Conditions: HIV Infections Tuberculosis
Keywords: Levonorgestrel Pharmacokinetics Efavirenz Dolutegravir Rifampin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 122
Healthy volunteers: no

Brief summary:
The purpose of this pharmacokinetic (PK) study was to evaluate if a double dose (3 mg) of levonorgestrel (LNG) overcomes known drug-drug interactions (DDIs) with efavirenz (EFV)-based antiretroviral therapy (ART) or rifampicin (RIF)-containing tuberculosis (TB) therapy. The safety of double-dose (3.0 mg) LNG versus standard-dose (1.5 mg) was also compared.

Detailed description:
This pharmacokinetic (PK) study evaluated if a double dose (3.0 mg) of levonorgestrel (LNG) overcomes known drug-drug interactions (DDIs) with efavirenz (EFV)-based antiretroviral therapy (ART) or rifampicin (RIF)-containing tuberculosis (TB) therapy. The safety of double-dose (3.0 mg) LNG versus standard-dose (1.5 mg) was also compared.

Participants were volunteers who did not require emergency contraception (EC) for contraception at the time of trial participation. This trial enrolled persons assigned female sex at birth who were 16 years of age or older. Group assignment was determined by disease status (HIV or TB; participants could not have been living with both HIV and TB), and, for those with HIV, by ART regimen at enrollment. Participants with HIV who were taking EFV-based ART were randomized to receive a standard dose LNG (Group A) or a double dose of LNG (Group B). Participants taking dolutegravir (DTG)-based ART were assigned to a standard dose of LNG (Group C). Participants in the continuation phase of active TB treatment taking RIF and isoniazid (INH) with or without ethambutol were assigned to a double dose of LNG (Group D).

At study entry, participants in Groups A and C received a standard single dose of LNG. Participants in Groups B and D received a double dose of LNG. Intensive PK monitoring was conducted pre-dose, and after the LNG dose. Participants were expected to remain at the clinical site while the initial 8 hour PK samples were collected, and to return to the clinical site for the 24 and 48 hour samples.

All participants completed self-report questionnaires to assess adherence to TB therapy and ART, menstrual history and patterns after LNG administration, and to collect adverse effects commonly reported with LNG (i.e., irregular bleeding patterns). Adherence to ART and RIF was also assessed by collecting hair samples and single plasma concentrations at entry. Participants were followed for 4 weeks.

Arms:
arm 1: Participants received 1.5 mg of LNG once orally on Day 0 and were followed post-treatment for 4 weeks. arm 2: Participants received 3mg of LNG once orally on Day 0 and were followed post-treatment for 4 weeks. arm 3: Participants received 1.5 mg of LNG once orally on Day 0 and were followed post-treatment for 4 weeks. arm 4: Participants received 3mg of LNG once orally on Day 0 and were followed post-treatment for 4 weeks.

Interventions: intervention 1: Levonorgestrel (LNG)
Intervention descriptions: intervention 1: LNG tablet(s) were administered by mouth in a directly observed manner.

Protocol document:
ICF_002.pdf: 
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University of North Carolina-Chapel Hill 
Consent to Participate in a Research Study 
Adult Participants 
Biomedical Form – Screening and Enrollment 
________________________________________________________________________ 
IRB Study # 18-3402 
Consent Form Version Date: Version 1.0 January 31, 2019 
 
Title of Study: A5375 - An Open-Label, Phase II Pharmacokinetic Study to Evaluate Double-
Dose Levonorgestrel Emergency Contraception in Combination with Efavirenz-Based 
Antiretroviral Therapy or Rifampicin-Containing Anti-Tuberculosis Therapy 
 
Short Title For The Study: Optimize LNG EC 
Protocol Final version 1.0 2018-11-20 
 
Principal Investigator: David Wohl, MD 
UNC-Chapel Hill Department: Medicine 
UNC-Chapel Hill Phone number: 
 
Email Address: 
 
Co-Investigators: Joseph Eron, MD; Cynthia Gay, MD; Michelle Floris-Moore, MD; Christopher 
Hurt, MD 
 
Funding Source and/or Sponsor: United States (US) National Institute of Allergy and Infectious 
Diseases (NIAID) 
 
Study Contact telephone number:  Miriam Chicurel-Bayard 
 
Study Contact Email: 
 
_________________________________________________________________ 
 
This is a research study to test if a higher dose of Levonorgestrel (LNG) emergency contraception 
needs to be used to prevent pregnancy in girls and women who are taking some types of anti-HIV or 
anti-TB medications that are known to decrease the effectiveness of this form of birth control. 
 
If you take efavirenz, you will be randomized to take either the standard LNG dose or a double LNG 
dose. If you take dolutegravir, you will take the standard LNG dose. If you take rifampin you will 
take a double LNG dose. At entry, you will have blood drawn 9 times over about 9 hours. You will 
return to the clinic for a blood draw at 24 and 48 hours after you took the LNG dose. You will have a 
small sample of hair cut from your head to measure levels of the HIV or TB drugs. You will be 
contacted by site staff to complete a phone survey at weeks 1, 2, and 4. 
 
There are risks to this study drug that are described in this document. Some risks include: nausea, 
stomach pain, tiredness, headache, dizziness, breast pain, vomiting. Information learned from this 
study may help other women who have HIV or TB. 
 
If you are interested in learning more about this study, please continue reading below. 


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What are some general things you should know about research studies? 
You are being invited to take part in a research study. To join the study is voluntary. 
You may refuse to join, or you may withdraw your consent to be in the study, for any reason. 
 
Research studies are designed to obtain new knowledge that may help other people in the future.  
You may not receive any direct benefit from being in the research study. There also may be risks to 
being in research studies. 
 
Deciding not to be in the study or leaving the study before it is done will not affect your relationship 
with the researcher, your health care provider, or the University of North Carolina Chapel Hill.  If 
you are a patient with an illness, you do not have to be in the research study in order to receive 
health care.  
 
Details about this study are discussed below.  This is a consent form. It gives you information about 
this study. The study staff will talk with you about this information. You are free to ask questions 
about this study at any time. If you agree to take part in this study, you will be asked to sign or 
make your mark on this consent form. You will get a copy to keep. You should ask the researchers 
named above, or staff members who may assist them, any questions you have about this study at 
any time. 
 
What is the purpose of the study? 
Emergency contraception is birth control that prevents pregnancy. Girls and women use it after 
having unprotected sex. Levonorgestrel (LNG) emergency contraception is commonly known as 
Plan B® One-Step, or the Morning After Pill. This study will test if a higher dose of LNG needs to 
be used to prevent pregnancy in girls and women who are taking some types of anti-HIV or anti-TB 
medications. This study will also test if a higher dose of LNG is safe.  
The United States Food and Drug Administration (US FDA) has approved LNG for prevention of 
pregnancy.  
 
