence will be withdrawn from the study. 
 
8.3.4 Safety laboratory evaluations 
All safety laboratory investigations (including hemoglobin, serum creatinine, glycosylated 
hemoglobin (HBA1c), and ALT) will be performed in real-time at the Makerere University – Johns 

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Hopkins (MU-JHU) core laboratory within the IDI main building, as indicated in the Schedule of 
Events in section 6.2. This laboratory maintains annual External Quality Assurance certification 
of the College of American Pathologists.  
 
A viral load (HIV RNA) will be performed in real time at the screening visit to ensure all 
participants are currently virologically suppressed (per entry criteria). A viral load will be 
performed at regular intervals during the study period according to the schedule of events to ensure 
participants have remained suppressed throughout the study. Viral load measurements above 400 
copies/mL will be considered AEs. 
 
CD4 cell count will be documented at entry for all participants and then according to the schedule 
of events. 
 
8.3.5 Phone calls to assess ART adherence and ENG related AEs 
During the first 6 months of study participation, when ENG concentrations are expected to be 
highest, participants will be contacted by phone according to the schedule of events. Participants 
will be asked about any adverse events they may be experiencing. Adherence to ART will also be 
evaluated during these phone calls by study staff. Methods of assessment will include direct 
questioning of dosing schedules, missed or late doses in the past 30 days or since the last visit. 
 
8.4 Pregnancy Testing 
For all women interested in study participation, a urine pregnancy test will be performed at 
screening and entry visits, prior to enrolment. Women with positive pregnancy tests will be 
excluded. Enrolled women will be counseled to use a barrier contraception method (e.g. condoms) 
to prevent pregnancy. Enrolled women will have a urine pregnancy test at each visit (except the 
optional study visits on Days 1-4). Women who become pregnant during the study will be excluded 
from further study participation and drug treatments stopped.  All pregnancy exposures will be 
reported to the IRB and the Uganda National Drug Authority (NDA). 
 
8.5 Pharmacokinetics Assessments  
 
8.5.1 Blood for PK analysis of ENG or efavirenz 
Based on the study schedule of events outlined in section 6.2, one 6 mL whole blood sample will 
be collected to measure ENG concentrations and a second 4 mL whole blood sample will be 
collected to measure EFV concentrations. The maximum number of blood draws that a patient will 
have is 16, over the course of 3 years. EFV plasma concentrations will be analyzed at the Makerere 
University laboratory using previously described high performance liquid chromatography 
(HPLC) methods50. ENG will be analyzed at the University of Pittsburgh Small Biomarkers Core 
Laboratory using a validated, published method by HPLC linked to mass spectrometry (LC-
MS/MS)51. This method includes evaluation for and quantification of all progestins (synthetic and 
endogenous).  This will allow the study team to know if the study participants were using any 
external synthetic progestins, that could confound the study results.  Additionally, this method will 
also quantify estradiol in the first year of the study procedures. This will evaluate the impact of the 
higher dose of etonogestrel evaluated on circulating endogenous progestin, therefore allowing 
quantitative assessment if there is any concerns regarding any adverse events related to 
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All efforts will be made to obtain the PK samples at the scheduled nominal time relative to dosing 
(see section 6.0).  If a scheduled blood sample collection cannot be completed for any reason, the 
missed sample time may be re-scheduled with agreement of clinical investigators.  
 
8.5.2 Sample Handling  
For each PK sample, whole blood will be obtained and collected into vacutainers containing 
ethylenediaminetetraacetic acid anticoagulant.  
 
Within one hour of collection, samples will be transported by dedicated sample transport personnel 
from the IDI clinic to the Makerere-University Johns Hopkins University Core Laboratory. 
Samples will be centrifuged at 3000 revolutions per minute for 10 minutes to separate plasma. 
This sample is expected to yield two or three aliquots of plasma (each approximately 0.7 mL). 
Plasma aliquots will be stored at -70o Celsius.  
 
8.5.3  Justification for PK shipment  
One aliquot of the ENG PK specimen will be shipped to the University of Pittsburgh according to 
the schedule outlined for safety evaluations in section 9.4 Duplicates will be retained at IDI until 
results from the shipped batch become available. PK samples will be assayed for ENG using a 
validated analytical method. Drug concentrations will be determined by high performance liquid 
chromatography with tandem mass spectrometry (LC-MS/MS)51. The IDI has a HPLC machine, 
however mass spectrometry equipment is expensive and not available in Uganda. Sample transfer 
and analysis will be governed by a material transfer agreement that will be signed between both 
parties. At the end of the analysis, unused samples will be discarded. 
 
8.6 Other measurements 
 
8.6.1 Patient characteristics that may influence pharmacokinetic properties 
Body weight (as Kg) will be measured according to the schedule of events as ENG concentrations 
have been correlated with body weight. Height will be documented at screening to calculate body 
mass index. 
  
Albumin and sex hormone binding globulin will be measured according to the schedule of events, 
as ENG binds to both serum albumin and sex hormone binding globulin. Blood samples for 
albumin will be processed at the MU-JHU core laboratory and samples for sex hormone binding 
globulin will be processed at Lancet Lab, Kampala, Uganda.  
 