LNG works mainly by stopping the release of an egg from the ovary. It may also work by 
preventing fertilization of an egg, or by preventing attachment to the uterus. Girls and women can 
use emergency contraception to prevent pregnancy if regular birth control was used incorrectly or 
fails, or no birth control was used. LNG will not disrupt an existing pregnancy and using LNG does 
not affect your ability to have a baby in the future. After you take LNG as part of this study, you 
may attempt to get pregnant again as soon as your next menstrual cycle (after your next period), if 
you want to. 
 
Efavirenz (EFV) is a medication commonly used to treat HIV. Rifampicin (RIF) is a medication 
commonly used to treat tuberculosis. Both of these medications lower the amount of LNG in your 
blood by about half. This may make LNG not work as well as it normally would. It is unknown if 
the current dose of LNG emergency contraception, in combination with EFV or RIF, is enough to 
prevent a pregnancy. To learn if a higher dose is needed to prevent pregnancy, you will take either a 
regular dose or a double dose of LNG emergency contraception. 
 
Dolutegravir (DTG) is an anti-HIV medication that does not lower the amount of LNG in your 
blood. It is being used as a comparison to the other groups.   


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In this study, you will not be taking LNG for contraception (to prevent pregnancy), you will be 
volunteering to take it so that we can evaluate the impact of your other medications on the amount 
of LNG in your blood. You will take a dose of LNG emergency contraception by mouth. After you 
take the dose of LNG, the amount of LNG that is in your blood will be measured. This study will 
also take a hair sample that will tell researchers how often you have taken EFV, INH, and DTG 
over the past few weeks. 
 
You are being asked to take part in this research study because you are a woman at least 18 years of 
age and: 
 
1. You are living with human immunodeficiency virus (HIV-1) and you have been taking a 
combination of antiretroviral drugs (ARV) that includes either efavirenz (EFV) or dolutegravir 
(DTG) 
 
OR 
 
2. You are living with tuberculosis (TB) infection, and you have completed the intensive phase of 
TB therapy and are now completing the continuation phase of TB treatment that requires taking 
isoniazid (INH) and rifampicin (RIF) daily. 
 
The researcher in charge of this study at this site is Dr. David Wohl. Before you decide if you want 
to be a part of this study, we want you to know about the study. 
 
Are there any reasons you should not be in this study? 
You cannot be in this study if you: 
 
• Have known allergy/sensitivity or any hypersensitivity to LNG.  
• Have had Bilateral oophorectomy, hysterectomy, or postmenopausal. 
• Are currently pregnant, within 6 weeks of delivery, or currently breastfeeding an infant 
under 6 months of age. 
• Received LNG within 30 days prior to study entry. 
• Received hormonal contraceptives within 30 days prior to study entry.  
• Have used any drugs other than RIF and EFV known to: 1) induce CYP3A4 system within 
30 days prior to study entry, and 2) inhibit the CYP3A4 system within 7 days prior to study 
entry.  
• Have active drug or alcohol use or dependence  
• Have acute or serious illness requiring systemic treatment and/or hospitalization within 14 
days prior to study entry. 
• Have other medical, psychiatric, or psychological condition that, in the opinion of the site 
investigator, would interfere with completion of study procedures and or adherence to study 
drug. 
• You are living with HIV and are currently receiving medications for TB infection. 
• You are living with HIV and missed one or more of the prescribed doses of HIV 
medications within 3 days prior to study entry. 


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• You are HIV-negative and being treated for TB and missed one or more of the prescribed 
doses of TB medication within 3 days prior to study entry. 
 
How many people will take part in this study? 
About 116 women will take part in this study at many sites; including about 5 women from this site. 
 
How long will your part in this study last?  
You will be in this study for about 4 weeks. 
 
What will happen if you take part in the study? 
If you decide to take part in this research study, you will be asked to sign this consent form. A 
screening visit will be done to make sure you are eligible to join the study. If you are found eligible, 
you will have one entry visit that will last 9-10 hours, a 1 hour visit 24 hours after entry, and a 1 
hour visit 48 hours after entry. You will be asked to take a questionnaire over the phone 1 week, 2 
weeks, and 4 weeks after entry. 
 
If you enter the study 
• At the study entry visit, you will be assigned to a study group. There are four study groups. Two 
will receive a standard dose of LNG, and two will receive twice the standard dose of LNG. You 
will not be able to choose your study group, but you will know what study group you are in.  
• If you are taking EFV for HIV treatment, you will be randomly assigned (like a coin flip) to one 
of two possible doses of LNG. Some women will take a standard dose of LNG, other women 
will take twice the standard dose of LNG. More women will be assigned to take twice the 
standard dose, so it is more likely that you will be in this group.  
• If you are taking DTG for HIV treatment, you will be assigned to receive a standard dose of 
LNG. 
• If you are taking RIF for TB treatment, you will be assigned to receive twice the standard dose 
of LNG. 
 
You will have blood samples taken during the study to measure the amount of LNG in your blood.  
 
You will have a small sample of hair cut from your head so that we can measure levels of the anti-
TB or anti-HIV drugs in this small hair sample. You may decline this procedure. 
 
You will be asked questions about how well you take your anti-HIV or anti-TB medications and if 
you have any concerns about taking LNG. 
 
You will be asked to use a reliable form of non-hormonal birth control every time you have sex that 
could lead to pregnancy until the study is completed. You may not enter the study if you have had 
sex that could lead to pregnancy within 14 days prior to starting the study. 
 
Other 
Some of your blood that is left over after all required study testing is done may be stored (with usual 
protectors of identity) and used for ACTG-approved HIV-related research. 
 
Samples collected from you will be stored in the US. These samples may be stored for an indefinite 


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period of time. Results of testing performed on these samples will not be given to you. You may 
withdraw your consent for research on stored specimens at any time and the specimens will be 
thrown away. No matter what you decide, it will not affect your participation in this study. If you 
agree, you will be asked to sign a separate informed consent. 
 
A5375 Study Visits 
The study staff can answer any questions you have about individual study visits, and how long they 
will last, or about the tests that will occur. The table below can be used as a quick reference for you, 
along with the explanations that follow. 
 
 
 
 


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Table 1: Study Schedule 
Evaluation or Procedure 
Screening 
Entry 
Visit 
Study Visits 
Follow-Up Calls 
Clinically 
Indicated 
Visit 
Early Study 
Discontinuation 
Day 0 
Day 1 
Day 2 
Day 7 
Day 14 
Day 28 
1 hour 
9-10 
hours 
1 hour 
1 hour 
30 
minutes 
30 
minutes 
30 
minutes 
1 hour 
30 minutes 
Documentation of HIV Status 
√ 
 
 
 
 
 
 
 
 
Medical/ Medication History 
√ 
√ 
 
 
 
 
 
 
 
Questions About Your 
Menstrual Cycle 
√ 
√ 
 
 
√ 
√ 
√ 
 
√ 
Diagnoses Questions 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Medication Questions 
 
√ 
√ 
√ 
 
 
√ 
√ 
√ 
Acceptability and Practicality 
Questionnaire 
 
√ 
 
√ 
 
√ 
√ 
 
√ 
Adherence Assessment 
√ 
√ 
√ 
√ 
 
 
 
 
 
Physical Exam 
√ 
√ 
 
 
 
 
√ 
 
Blood Collection 
√ 
√ 
 
 
 
 
 
 
 
Pregnancy Testing 
√ 
√ 
 
 
√ 
Hair Collection 
√ 
 
LNG EC Administration 
 
√ 
 
 
 
 
 
 
 
Pharmacokinetic Sampling 
(blood collection) 
 
√ 
√ 
√ 
 
 
 
 
 
 


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Screening 
If you would like to be in this study, after you have read and signed this informed consent form, you 
will come to the clinic for a screening visit to make sure you meet the requirements for joining the 
study. This visit will take about 1 hour. Up to 18 mL (1.4 tablespoons) of blood will be drawn at 
this visit.  
• Your HIV infection status will be confirmed. If there is no record available, another HIV test 
will be done. You may have to sign a separate consent form before this is done. 
• You will be asked questions about your medical and medication history and any medications 
you are currently taking. You will be asked about your menstrual period. 
• You will be asked about adherence to your anti-HIV or anti-TB medications (how correctly you 
are taking your medications). 
• You will have a physical exam. 
• You will have blood drawn for routine lab tests for safety. You will be told the results of these 
tests when they become available.  
• You will give a urine sample or have blood drawn to see if you are pregnant. This test must 
show that you are not pregnant for you to enroll in the study. You will be told the result of the 
test when it becomes available. 
 
Entry Visit (Day 0) 
If you are eligible for the study and you choose to enroll, you will come back to the clinic for an 
entry visit. This visit will last about 9 or 10 hours. Up to 75 mL (5.8 tablespoons) of blood will be 
drawn at this visit. 
• You will be asked about:  your medical history and any medications you are taking, your 
menstrual period and if there has been a change in your menstrual period since the screening 
visit, and adherence to your anti-HIV or anti-TB medications. 
• You will have a physical exam, including measuring your neck, waist, and hips. 
• If you are HIV positive, you will have blood drawn to test how much HIV is in your blood, and 
to test how many CD4 cells (infection-fighting cells) are in your blood. You will be told the 
results of these tests when they become available. 
• You will have blood drawn and stored for a genetic test (a test of your DNA [genes] to better 
understand how fast your body removes the study drugs from your blood). Genetic testing looks 
at differences in people’s genes. Your body, like all living things, is made up of cells, and cells 
contain deoxyribonucleic acid, also known as “DNA.” DNA is like a string of information put 
together in a certain order. Parts of the string make up “genes.” Genes contain instructions on 
how to make your body work and fight disease. The testing in this study will only look at certain 
genes that are known to have an effect on how your body uses hormones. The tests will not look 
at any other genes. You will not receive the results of these tests. 
• You will give a urine sample or have blood drawn to see if you are pregnant. This test must 
show that you are not pregnant for you to remain in the study. You will be told the result of the 
test when it becomes available. 
• You will have a small sample of hair (about 50 strands) cut from your head to measure 
levels of the HIV or TB drugs in this hair sample. Humans lose about 100 hairs from their 
head every day naturally, so this amount of hair removal should not be noticeable. If you 
decide not to provide a hair sample, you can still be in the study. Results of this testing will 
not be available to you since hair levels are still a research tool. 


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• You will take a dose of LNG emergency contraception by mouth.  
• You will be asked to remain at the clinic all day for an intensive pharmacokinetic (PK) 
blood sampling. For this intensive PK sampling, you will have blood drawn over 8 hours to 
measure the amount of LNG in your blood. To avoid many needle sticks, a small tube 
(intravenous device) will be placed into a vein in your arm and left in place during your stay. 
You will be able to move around and should not have any significant pain or discomfort 
once the tube is in place. Blood will be taken before you take the LNG emergency 
contraception dose, and then at 30 minutes, 1, 1.5, 2, 3, 4, 6, and 8 hours after you take the 
LNG emergency contraception dose.  
• You will be asked if you have any problems or concerns after taking the LNG emergency 
contraception dose.  
 
Study Visits (Days 1 and 2) 
After the entry visit, you will come back to the clinic for two more study visits. The first will be 1 
day after your entry visit, and the second will be 2 days after your entry visit. These study visits will 
last about 1 hour. Up to 6 mL (0.4 tablespoons) of blood will be drawn at this visit. 
• You will have about blood drawn for PK blood sampling. 
• You will be asked about: your adherence to medications, changes in your medications and 
diagnoses, the acceptability and practicality of emergency contraception, and any problems or 
concerns you have after taking the LNG emergency contraception dose.  
 
Follow-up 
A member of the study staff will call you 7 days after study entry to ask you about your menstrual 
period. You will also be asked about changes in your diagnoses. 
 
A member of the study staff will call you 14 and 28 days after study entry to ask you about: changes 
in your diagnoses and (on day 28 only) your medications, your menstrual period, the acceptability 
and practicality of emergency contraception, and any problems or concerns you have after taking 
the LNG emergency contraception dose.  
 
Clinically Indicated Visit 
If you become pregnant or have an adverse event, you may be asked to return to the clinic for a 
physical exam and pregnancy test, and to discuss any changes in your medications or diagnoses. 
 
Early Study Discontinuation (Leaving the Study Early)  
If you leave the study early, you will be asked questions about your menstrual period, changes in 
your medications or diagnoses, questions to determine the acceptability and practicality of 
emergency contraception, and questions about any problems or concerns you have after taking the 
LNG emergency contraception dose. 
 
What are the possible benefits from being in this study? 
Research is designed to benefit society by gaining new knowledge.  You will receive no benefit 
from being in this study. Information learned from this study may help other women who have HIV 
or TB. 
 
 


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What are the possible risks or discomforts involved with being in this study?  
 
The drugs used in this study may have side effects, some of which are listed below. Please note that 
these lists do not include all the side effects seen with these drugs. These lists include the more 
serious or common side effects with a known or possible relationship. If you have questions 
concerning the additional study drug side effects please ask the medical staff at your site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are taken 
with the study drugs. For your safety, you must tell the study doctor or nurse about all medications 
you are taking before you start the study and also before starting any new medications while on the 
study. Also, you must tell the study doctor or nurse before enrolling in any other clinical trials while 
on this study. 
 
Risks of Levonorgestrel (LNG, Plan B® One-Step) 
The following side effects have been associated with the use of LNG: 
• Nausea 
• Lower stomach (abdominal) pain 
• Tiredness 
• Headache 
• Dizziness 
• Breast pain 
• Vomiting 
• Diarrhea 
 
Some women will have menstrual changes such as spotting or bleeding before their next period. 
Some women may have a heavier or lighter next period, or a period that is early or late.  
• If your period is more than a week late, you should get a pregnancy test 
 
Since the dose of LNG used in two study groups is not FDA approved (known as "off label" use), 
these risks could be worse in severity, and there may be additional risks that are not yet known. 
 