Participants will be asked to contribute a single blood sample for pharmacogenetic analysis at 
study entry.  This will be an optional study element and participants may refuse to participate in 
this pharmacogenetic research and still participate in the study. Blood samples for 
pharmacogenetic analysis of functional polymorphisms known to influence the disposition of EFV 
or ENG will be processed at the IDI translational laboratory. 
 

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8.6.2 Endogenous progesterone as a measure of ovulation and cervical mucus 
assessment 
As a laboratory marker to assess recent ovulation, endogenous progesterone will be evaluated at 
study visits at weeks 9, 10, 11, 12, 21, 22, 23, 24, 45, 46, 47, and 48, ideally on the same day of 
the week.  Evaluation will continue during years 2 and 3 if safety and efficacy standards are met. 
Samples for measurement of endogenous progesterone will be processed at Lancet Lab, Kampala, 
Uganda.  
 
In order to assess the contraceptive effect of ENG on the cervical mucus, cervical mucus samples 
will be collected at weeks 9, 10, 11, 12, 21, 22, 23, 24, 45, 46, 47, and 48.  The collection procedure 
will be performed according the WHO manual for Examination and processing of human semen, 
5th edition, Appendix 5 (Cervical Mucus), specifically section A5.2 (Collection and preservation 
of cervical mucus)39.  The cervical mucus will be evaluated by an assessor blinded to the 
participant’s study arm immediately after collection and scored according to section A5.3 
(Evaluation of cervical mucus)39.  Every effort will be made to have the cervical mucus assessment 
completed by the same assessor.  A score of greater than 10 is favorable for sperm penetration 
indicating a lack of contraceptive effect39.  The cervical mucus collection was discontinued on 
October 19th, 2020. 
 
9. ADVERSE EVENT REPORTING 
9.3 Adverse Events 
All observed or volunteered AEs regardless of suspected causal relationship will be reported.  
 
For all AEs, the investigator must pursue and obtain information adequate both to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as a serious adverse 
event (SAE) requiring immediate notification (see section 8.5).  For all AEs, sufficient information 
should be obtained by the investigator to determine the causality of the AE.  The investigator is 
required to assess causality.  Follow-up by the investigator may be required until the event or its 
sequelae resolve or stabilize at a level acceptable to the investigator. 
 
During each study visit the co-investigator will assess AEs that may have occurred since the 
previous visit. This will be done by:  
• Active interrogation and collection of reported information from the participant at each 
study visit or phone call. Patients will be questioned specifically about study drug 
associated AEs and any other unanticipated AEs. 
• The contraceptive satisfaction questionnaire will be administered to the participant and 
completed by the study nurse at each study visit after the ENG subdermal implant is placed. 
This will also highlight known ENG toxicities as well as family planning method 
satisfaction. 
• Safety labs will be performed as outlined in the schedule of events. 
 
9.4 Serious Adverse Events 
An SAE is any untoward medical occurrence at any dose that:  
Results in death; Is life-threatening (immediate risk of death); Requires inpatient 
hospitalization or prolongation of existing hospitalization; Results in persistent or 

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significant disability/incapacity (substantial disruption of the ability to conduct normal life 
functions); Results in congenital anomaly/birth defect, may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
9.5 Severity Assessment 
The severity of AEs will be graded according to the National Institute of Health Division of AIDS 
(DAIDS) classification system for reporting adverse experiences in adults52.  
 
9.6 Causality Assessment 
The investigator will assess causality for all AEs (serious and non-serious) and record the causal 
relationship in the CRF, as appropriate, and report such an assessment in accordance with the SAE 
reporting requirements. The relationship to study drug of each AE will be assessed using the 
following definitions: 
 
DEFINITE: distinct temporal relationship with drug treatment. Known reaction to agent or 
chemical group, or predicted by known pharmacology. Event cannot be explained by participant’s 
clinical state or other factors. 
 
PROBABLE: reasonable temporal relationship with drug treatment. Likely to be known reaction 
to agent or chemical group, or predicted by known pharmacology. Event cannot easily be 
explained by participant’s clinical state or other factors. 
 
POSSIBLE: reasonable temporal relationship with drug treatment. Event could be explained by 
participant’s clinical state or other factors. 
 
UNLIKELY: poor temporal relationship with drug treatment. Event easily explained by 
participant’s clinical state or other factors. 
 
UNRELATED: the event occurs prior to dosing. Event or concurrent illness is due wholly to 
factors other than drug treatment. 
 
9.7 Reporting Requirements 
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow IRB, local and international regulations, as appropriate. All SAEs 
determined to be related to the study will be reported to IDI Scientific Review Committee, the  
Joint Clinical Research Centre IRB, the Uganda National Council of Science and Technology 
(UNCST), the Uganda National Drug Authority (NDA). All SAEs determined to be related to the 
study will be reported to the project and consortium PIs within 24 hours of knowing about the 
event and to the ethics committee, UNCST and NDA within seven days of knowing about the 
event. Principal Investigator shall forward to Merck’s Global Safety (“Merck GS”) group and to 
the Safety Monitoring Committee (SMC), any SAE determined to be related to the study, within 
two (2) business days but not longer than three (3) calendar days of receipt of learning of the 
information.  Further relevant follow-up information will be given as soon as possible. Follow-up 
will continue until the event resolves. 
 