Risks of Drawing Blood 
Taking blood may cause some discomfort, bleeding, or bruising where the needle enters the body, 
lightheadedness, and in rare cases, fainting or infection. 
 
Risks of Hair Collection 
There is a small risk of cutting or nicking the scalp during the hair collection, although this is 
extremely rare. 
 
Risks of Social Harm 
It is possible that participating in this study will make it difficult for you to keep your HIV or TB 
status, or information about your sexual activity, secret from people close to you.. This may lead to 
unwelcome discussions about or reactions to your HIV or TB status. Please talk with the study staff 
if you have any concerns about this. 
 


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ARE THERE RISKS RELATED TO PREGNANCY? 
 
It is not known if the drug or drug combinations in this study harm unborn babies. If you are having  
sex that could lead to pregnancy, you must agree not to become pregnant until you complete the 
study. You may not enter the study if you have had sex that could lead to pregnancy within 14 days 
prior to starting the study. 
 
You and your partner must use reliable birth control that you discuss with the study staff. You must 
continue to use birth control while in the study. You may choose one of the birth control methods 
below:  
• Male condom with or without a spermicidal agent 
• Diaphragm or cervical cap with spermicide 
• Non-hormonal IUD 
• Bilateral tubal ligation 
• Male partner vasectomy 
  
If you can become pregnant, you must have a pregnancy test before you enter this study. The test 
must show that you are not pregnant. If you think you may be pregnant at any time during the study, 
tell your study staff right away. The study staff will talk to you about your choices. A pregnancy 
test may not detect a very early pregnancy, which is why the study team asks that you not enter the 
study if you have had sex that could lead to pregnancy within 14 days of study entry.   
 
If you become pregnant while on study, the study staff would like to obtain information from you 
about the outcome of the pregnancy (even if it is after your participation in the study ends). If you 
are taking anti-HIV drugs when you become pregnant, your pregnancy will be reported to an 
international database that collects information about pregnancies in women taking anti-HIV drugs. 
This report will not use your name or other information that could be used to identify you. 
 
Breastfeeding 
Breastfeeding women will be included only after their infants are at least 6 months old. Birth 
control like LNG is allowed during breastfeeding. During long-term use of drugs like LNG, called 
progestins, the amount of progestin in infant blood is only 1-6% of the amount in maternal blood. 
No side effects of progestins have been found on breastfeeding (quality or quantity of milk), or on 
the health or development of the infant due to this low progestin exposure. 
 
What if we learn about new findings or information during the study?  
You will be told any new information learned during this study that might affect your willingness to 
stay in the study. For example, if information becomes available that shows that the medication may 
be causing bad effects, you will be told about this. You will also be told when the results of the 
study may be available, and how to learn about them.   
 
How will your privacy be protected?   
 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff to 
help keep your personal information private, we have gotten a Certificate of Confidentiality from 


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the US Federal Government. This certificate means that researchers cannot be forced to tell people 
who are not connected with this study, such as the court system, about your participation. Also, any 
publication of this study will not use your name or identify you personally.  
 
Your records may be reviewed by the US Food and Drug Administration (FDA), the ACTG, the US 
Office for Human Research Protections (OHRP), or other local, US, and international regulatory 
entities as part of their duties, University of North Carolina at Chapel Hill Institutional Review 
Board (IRB) (a committee that protects the rights and safety of participants in research), National 
Institutes of Health (NIH), study staff, study monitors, and their designees. Having a Certificate of 
Confidentiality does not prevent you from releasing information about yourself and your 
participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by US 
law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time. 
 
What will happen if you are injured by this research? 
All research involves a chance that something bad might happen to you.  This may include the risk 
of personal injury. In spite of all safety measures, you might develop a reaction or injury from being 
in this study.  If you are injured as a result of your being in this study, the researchers will help you 
get medical care, but any costs for the medical care will be billed to you and/or your insurance 
company.  The University of North Carolina at Chapel Hill has not set aside funds to pay you for 
any such reactions or injuries, or for the related medical care. There is no program for compensation 
either through this institution or the National Institutes of Health. You will not be giving up any of 
your legal rights by signing this consent form. 
 
What if you want to stop before your part in the study is complete? 
You are free to leave the study at any time and for any reason.  
 
Why Would The Study Doctor Take You Off This Study Early? 
 
The study doctor may need to take you off the study early without your permission if: 
 
• The study is stopped or cancelled  
• You are not able to attend the study visits as required by the study 
• You have a positive pregnancy test before you take the LNG dose for the study 
• Your primary care doctor requests that you be taken off the study 
 
After the study: 
 
After you have completed your study participation, the study will not be able to continue to provide 
you with the LNG you received on the study. If similar drugs/agents would be of benefit to you, the 
study staff will discuss how you may be able to obtain them. 


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Version 1.0 2019-01-31 
 
 
If you choose not to be in the study, what other options do you have? 
Taking part in this study is completely voluntary. You may choose not to take part in this study or 
leave this study at any time. Your decision will not have any impact on your participation in other 
studies conducted by NIH and will not result in any penalty or loss of benefits to which you are 
otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
If you do not enroll into the study 
If you decide not to take part in this study or if you do not meet the eligibility requirements, we will 
still use some of your information. As part of this screening visit, some demographic (for example, 
age, gender, race), clinical (for example, disease condition, diagnosis), and laboratory (for example, 
pregnancy test) information is being collected from you so that AIDS Clinical Trials Group 
(ACTG) researchers may help determine whether there are patterns or common reasons why people 
do not join a study 
 
Will you receive anything for being in this study? 
 
If you participate in this study, you will receive $25 at the end of each completed visit at Screening, 
24 hour PK, 48 hour PK, and telephone contact interview at weeks 1, 2, & 4. You will receive $150 
at the end of the entry visit which includes the 8 hour PK. 
If you complete all procedures for the entire study, you will receive a total of $300. 
 
If you travel more than 50 miles to get to the clinic for your study visit, assistance with family care 
and/or additional travel assistance will be made available by the site with the amount determined on 
a case by case basis. Parking vouchers will be provided at all visits. 
 
Will it cost you anything to be in this study? 
There will be no cost to you for LNG, study-related visits, physical examinations, laboratory tests, 
or other study procedures. Anti-HIV and anti-TB medicines will not be provided by the study.  
 
You or your insurance company, or your health care system will be responsible for the costs of your 
regular medical care as well as for the costs of drugs not given by the study. In some cases it is 
possible that your insurance company will not pay for these costs. 
 
Who is sponsoring this study? 
This research is funded by NIH National Institute of Allergy and Infectious Diseases (NIAID) (the 
Sponsor). This means that the research team is being paid by the sponsor for doing the study. In 
addition, Dr. David Wohl, the principal investigator on this study, received income from Bristol-
Myers Squibb Company an entity that manufactures a drug used in this study. These activities are 
not part of this study and may include consulting, service on advisory boards, giving speeches, or 
writing reports. 
 


A5375                                           Page 13 of 14  
UNC English Adult  
Protocol Version 1.0 2018-11-20 
 
Screening and Enrollment ICF  
 
 
Version 1.0 2019-01-31 
 
If you would like more information, please ask the researchers listed in the first page of this form. 
 
What if you have questions about this study? 
Taking part in this study is completely voluntary. You may choose not to take part in this study or 
leave this study at any time. Your decision will not have any impact on your participation in other 
studies conducted by NIH and will not result in any penalty or loss of benefits to which you are 
otherwise entitled.  
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
If you ever have any questions about the study, or if you have a research-related injury, you should 
contact the researchers listed on the first page of this form.   
 
What if you have questions about your rights as a research participant? 
All research on human volunteers is reviewed by a committee that works to protect your rights and 
welfare.  If you have questions or concerns about your rights as a research participant, or if you 
would like to obtain information or offer input, you may contact the UNC Institutional Review 
Board at 
or by email to
 
 
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


A5375                                           Page 14 of 14  
UNC English Adult  
Protocol Version 1.0 2018-11-20 
 
Screening and Enrollment ICF  
 
 
Version 1.0 2019-01-31 
 
SIGNATURE PAGE 
 
IRB Study # 18-3402 
 
Title of Study: A5375 - An Open-Label, Phase II Pharmacokinetic Study to Evaluate Double-
Dose Levonorgestrel Emergency Contraception in Combination with Efavirenz-Based 
Antiretroviral Therapy or Rifampicin-Containing Anti-Tuberculosis Therapy 
 
Protocol Final version 1.0 2018-11-20 
 
Principal Investigator: David Wohl, MD 
 
SCREENING AND ENROLLMENT CONSENT 
 
Participant’s Agreement:  
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
 
____________________________ 
___________________________   __________ 
Participant’s Name (print) 
Participant’s Signature                         Date 
 
 
 
____________________________ 
___________________________   ___________ 
Study Staff Conducting 
Study Staff’s Signature                        Date 
Consent Discussion (print)  
 
 
 
 

Prot_000.pdf: 
 
 
A5375 
 
An Open-Label, Phase II Pharmacokinetic Study to Evaluate 
Double-Dose Levonorgestrel Emergency Contraception in 
Combination with Efavirenz-Based Antiretroviral Therapy or 
Rifampicin-Containing Anti-Tuberculosis Therapy 
 
 
 
NIAID CRMS # 38493 
 
 
 
 
 
This file contains the current ACTG A5375 protocol:  
 
• Protocol Version 2.0, dated 30 October 2020  


 
A5375 
 
 
An Open-Label, Phase II Pharmacokinetic Study to Evaluate Double-Dose 
Levonorgestrel Emergency Contraception in Combination with Efavirenz-Based 
Antiretroviral Therapy or Rifampicin-Containing Anti-Tuberculosis Therapy 
 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
Sponsored by: 
 
National Institute of Allergy 
and Infectious Diseases 
 
Non-IND Protocol 
 
 
 
The Antiretroviral Therapy Strategies  
Transformative Science Group:  
 
 
 
Raphael Landovitz, MD, Chair 
 
The ACTG/IMPAACT Women’s Health  
Inter-Network Scientific Committee: 
 
 
Elizabeth Connick, MD, Chair 
 
Protocol Chair:  
 
 
 
 
 
Kimberly Scarsi, PharmD, MS 
 
 
Protocol Vice Chair:  
 
 
 
 
Rosie Mngqibisa, MB, ChB, MPH 
 
DAIDS Clinical Representative: 
Pablo Belaunzaran Zamudio, MD, 
DTM&H, MSc  
 
Clinical Trials Specialist:   
 
 
 
Elizabeth Woolley, MPH 
 
 
 
 
 
FINAL Version 2.0 
October 30, 2020 


 
 
A5375 
 
 
FINAL Version 2.0 
 
 
10/30/20 
 
 
An Open-Label, Phase II Pharmacokinetic Study to Evaluate Double-Dose Levonorgestrel 
Emergency Contraception in Combination with Efavirenz-Based Antiretroviral Therapy or 
Rifampicin-Containing Anti-Tuberculosis Therapy 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable US Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: ___________________________________ Date: _____________ 
 Name/Title 
 
 
 


 
 
A5375 
 
 
FINAL Version 2.0 
 
 
10/30/20 
 
TABLE OF CONTENTS 
Page 
SIGNATURE PAGE ...................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY ..................................................................................... 5 
PROTOCOL TEAM ROSTER ....................................................................................................... 6 
STUDY MANAGEMENT ............................................................................................................... 9 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ...................................................................... 11 
SCHEMA ..................................................................................................................................... 12 
1.0 
HYPOTHESES AND STUDY OBJECTIVES................................................................... 14 
1.1 
Hypotheses ......................................................................................................... 14 
1.2 
Primary Objectives .............................................................................................. 14 
1.3 
Secondary Objectives ......................................................................................... 14 
1.4 
Exploratory Objectives ........................................................................................ 15 
2.0 
INTRODUCTION ............................................................................................................. 15 
2.1 
Background ......................................................................................................... 15 
2.2 
Rationale ............................................................................................................. 21 
3.0 
STUDY DESIGN ............................................................................................................. 26 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................. 27 
4.1 
Inclusion Criteria .................................................................................................. 27 
4.2 
Exclusion Criteria ................................................................................................ 29 
4.3 
Study Enrollment Procedures .............................................................................. 30 
4.4 
Co-enrollment Guidelines .................................................................................... 31 
5.0 
STUDY TREATMENT ..................................................................................................... 32 
5.1 
Regimens, Administration, and Duration ............................................................. 32 
5.2 
Study Product Formulation and Preparation ....................................................... 32 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability ............................... 33 
5.4 
Concomitant Medications .................................................................................... 34 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ............................................................ 35 
6.1 
Schedule of Evaluations (SOE) ........................................................................... 35 
6.2 
Timing of Evaluations .......................................................................................... 36 
6.3 
Instructions for Evaluations ................................................................................. 37 
7.0 
ADVERSE EVENTS AND STUDY MONITORING.......................................................... 44 
7.1 
Definition of Adverse Events ............................................................................... 44 
7.2 
Adverse Event Collection Requirements for this Protocol ................................... 44 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS ......................................... 45 
7.4 
Study Monitoring ................................................................................................. 46 
8.0 
CLINICAL MANAGEMENT ............................................................................................. 47 
8.1 
Toxicity ................................................................................................................ 47 
8.2 
Pregnancy ........................................................................................................... 47 
8.3 
Breastfeeding ...................................................................................................... 48 