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All AEs will be tabulated and reported to the JCRC IRB in annual study reports. SAEs will be 
reported to IRB and the regulatory authorities within seven days from the time the study team 
becomes aware of the occurrence of the SAE. All AEs will be reported on the participant and study 
AE log. The same AE term(s) should be used consistently across all AE-related forms. AEs should 
be reported using concise medical terminology on the CRFs as well as on the form for collection 
of SAE information. 
 
Study team AE reporting: All other AEs will be compiled weekly and submitted to the project 
and consortium PI. The protocol team will discuss the weekly AE reports on regularly scheduled 
biweekly teleconferences. The Safety and Monitoring Committee (SMC) will be identified prior 
to study initiation.  The SMC will have the authority to suspend any study related activity at any 
time based on their assessment of AEs (see section 9.6). 
 Any contraception related AE requiring medical management, including contraceptive 
failure resulting in pregnancy, will be discussed with the consultant OB/Gyne in the United 
States and in Uganda. 
 Any HIV related AE requiring medical management would be discussed with the IDI 
primary care provider who is providing HIV care to the participant.  Additionally, the study 
team HIV physician will be notified. 
 
9.8 Post-Recruitment Illness 
All participants with post-recruitment illness will be evaluated at the IDI clinic and if necessary, 
be referred for care at Mulago National Referral and Teaching Hospital and patients will be 
managed in accordance with Uganda national treatment guidelines.  
 
10. DATA ANALYSIS/STATISTICAL METHODS 
 
10.3 Sample Size Determination 
To evaluate our primary outcome of ovulation frequency in the standard-dose ENG implant vs. 
the dose-escalated ENG implant groups, we estimate a desired sample size of 36 participants per 
group or 72 participants total and will allow for attrition of 4 participants total. This sample size is 
based on unpublished data from our previous study which showed an ovulation rate of 0.15/month 
(9 ovulations noted in 20 participants) when sampling at month 1, 3, and 6 with standard dose 
ENG implant with women on EFV1.  The progesterone sampling was performed simultaneously 
with the ENG sampling at only one time per month, therefore ovulations were likely missed.  
Additionally, we assumed that with the dose-escalated ENG implant use in women on EFV that 
there would be only one ovulation in twenty participants within six months, or a cumulative 
ovulations rate of 0.017/month.  The sample size of 34 per group was determined using a method 
published by Leon based on mixed-effects logistic regression with a two-tailed alpha level of 0.05, 
a power of 0.80 and assuming an intraclass correlation coefficient of 0.2553.   
Additionally, for the PK outcome, this sample size provides an estimated power of 0.80 to detect 
a 30% change in ENG concentrations at 6 months between the dose-escalated ENG implant + 
EFV-based ART and the historical control (standard-dose ENG implant without ART) using an 
alpha level of 0.05.  This estimate is based on an mean ENG concentration of 361.54 pg/mL (SD 
144.16 pg/mL) in HIV+ Ugandan women not on ART at 6 months post implant insertion (n=20)35. 

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Participants found to be nonadherent to EFV by an serum EFV concentration of less than 
200ng/mL will be excluded from the analysis.   
10.4 Analysis of Endpoints 
 
10.4.1 Ovulation frequency and cervical mucus assessment 
Between-group comparisons will evaluate the differences in ovulatory frequency (progesterone 
>3ng/mL) and WHO cervical mucus scores greater than 10 (indicating lack of contraceptive 
effect) between the standard-dose ENG implant (68mg) control group and the dose-escalated 
ENG implant (136mg) treatment group.  Ovulation will be assessed by weekly serum 
endogenous progesterone measurements after 3 months of implant use (weeks 9-12), 6 months of 
implant use (weeks 21-24) and 12 months of implant use (weeks 45-48).  Any progesterone 
measurement greater than 3ng/mL will indicate that an ovulation occurred in that participant 
during that month and the number of participants ovulating in one month will be determined. 
Similarly, cervical mucus will be assess by the WHO cervical mucus score collected after 3 
months of implant use (weeks 9-12), 6 months of implant use (weeks 21-24) and 12 months of 
implant use (weeks 45-48).  Any WHO mucus score greater than 10 will indicate that the mucus 
is favorable for sperm penetration, or a lack of contraceptive effect.    The ovulatory rate and the 
rate of cervical mucus scores greater than 10 will be compared between the groups (standard-
dose vs. dose escalated implant groups) at months 3, 6 and 12 of implant use using mixed-effects 
logistic regression to account for multiple assessments in each participant over time.    
10.4.2 Analysis of ENG concentrations 
Between-group comparisons will evaluate changes in ENG PK parameters between the treatment 
group (dose-escalated ENG implant +EFV-based ART, n=36) and a historical control group 
(standard dose ENG implant without ART, n=20). Log transformed area under the concentration 
time curve of ENG will be compared between the historical control group and the double dose 
ENG EFV group using a student’s t-test or Wilcoxon rank sum test, based on the normality of 
result distribution. Drug concentrations will be summarized descriptively (mean, median, 
minimum, maximum, standard deviation) by study visit and compared between groups using a 
geometric mean ratio. The ENG concentration-time curve will be pharmacokinetically modeled 
using Phoenix modeling software (Pharsight®). Pharmacokinetics after switch from EFV 600mg 
to alternative regimens (EFV 400mg or DTG), ENG PK will be described descriptively after 
switch. 
 