A5375 
 
 
FINAL Version 2.0 
 
 
10/30/20 
 
 
CONTENTS (Cont’d) 
Page 
 
9.0 
CRITERIA FOR DISCONTINUATION............................................................................. 48 
9.1 
Premature Treatment Discontinuation ................................................................. 48 
9.2 
Premature Study Discontinuation ........................................................................ 48 
10.0 
STATISTICAL CONSIDERATIONS ................................................................................ 48 
10.1 
General Design Issues ........................................................................................ 48 
10.2 
Outcome Measures ............................................................................................. 49 
10.3 
Randomization and Stratification ......................................................................... 50 
10.4 
Sample Size and Accrual [53, 78-80] .................................................................. 50 
10.5 
Data and Safety Monitoring ................................................................................. 53 
10.6 
Analyses .............................................................................................................. 54 
11.0 
PHARMACOLOGY PLAN ............................................................................................... 57 
11.1 
Pharmacology Objectives .................................................................................... 57 
11.2 
Pharmacology Study Design ............................................................................... 57 
11.3 
Primary and Secondary Data, Modeling, and Data Analysis ............................... 57 
11.4 
Anticipated Outcomes ......................................................................................... 58 
12.0 
DATA COLLECTION AND MONITORING ...................................................................... 58 
12.1 
Records to Be Kept ............................................................................................. 58 
12.2 
Role of Data Management .................................................................................. 58 
12.3 
Clinical Site Monitoring and Record Availability .................................................. 59 
13.0 
PARTICIPANTS .............................................................................................................. 59 
13.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 59 
13.2 
Participant Confidentiality .................................................................................... 59 
13.3 
Study Discontinuation .......................................................................................... 59 
14.0 
PUBLICATION OF RESEARCH FINDINGS ................................................................... 60 
15.0 
BIOHAZARD CONTAINMENT ........................................................................................ 60 
16.0 
REFERENCES ................................................................................................................ 61 
APPENDIX I: SAMPLE INFORMED CONSENT ........................................................................ 67 
ATTACHMENT I-A: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES ..................... 81 
APPENDIX II: SAMPLE PARENTAL INFORMED CONSENT.................................................... 83 
ATTACHMENT II-A: PARENTAL CONSENT FOR USE OF SAMPLES IN OTHER 
STUDIES ......................................................................................................................... 97 
APPENDIX III: SAMPLE ASSENT FORM .................................................................................. 99 
APPENDIX IV: PROHIBITED AND PRECAUTIONARY MEDICATIONS ................................. 106 
 


 
5 
A5375 
 
 
FINAL Version 2.0 
 
 
10/30/20 
 
SITES PARTICIPATING IN THE STUDY 
 
A5375 is a multicenter study open to all US and non-US ACTG clinical research sites (CRSs).  
 
 
 
 
 
 
 


 
6 
A5375 
 
 
FINAL Version 2.0 
 
 
10/30/20 
 
PROTOCOL TEAM ROSTER 
 
Chair/Pharmacologist 
Kimberly Scarsi, PharmD, MS 
Northwestern University CRS 
University of Nebraska Medical Center 
Antiviral Pharmacology Laboratory 
College of Pharmacy 
Room 3021 
986145 Nebraska Medical Center 
Omaha, NE 68198-6145 
Phone: 402-559-9916 
E-mail: kim.scarsi@unmc.edu 
 
Vice Chair 
Rosie Mngqibisa, MBChB, MPH 
Durban International CRS 
Enhancing Care Foundation 
16 Charles Strachan 
Westridge 
Durban, KwaZulu Natal 4091 
SOUTH AFRICA 
Phone: 27-31-2611093 
E-mail: mngqibisa@ecarefoundation.com 
 
DAIDS Clinical Representative  
Pablo Belaunzaran Zamudio, MD, 
DTM&H, MSc 
HIV Research Branch,  
TRP, DAIDS, NIAID, NIH  
5601 Fishers Lane, Room 9E40B 
Rockville, MD 20852 
Phone: 240-292-4423 
E-mail: pablo.zamudio@nih.gov 
 
Clinical Trials Specialist 
Elizabeth Woolley, MPH 
ACTG Network Coordinating Center 
Social & Scientific Systems, a DLH Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3282 
E-mail: elizabeth.woolley@dlhcorp.com 
Statisticians 
Maxine Olefsky, MS 
ACTG Statistical & Data Analysis Center 
Harvard School of Public Health 
FXB 549 
Boston, MA 02115 
Phone: 617-432-3263 
E-mail: molefsky@sdac.harvard.edu  
 
Laura Smeaton, MS 
Statistical and Data Analysis Center 
Harvard TH Chan School of Public Health 
FXB Building, Room 511 
651 Huntington Avenue 
Boston, MA 02115-6017 
Phone: 617-432-2525 
E-mail: smeaton@sdac.harvard.edu 
 
Data Managers 
Mia Byrd, BA 
ACTG Data Management Center 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 
E-mail: byrd@frontierscience.org 
 
Kristine Coughlin, BA 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: 716-834-0900 Ext. 7239 
E-mail: coughlin@fstrf.org 
 
Tydie Higgins, MHA 
ACTG Data Management Center 
Frontier Science & Technology Research 
Foundation, Inc., 4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 
E-mail: thiggins@frontierscience.org 
 


 
7 
A5375 
 
 
FINAL Version 2.0 
 
PROTOCOL TEAM ROSTER (Cont'd) 
10/30/20 
 
DAIDS Pharmacists 
Kelly Parsons, PharmD 
Pharmaceutical Affairs Branch 
DAIDS, OCSO, PAB 
5601 Fishers Lane 
Room 9E15 
Rockville, MD 20852 
Phone: 240-669-5721 
E-mail: kelly.parsons@nih.gov 
 
Irene Rwakazina, PharmD 
Pharmaceutical Affairs Branch 
DAIDS, OCSO, PAB 
5601 Fishers Lane 
Room 9E14 
Rockville, MD 20852 
Phone: 301-761-7269 
E-mail: irene.rwakazina@nih.gov 
 
Pharmacologist 
Anthony Podany, PharmD 
University of Nebraska Medical Center 
Antiviral Pharmacology Laboratory 
College of Pharmacy 
986145 Nebraska Medical Center 
Omaha, NE 68198-6145  
Phone: 402-559-1939 
E-mail: apodany@unmc.edu 
 
Investigators  
Sharlaa Badal-Faesen, MD 
MBBCH/Diploma in HIV Mana 
University of the Witwatersrand  
Helen Joseph (WITS HJH) CRS 
Perth Road, Westdene 
Johannesburg, Gauteng 2041 
SOUTH AFRICA 
Phone: 27-11-278818 
E-mail: sfaesen@witshealth.co.za 
 
Investigators (Cont’d)  
Sara Bares, MD 
Specialty Care Center CRS 
University of Nebraska Medical Center 
988106 Nebraska Medical Center 
Omaha, NE 68198-8106 
Phone: 402-559-8218 
E-mail: sara.bares@unmc.edu 
 
Liz Barr, PhD, MS 
AIDS Clinical Trials Unit 
1830 E. Monument Street, Suite 8074 
Baltimore, MD 21205 
E-mail: barrlizbarr@gmail.com 
 