10.4.3 Analysis of EFV concentrations 
Within group comparisons will evaluate changes in EFV concentrations from prior to the ENG 
implant insertion. Mean EFV concentrations will be compared at each time point within both the 
single ENG implant group and the double dose implant group using a paired student’s t-test or 
Wilcoxon signed-rank test, based on the normality of result distribution. Drug concentrations will 
be summarized descriptively (mean, median, minimum, maximum, standard deviation) by study 
visit and used to assess the relationship between ENG and EFV exposure.  
 
10.5 Analysis of Other Endpoints 
Additional data will be compared between the single ENG implant group vs. the two ENG implants 
group in the current study all on EFV-based ART using standard methods of student’s t-test or 

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nonparametric tests for two group comparisons of continuous variables, as appropriate, and chi-
square or Fisher’s exact test for discrete data.   
 
10.6 Safety Analysis 
ENG efficacy and safety based on PK exposure: To mitigate the risk for any unexpected ENG 
dose-related AEs related to supratherapeutic ENG concentrations, any ENG concentration that is 
1.5-fold higher than the control group’s geometric mean ENG level (Table 1) will be reported to 
the study’s key personnel and the SMC chair within 1 week of detection. Current AE reports for 
that participant will simultaneously be provided for SMC review. This strategy employs an 
abundance of caution, given that a 1.5-fold higher ENG concentration from the implant is still 
significantly lower than ENG exposure from the etonogestrel vaginal ring (NuvaRing®)44. 
 
To ensure subjects do not receive long-term, suboptimal hormonal contraception, we will also 
assess futility of increased dose ENG implant and EFV-based ART throughout the study period. 
Absence of contraceptive effect will be determined by reviewing all ENG plasma concentrations, 
serum progesterone measurements, and WHO cervical mucus score assessments. The criteria for 
determining absence of contraceptive effect will be agreed upon by the SMC and the safety team, 
but will include lack of contraceptive effect as evidence by ENG <90pg/mL, progesterone 
concentration >3ng/mL and/or WHO cervical mucus scores >10.   
 
All safety and AE data will be descriptively summarized by severity, incidence and number of 
patients affected. 
 
10.7 Interim Analysis  
The first PK analysis of the ENG concentrations will occur as soon as 20 participants (at least 10 
in each group) completes 24 weeks of combined use ENG and EFV use, and will continue every 
6 months or sooner if a grade 3 or 4 study medication-related adverse event occurs or if there is 
significant concern of lack of contraceptive effect as evidenced by the serum progesterone 
concentrations and the WHO cervical mucus scores. SMC in conjunction with the study team will 
review all available PK/PD outcomes and safety data and will determine if either arm should be 
stopped.  These recommendations will be based on 2 different criteria:  
1) Safety - all the adverse events and the contraceptive satisfaction survey will be reviewed.  If 
one arm has a Grade 3 or 4 adverse events that are deemed related to the study medication, then 
consideration will be made to stopping the trial.  
2) Absence of contraceptive effect – all available ENG, progesterone and cervical mucus data will 
be reviewed.  The criteria for determining absence of contraceptive effect will be agreed upon by 
the SMC and the safety team, but will include lack of contraceptive effect as evidence by ENG 
<90pg/mL, progesterone concentration >3ng/mL and/or WHO cervical mucus scores >10 
occurring within the same participant during the same month. 
 
At the same time points as the PK interim analyses, study AEs and endogenous progesterone levels 
will be summarized for simultaneous review by the SMC to inform their study decision. As 
described in section 9.4, any supratherapeutic ENG concentration will be reported to the study’s 
key personnel and the SMC chair within 1 week of detection.  

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10.8 Data Safety and Monitoring Committee  
The SMC will include professionals who have no conflict with serving on the SMC.  The SMC 
will include medical professionals with expertise in the design, conduct and analysis of PK 
studies, HIV clinical care and research, and/or obstetrics and gynecology and family planning. 
The SMC will convene either in person, or via teleconference at the following times: 
• Prior to the study opening to enrollment:  
o Review the research protocol, informed consent, and ethics approvals. 
o Make recommendations about the readiness to open the study 
• Within 2 weeks after 20 participants (at least 10 in each group) complete 24 weeks of 
combined use ENG and EFV use: 
o Assess if the ENG PK, serum progesterone, and WHO cervical mucus score results 
indicate excess risk of pregnancy or toxicity in study subjects 
o Review all study related AEs or subject concerns 
o Make recommendations about continuation or conclusion of the study 
• Every 6 months during follow-up: 
o Assess if the ENG PK, serum progesterone, and WHO cervical mucus score results 
indicate excess risk of pregnancy or toxicity in study subjects 
o Review all study related AEs or subject concerns 
o Make recommendations about continuation or conclusion of the study at week 48 
• Annually, the SMC will perform the following activities: 
o Review the research protocol and any changes that occurred over the year 
o Review all study related AEs or subject concerns 
o Assess study progress, including enrollment, data quality, risk vs. benefit, and any 
interim or final study results 
o Evaluate if there have been scientific or therapeutic developments that impact the 
conduct of the study 
o Make recommendations about continuation or conclusion of the study 
 Ad hoc: any time there is a Grade 3 or 4 adverse event related to the study medication or 
as the SCM chair, project or consortium PI deems necessary  
 
11. QUALITY CONTROL AND QUALITY ASSURANCE 
 
During study conduct periodic monitoring may be conducted to ensure that the protocol and Good 
Clinical Practices (GCPs) are being followed.  The monitors may review source documents to 
confirm that the data recorded on CRFs is accurate.  Additionally, the study site may be participant 
to review by the IRB and/or to inspection by appropriate regulatory authorities. 
 
12. DATA HANDLING/RECORD RETENTION 
 
12.3 Case Report Forms (CRF)/Electronic Data Record 
A CRF is required and should be completed for each included participant. The investigator has 
ultimate responsibility for the collection and reporting of all clinical, safety and laboratory data 
entered on the CRFs and any other data collection forms (source documents) and ensuring that 
they are accurate, authentic / original, attributable, complete, consistent, legible, timely 
(contemporaneous), enduring and available when required.  The CRFs must be signed by the 

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investigator or by an authorized staff member to attest that the data contained on the CRFs is true.  
Any corrections to entries made in the CRFs, source documents must be dated, initialed and 
explained (if necessary) and should not obscure the original entry.  
 
12.4 Record Retention 
To enable evaluations and/or audits, the investigator agrees to keep records, including the identity 
of all participating patients (sufficient information to link records, eg, CRFs and hospital records), 
all original signed informed consent documents, copies of all CRFs, safety reporting forms, source 
documents, and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports). 
Investigator records will be kept in accordance with current UNCST and the NDA guidelines. 
 
12.5 Confidentiality 
Clinical data will be entered into a study specific database by designated staff on a regular basis 
from completed CRF. CRFs and other source documents will be kept in locked cabinets. Data will 
be entered on a regular basis to ensure that it is up to date. The database will be on a password 
protected, secure PC, as will the PK database that will be received by the laboratories. Access to 
database will be given to authorized personnel only (members of the immediate study team) and a 
log of authorized personnel will be stored in the trial master file. Hard copies of CRFs and trial 
documents will be kept in locked cabinets. No participant identifying information will be disclosed 
in any publication or at any conference activities arising from the study. 
 
12.6 Missing Data 
All efforts will be made to collect required data at each study visit within one month after the study 
visit. Any remaining missing clinical data will be considered ‘missing’ during statistical analysis. 
 
13. ETHICS 
13.3 Institutional Review Board (IRB) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents from the IRB.  
All correspondence with the IRB should be retained in the regulatory or trial master file. Copies 
of IRB approvals should be filed with other study documents. 
 
13.4 Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as the 
general principles set forth in the International Ethical Guidelines for Biomedical Research 
Involving Human Participants and the Declaration of Helsinki. In addition, the study will be 
conducted in accordance with the protocol, GCP guidelines, and applicable local regulatory 
requirements and laws. 
 
13.5 Participant Information and Consent 
All parties will ensure protection of participant personal data and will not include participant 
names on any forms, reports, publications, or in any other disclosures, except where required by 
laws.  
 

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The informed consent document used in this study, and any changes made during the course of the 
study, must be prospectively approved by the IRB. 
 
The investigator, or a person designated by the investigator, will obtain written informed consent 
from each participant or the participant's legal representative before any study-specific activity is 
performed. The investigator will retain the original of each participant's signed consent document. 
 
13.6 Risks and benefits 
Risks of study participation include risk of infection or hemorrhage at the site of venipuncture or 
cannulation, and the risk of loss of confidentiality. The study will take all reasonable steps to 
minimize or eliminate these risks.  
 
Changes to ART or HIV care and treatment are not planned during the study period, therefore we 
don’t expect additional ART related toxicities. The risk of AEs associated with the use of ENG 
implants exists, though because the increased dose of ENG given in combination with EFV is 
expected to be similar to the ENG exposure in a normal population, it is not expected to be higher 
in this study as compared to standard use of the implant. ENG implant may have the following 
side effects: 
 
Physical: There may be slight pain, discomfort, redness or swelling associated with the subdermal 
ENG implant insertion. Some of the more common AEs include menstrual irregularities (increased 
or decreased menstrual flow, spotting, irregularity and amenorrhea), weight gain, headache, 
depression or mood changes, nausea, nervousness, and dizziness.  
 
Psychological: Participants may experience psychological risks if pregnancy were to occur during 
the study period, as this would be unintended.  
 