Susan E. Cohn, MD, MPH 
Northwestern University CRS 
Feinberg School of Medicine 
Infectious Diseases Division 
645 North Michigan Avenue, Suite 900 
Chicago, IL 60611 
Phone: 312-926-3693 
E-mail: susan-cohn@northwestern.edu 
 
Monica Gandhi, MD, MPH 
University of California, San Francisco 
HIV/AIDS CRS 
4th Floor, Building 80, Room 423D 
995 Potrero Avenue 
San Francisco, CA 94110 
Phone: 415-476-4082 Ext. 127 
E-mail: monica.gandhi@ucsf.edu  
 
David Haas, MD 
Vanderbilt Therapeutics CRS 
One Hundred Oaks 
719 Thompson Lane, Suite 47183 
Nashville, TN 37204 
Phone: 615-936-8594 
E-mail: david.haas@vanderbilt.edu 
 


 
8 
A5375 
 
 
FINAL Version 2.0 
 
PROTOCOL TEAM ROSTER (Cont'd) 
10/30/20 
 
Investigators (Cont’d) 
Felix Muhlanga, MM, MBChB, MMed 
ObGyn 
UZCHS- CTU 
15 Phillips Road Belgravia 
Harare, 111 
ZIMBABWE 
Phone: 263-4704966 
E-mail: fmhlanga@uzchs-ctu.org 
 
Field Representative 
Becky Straub, RN, BSN, MPH 
Chapel Hill CRS 
2nd Floor, Bioinformatics 
130 Mason Farm Road 
Chapel Hill, NC 27599 
Phone: 919-843-9975 
E-mail: bstraub@med.unc.edu 
 
Laboratory Technologists 
Robin DiFrancesco, MT, (ASCP), MBA 
NYS Center of Excellence in Bioinformatics 
and Life Sciences 
State University of New York at Buffalo PSL 
TPRC 
701 Ellicott Street 
Buffalo, NY 14203 
Phone: 716-881-7465 
E-mail: rda@buffalo.edu 
 
Chiraphorn Kaewkosaba, BSc 
Chiang Mai University HIV Treatment 
(CMU HIV Treatment) CRS 
110 Intavaroros Road, Sriphum 
Muang, Chiang Mai 50200 
THAILAND 
Phone: 66-53-945-055 Ext. 119 
E-mail: chiraphorn@rihes-cmu.org 
 
Community Scientific Subcommittee (CSS) 
Representative 
Cebisile Nkosi 
Durban International CRS 
Gate 1 King Edwards Hospital 
719 Umbilo Road 
Durban, Kwazulu, 4001 
SOUTH AFRICA 
Phone: 27-312054421 
E-mail: nkosic@mut.ac.za  
 
ACTG International Site Specialist 
Morgan Gapara, MPH 
ACTG Network Coordinating Center 
Social & Scientific Systems, a DLH Company 
4505 Emperor Boulevard, Suite 400 
Durham, NC 27703 
Phone: 919-287-4503 
E-mail: morgan.gapara@dlhcorp.com 
 
Laboratory Data Manager 
Mark Lojacono, MA, MSc 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: 716-834-0900 Ext. 7346 
E-mail: lojacono@fstrf.org 
 
ACTG Laboratory Specialist 
Sara Zabih, MS 
ACTG Laboratory Center at UCLA (ALC-
UCLA) 
11075 Santa Monica Blvd. 
Suite #200 
Los Angeles, CA 90025 
Phone: 310-794-9052 
E-mail: szabih@milabcentral.org 


 
9 
A5375 
 
 
FINAL Version 2.0 
 
 
10/30/20 
 
STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teamA5375@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.teamA5375@fstrf.org. A 
response should generally be received within 24 hours (Monday through Friday). 
 
Protocol E-mail Group 
Sites should contact the User Support Group at the Data Management Center (DMC) as soon 
as possible to have the relevant personnel at the site added to the actg.protA5375 e-mail group. 
Include the protocol number in the e-mail subject line.  
• 
Send an e-mail message to actg.user.support@fstrf.org.  
 
Clinical Management:  
For questions concerning entry criteria, toxicity management, concomitant medications, and co-
enrollment, contact the core protocol team.  
• 
Send an e-mail message to actg.coreA5375@fstrf.org. Include the protocol number, patient 
identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to pharmacologic laboratory tests, contact the 
Pharmacologists.  
• 
Send an e-mail message to actg.teamA5375@fstrf.org (ATTENTION: Kimberly Scarsi and 
Anthony Podany). 
 
Data Management 
• 
For nonclinical questions about transfers, inclusion/exclusion criteria, electronic case report 
forms (eCRFs), randomization/registration, and other data management issues, contact the 
Data Manager. Completion guidelines for eCRFs and participant-completed CRFs can be 
downloaded from the FSTRF website at www.frontierscience.org. 
• 
For transfers, reference the Study Participant Transfer SOP 119, and contact Tydie 
Higgins, Mia Byrd, and Kristine Coughlin directly.  
• 
For other questions, send an e-mail message to actg.teamA5375@fstrf.org (ATTENTION: 
Tydie Higgins, Mia Byrd, and Kristine Coughlin).  
• 
Include the protocol number, PID, and a detailed question. 
 
Randomization/Participant Registration 
For randomization/participant registration questions or problems and study identification number 
SID lists:  
• 
Send an e-mail message to rando.support@fstrf.org or call the DMC Randomization Desk at 
716-834-0900, extension 7301.  
 
DMC Portal and Medidata Rave Problems  
Contact DMC User Support. 
• 
Send an e-mail message to actg.user.support@fstrf.org or call 716-834-0900 Ext.7302. 
 


 
10 
A5375 
 
 
FINAL Version 2.0 
 
STUDY MANAGEMENT (Cont'd) 
10/30/20 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialist.  
• 
Send an e-mail message to actg.teamA5375@fstrf.org (ATTENTION: Elizabeth Woolley). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send an e-mail message to ACTGNCC@s-3.com. 
Electronic copies can be downloaded from the ACTG website at https://www.actgnetwork.org. 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to Protocol@tech-res.com or call 
301-897-1707.  
 
Protocol Activation 
For questions related to protocol activation at US sites contact the Clinical Trials Specialist.  
• 
Send an e-mail message to actg.teamA5375@fstrf.org (ATTENTION: Elizabeth Woolley). 
 