The copper IUD may have the following side effects: 
Physical: Changes in the bleeding patterns (especially in the first 3-6 months) including heavier 
menstrual bleeding, irregular bleeding, or uterine cramping.  
Adverse Events: The risk of AEs associated with the use of copper IUDs exist, though is not 
expected to be in higher in this study as compared to standard use of copper IUD. Some of the rare 
AEs include: infection, uterine perforation, IUD expulsion, difficult IUD removal, and pregnancy, 
including ectopic pregnancy.   
 
Benefits: Evidence is accumulating that subjects using an ENG implant while on EFV-based ART 
have suboptimal ENG drug concentrations, which may lead to increased risk of unintended 
pregnancies. Participating in the proposed research study will allow subjects to receive increased 
dose ENG implants to possibly overcome this drug interaction, with the goal to achieve ENG PK 
exposure similar to normal dose ENG without EFV-based ART. Although we do not expect an 
increased rate of toxicity with the increased dose ENG implant, we have implemented a rigorous 
safety monitoring plan to allow early identification of safety concerns should they occur. 
Importantly, this strategy may improve the contraceptive safety and efficacy for women receiving 
EFV-based ART. 
 

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The potential benefit of the proposed research to participants, as well as others, include providing 
new data regarding the potential interaction between ENG implants and ART. Based on study 
findings, we will be able to inform changes in clinical practice to offer guidance on the safe dose 
and duration of concomitant use of EFV-based ART and ENG implants, thereby reducing risk of 
unintended pregnancy for HIV-infected women receiving these therapies and improving 
women’s health. The study will also monitor the HIV-RNA (viral load) and CD4 cell count as an 
assessment of HIV disease throughout the study period. 
 
14. DEFINITION OF END OF TRIAL 
This study is complete when participants have completed follow up to week 144, unless the trial 
is suspended prior to week 144.  
 
15. PUBLICATION OF STUDY RESULTS 
Study findings will be disseminated to researchers through oral or written presentations at 
scientific conferences and through peer-reviewed journals. Full anonymity of participant’s details 
will be maintained throughout. Participants wanting to see the results of the trial can request a copy 
of the article from the investigators once it has been published. In Uganda, study results will be 
communicated to Ministry of Health program managers through meetings and reports. Study 
summaries will be communicated to health workers in Uganda through the AIDS Treatment 
Information Centre newsletter, which is published by the IDI and distributed to all health workers 
in the public and not-for profit sectors in Uganda. The study will be registered on Clinicaltrials.gov. 
 
16. FUNDING 
 
This proposal is funded by the Merck Investigator Studies Program. No fault insurance will be 
procured to cover any study related adverse event that occurs during the study. 
 
 

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17. REFERENCES 
 
 
1. 
Chappell CA, Scarsi KK, Nalakema S, Chen BA, Riddler SA, Cohn S, Darin KM, 
Achilles SL, Lamorde ML, Efavirenz significantly decreases etonogestrel exposure: 
results of a bidirectional pharmacokinetic evaluation of efavirenz- and nevirapine-based 
antiretroviral therapy plus etonogestrel contraceptive implants. J Int AIDS Soc, 2016. 19(8Suppl 
7): p. 21487. 
2. 
Darroch JE, Singh S. Trends in contraceptive need and use in developing countries in 
2003, 2008, and 2012: an analysis of national surveys. Lancet 2013;381:1756-62. 
3. 
Darroch JE. Trends in contraceptive use. Contraception 2013;87:259-63. 
4. 
Singh S and Darroch JE, Adding It Up: Costs and Benefits of Contraceptive Services—
Estimates for 2012, New York: Guttmacher Institute and United Nations Population Fund 
(UNFPA), 2012, < http://www.guttmacher.org/pubs/AIU-2012-estimates.pdf>. Accessed: 6 
April 2017. 
5. 
World Health Organization. Global summary of the AIDS epidemic, December 2014. 
Available at: http://www.who.int/hiv/data/epi_core_july2015.png?ua=1. Accessed: 14 Sept 
2015. 
6. 
Reynolds HW, Janowitz B, Homan R, Johnson L. The value of contraception to prevent 
perinatal HIV transmission. Sex Transm Dis 2006;33:350-6. 
7. 
Reynolds HW, Janowitz B, Wilcher R, Cates W. Contraception to prevent HIV-positive 
births: current contribution and potential cost savings in PEPFAR countries. Sex Transm Infect 
2008;84 Suppl 2:ii49-53. 
8. 
World Health Organization. Consolidated guidelines on the use of antiretroviral therapy 
for treating and preventing HIV infection: Recommendations for a public health approach, 
second edition. Geneva: World Health Organization, 2016.  
9. 
Mansour D, Mommers E, Teede H, et al. Clinician satisfaction and insertion 
characteristics of a new applicator to insert radiopaque Implanon: an open-label, noncontrolled, 
multicenter trial. Contraception 2010;82:243-9. 
10. 
Vieira CS, Bahamondes MV, de Souza RM, et al. Effect of antiretroviral therapy 
including lopinavir/ritonavir or efavirenz on etonogestrel-releasing implant pharmacokinetics in 
HIV-positive women. J Acquir Immune Defic Syndr 2014;66:378-85. 
11. 
Matiluko AA, Soundararjan L, Hogston P. Early contraceptive failure of Implanon in an 
HIV-seropositive patient on triple antiretroviral therapy with zidovudine, lamivudine and 
efavirenz. J Fam Plann Reprod Health Care 2007;33:277-8. 
12. 
McCarty EJ, Keane H, Quinn K, Quah S. Implanon(R) failure in an HIV-positive woman 
on antiretroviral therapy resulting in two ectopic pregnancies. Int J STD AIDS 2011;22:413-4. 
13. 
Leticee N, Viard JP, Yamgnane A, Karmochkine M, Benachi A. Contraceptive failure of 
etonogestrel implant in patients treated with antiretrovirals including efavirenz. Contraception 
2012;85:425-7. 
14. 
Patel RC, Onono M, Gandhi M, et al. Pregnancy rates in HIV-positive women using 
contraceptives and efavirenz-based or nevirapine-based antiretroviral therapy in Kenya: a 
retrospective cohort study. Lancet HIV 2015;2:e474-82. 
15. 
Implanon® [package insert]. Roseland, NJ. Organon USA Inc. Nov 2008. 
16. 
UNICEF statistics: Uganda. Available at: 
http://www.unicef.org/infobycountry/uganda_statistics.html. Accessed 19 January 2015.  

PK-20 
Protocol Version 4.0 
 
IDI CONFIDENTIAL 
Page 47 
17. 
Uganda Bureau of Statistics (UBOS) and ICF International, Uganda Demographic and 
Health Survey 2011, Kampala, Uganda: UBOS; and Calverton, MD, USA: ICF International, 
2012. 
18. 
Uganda Ministry of Health. Addendum to the national antiretroviral treatment guidelines. 
December 2013. 
19. 
World Health Organization. Hormonal contraceptive methods for women at high risk of 
HIV and living with HIV: 2014 guidance statement. (Geneva: World Health Organization). 
http://www.who.int/reproductivehealth/publications/family_planning/HC_and_HIV_2014/en/. 
Accessed 6 April 2017. 
20. 
World Health Organization. Medical eligibility criteria for contraceptive use - 5th edition 
2015. Available at: 
http://apps.who.int/iris/bitstream/10665/181468/1/9789241549158_eng.pdf?ua=1  Accessed: 15 
Feb 2016. 
21. 
Increasing Use of Contraceptive Implants and Intrauterine Devices To Reduce 
Unintended Pregnancy. ACOG Committee Opinion No. 450. American College of Obstetricians 
and Gynecologists. Obstet Gynecol 2009;114:1434–8. 
22. 
Huber J, Wenzl R. Pharmacokinetics of Implanon. An integrated analysis. Contraception 
1998;58:85S-90S. 
23. 
Sivin I, Stern J, Diaz S, et al. Rates and outcomes of planned pregnancy after use of 
Norplant capsules, Norplant II rods, or levonorgestrel-releasing or copper TCu 380Ag 
intrauterine contraceptive devices. Am J Obstet Gynecol 1992;166:1208-13. 
24. 
Diaz S, Pavez M, Cardenas H, Croxatto HB. Recovery of fertility and outcome of 
planned pregnancies after the removal of Norplant subdermal implants or Copper-T IUDs. 
Contraception 1987;35:569-79. 
25. 
Duvall S, Thurston S, Weinberger M, Nuccio O, Fuchs-Montgomery N. Scaling up 
delivery of contraceptive implants in sub-Saharan Africa: operational experiences of Marie 
Stopes International. Glob Health Sci Pract 2014;2:72-92. 
26. 
Perry SH, Swamy P, Preidis GA, Mwanyumba A, Motsa N, Sarero HN. Implementing 
the Jadelle implant for women living with HIV in a resource-limited setting: concerns for drug 
interactions leading to unintended pregnancies. Aids 2014;28:791-3. 
27. 
Scarsi KK, Darin KM, Nakalema S, et al. Unintended Pregnancies Observed With 
Combined Use of the Levonorgestrel Contraceptive Implant and Efavirenz-based Antiretroviral 
Therapy: A Three-Arm Pharmacokinetic Evaluation Over 48 Weeks. Clin Infect Dis 
2016;62:675-82. 
28. 
Rice CF, Killick SR, Dieben T, Coelingh Bennink H. A comparison of the inhibition of 
ovulation achieved by desogestrel 75 micrograms and levonorgestrel 30 micrograms daily. Hum 
Reprod 1999;14:982-5. 
29. 
Makarainen L, van Beek A, Tuomivaara L, Asplund B, Coelingh Bennink H. Ovarian 
function during the use of a single contraceptive implant: Implanon compared with Norplant. 
Fertil Steril 1998;69:714-21. 
30. 
Wenzl R, van Beek A, Schnabel P, Huber J. Pharmacokinetics of etonogestrel released 
from the contraceptive implant Implanon. Contraception 1998;58:283-8. 
31. 
Croxatto HB, Makarainen L. The pharmacodynamics and efficacy of Implanon. An 
overview of the data. Contraception 1998;58:91S-7S. 

PK-20 
Protocol Version 4.0 
 
IDI CONFIDENTIAL 
Page 48 
32. 
Darney P, Patel A, Rosen K, Shapiro LS, Kaunitz AM. Safety and efficacy of a single-
rod etonogestrel implant (Implanon): results from 11 international clinical trials. Fertil Steril 
2009;91:1646-53. 
33. 
Mornar S, Chan LN, Mistretta S, Neustadt A, Martins S, Gilliam M. Pharmacokinetics of 
the etonogestrel contraceptive implant in obese women. Am J Obstet Gynecol 2012;207:110 e1-
6. 
34. 
Landgren BM. Mechanism of action of gestagens. Int J Gynaecol Obstet 1990;32:95-110. 
35. 
Chappell CA, Scarsi KK, Nakalema S, et al. Efavirenz significantly decreases 
etonogestrel exposure: results of a bidirectional pharmacokinetic evaluation of efavirenz- and 
nevirapine-based antiretroviral therapy plus etonogestrel contraceptive implants. J Intern AIDS 
Soc. 2016, 19 (Suppl 7) p.215. 
36. 
Diaz S, Pavez M, Moo-Young AJ, Bardin CW, Croxatto HB. Clinical trial with 3-keto-
desogestrel subdermal implants. Contraception 1991;44:393-408. 
37. 
Lakhi N, Govind A. Implanon failure in patients on antiretroviral medication: the 
importance of disclosure. J Fam Plann Reprod Health Care 2010;36:181-2. 
38. 
Pyra M, Heffron R, Mugo NR, et al. Effectiveness of hormonal contraception in HIV-
infected women using antiretroviral therapy. Aids 2015;29:2353-9. 
39. 
World Health Organization laboratory manual for the examination and processing of 
human semen - Fifth edition. 2010. 
http://www.who.int/reproductivehealth/publications/infertility/9789241547789/en/. Accessed 6 
April 2017. 
40. 
Isentress® [package insert]. Whitehouse Station, NJ. Merck & Co., Inc. August 2014. 
41. 
Edelman AB, Cherala G, Munar MY, et al. Prolonged monitoring of ethinyl estradiol and 
levonorgestrel levels confirms an altered pharmacokinetic profile in obese oral contraceptives 
users. Contraception 2013;87:220-6. 
42. 
Westhoff CL, Torgal AH, Mayeda ER, Pike MC, Stanczyk FZ. Pharmacokinetics of a 
combined oral contraceptive in obese and normal-weight women. Contraception 2010;81:474-
80. 
43. 
Edelman AB, Cherala G, Munar MY, McInnis M, Stanczyk FZ, Jensen JT. Correcting 
oral contraceptive pharmacokinetic alterations due to obesity: a randomized controlled trial. 
Contraception 2014;90:550-6. 
44. 
NuvaRing® Package Insert. Oraganon USA Inc. Roseland, NJ 2005. 
45. 
Consolidated Guidelines for the Prevention and Treatment of HIV and AIDS in Uganda. 
The Republic of Uganda Ministry of Health. 
https://uac.go.ug/sites/default/files/Consolidated%20HIV%20Guidelines%202020.pdf Accessed 
on November 12, 2020. 
46. 
Bishop IJ, Gertz AM, Simon B, et al. Etonogestrel concentrations among contraceptive 
implant users in Botswana using and not using dolutegravir-based antiretroviral therapy. 
Contraception 2020;102:174-9. 
47. 
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of 
antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human 
Services. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed: 9 Feb 
2016. 
48. 
 Uganda Bureau of Statistics (UBOS) and ICF International, Uganda Demographic and 
Health Survey 2011, Kampala, Uganda: UBOS; and Calverton, MD, USA: ICF International, 
2012. 

PK-20 
Protocol Version 4.0 
 
IDI CONFIDENTIAL 
Page 49 
49. 
Jadelle® [package insert]. Auckland, New Zealand: Bayer New Zealand Limited 
Company. August 2010. 
50. 
Almond LM, Hoggard PG, Edirisinghe D, Khoo SH, Back DJ. Intracellular and plasma 
pharmacokinetics of efavirenz in HIV-infected individuals. J Antimicrob Chemother 
2005;56:738-44. 
51. 
Li W, Li YH, Li AC, Zhou S, Naidong W. Simultaneous determination of norethindrone 
and ethinyl estradiol in human plasma by high performance liquid chromatography with tandem 
mass spectrometry--experiences on developing a highly selective method using derivatization 
reagent for enhancing sensitivity. J Chromatogr B Analyt Technol Biomed Life Sci 
2005;825:223-32. 
52. 
US Department of Heath and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0. 2014. 
Available at: http://rsc.tech-res.com/docs/default-
source/safety/daids_ae_grading_table_v2_nov2014.pdf. Accessed 21 February 2017. 
53. 
Leon AC. Sample-size requirements for comparisons of two groups on repeated 
observations of a binary outcome. Eval Health Prof 2004;27:34-44.