For questions related to protocol activation at non-US sites contact the ACTG Site Coordination 
Group.  
• 
Send an email message to actgsitecoordination@dlhcorp.com.  
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, 
contact Pharmacists Irene Rwakazina and Kelly Parsons (kelly.parsons@nih.gov, 
irene.rwakazina@nih.gov). 
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 
Telephone Calls 
Sites are responsible for documenting telephone calls made to A5375 team members.  
• 
Send an e-mail message to actg.teamA5375@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 


 
11 
A5375 
 
 
FINAL Version 2.0 
 
 
10/30/20 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
AE 
 
 
adverse event 
ALT 
 
 
alanine aminotransferase 
ANC 
 
 
absolute neutrophil count 
ART 
antiretroviral therapy 
ARV 
antiretroviral  
AST 
aspartate transaminase 
AUC 
area under the curve 
BMI 
body mass index 
CLIA 
Clinical Laboratory Improvement Amendments 
CYP 
cytochrome 
DDI 
drug-drug interactions 
DMC 
Data Management Center 
DTG 
dolutegravir 
EC 
emergency contraception 
 
eCRF 
electronic case report form 
EFV 
efavirenz 
EMA 
European Medicines Authority 
EQA 
external quality assurance 
FTC 
emtricitabine 
GCLP 
Good Clinical Laboratory Practice 
INH 
isoniazid 
IRB/EC 
institutional review board/ethics committee 
IUD 
intrauterine device 
LMIC 
low- and middle-income countries 
LNG 
levonorgestrel 
MOPS 
manual of procedures 
OHRP 
Office for Human Research Protections 
PK 
pharmacokinetic 
POC 
point of care 
PSWP 
protocol-specific web page 
RIF 
rifampicin 
RSC 
Regulatory Support Center 
SNPs 
single nucleotide polymorphisms 
TB 
tuberculosis 
TFV 
tenofovir 
ULN 
upper limit of normal 


 
12 
A5375 
 
 
FINAL Version 2.0 
 
 
10/30/20 
 
SCHEMA 
 
A5375 
 
An Open-Label, Phase II Pharmacokinetic Study to Evaluate Double-Dose Levonorgestrel 
Emergency Contraception in Combination with Efavirenz-Based Antiretroviral Therapy or 
Rifampicin-Containing Anti-Tuberculosis Therapy 
 
DESIGN  
A5375 is a phase II, open-label, four parallel group, partially randomized, 
pharmacokinetic (PK) study to evaluate if a double dose of levonorgestrel 
(LNG) emergency contraception (EC) overcomes known drug-drug 
interactions (DDIs) with efavirenz (EFV)-based antiretroviral therapy 
(ART) or rifampicin (RIF)-containing tuberculosis (TB) therapy. The safety 
of double-dose LNG EC versus standard-dose will also be compared. 
 
Participants will be volunteers who do not currently require EC for 
contraception. Eligible participants will receive a single dose (1.5 mg) or a 
double dose (3.0 mg) of LNG EC based on their group assignment, which 
will be determined by their infection (HIV or TB; participants cannot be 
coinfected), and, for those who are living with HIV, by their ART regimen 
at enrollment (see Schema Figure 1). Women living with HIV who are 
taking EFV-based ART will be randomized to Group A or B (1:2 ratio). 
Women taking dolutegravir (DTG)-based ART will be assigned to Group 
C. Women who are HIV-negative and in the continuation phase of TB 
treatment taking RIF and isoniazid (INH) will be assigned to Group D. 
 
DURATION 
All participants will be followed for 4 weeks. 
 
SAMPLE SIZE 
116 participants; 17 in Group A, 33 in each of Groups B, C, and D.  
 
POPULATION 
Women who are 16 years of age or older, and who are either HIV+ and 
on stable ART, or who are HIV- and in the continuation phase of anti-TB 
therapy on daily INH/RIF.  
 
STRATIFICATION 
At entry, women with body mass index (BMI) ≥30 kg/m2 will be limited to 
no more than five within Groups B-D and no more than three within Group 
A. 
 
REGIMEN  
Women in Groups A and C will receive 1.5 mg LNG EC once at study 
entry.  
 
Women in Groups B and D will receive 3.0 mg LNG EC once at study 
entry. 
 
 
 


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1.0 
HYPOTHESES AND STUDY OBJECTIVES 
 
1.1 
Hypotheses 
 
1.1.1 Primary Hypotheses 
 
1.1.1.1 Women receiving double-dose levonorgestrel (LNG) emergency 
contraception (EC) with efavirenz (EFV)-based antiretroviral therapy (ART) 
will achieve similar LNG concentrations compared to women receiving 
standard-dose LNG EC on dolutegravir (DTG)-based ART. 
 
1.1.1.2 Women receiving double-dose LNG EC with rifampicin (RIF)-containing 
tuberculosis (TB) therapy will achieve similar LNG concentrations 
compared to women receiving standard-dose LNG EC on DTG-based ART. 
 
1.1.2 Secondary Hypotheses 
 
1.1.2.1 Among women receiving EFV-based ART, double-dose LNG EC will 
achieve significantly higher LNG concentrations than standard-dose LNG 
EC. 
 
1.1.2.2 Women receiving standard-dose LNG EC with EFV-based ART will achieve 
significantly lower LNG concentrations than women receiving standard-
dose LNG EC on DTG-based ART. 
 
1.1.2.3 Double-dose and standard-dose LNG EC will have similar safety profiles. 
 
1.2 
Primary Objectives 
 
1.2.1 To determine if doubling the dose of the LNG EC effectively overcomes the known 
drug-drug interaction (DDI) with EFV-based ART.  
 
1.2.2 To determine if doubling the dose of the LNG EC effectively overcomes the expected 
DDI with RIF-containing TB therapy. 
 
1.3 
Secondary Objectives 
 
1.3.1 To estimate the difference in LNG pharmacokinetic (PK) exposure with double-dose 
LNG EC compared to standard-dose LNG EC in women receiving EFV-based ART.   
 
1.3.2 To estimate the difference in LNG PK exposure with standard-dose LNG EC in 
women receiving EFV-based ART compared to women receiving DTG-based ART.   
 
1.3.3 To verify the absence of significant DDI between LNG EC and DTG-based ART. 
 
1.3.4 To compare the safety of double-dose LNG EC compared to standard-dose LNG EC.   


 
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1.3.5 To evaluate the relationship between baseline measures of body weight (body fat 
percentage, total weight, and body mass index [BMI]) and LNG PK exposure. 
 
1.4 
Exploratory Objectives  
 
1.4.1 To explore whether PK interactions between EFV, DTG, RIF, and LNG are affected 
by human genetic polymorphisms that have been reported to affect metabolism of 
these drugs. 
 
1.4.2 To characterize the relationship between short- and long-term adherence to ART or 
TB therapy and LNG exposure using objective pharmacologic measures. 
 
1.4.3 To assess the acceptability and practicality of EC as a contraceptive option in ACTG 
trials. 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
Despite progress in the global HIV response, adolescent girls and young women continue to 
be disproportionately affected by HIV, especially in sub-Saharan Africa. Globally, women 
constitute more than half of all people living with HIV, and 18.6 million girls and women were 
living with HIV in 2015 [1, 2]. In Sub-Saharan Africa, women account for approximately 56% 
of all new people living with HIV, and the incidence of HIV in women between the ages of 15 
and 24 years accounts for 25% of all new infections [1].  
 
Tuberculosis remains one of the greatest threats to public health, surpassing HIV as the 
leading cause of death from an infectious pathogen in 2015 [3]. Moreover, the HIV epidemic 
has fueled the resurgence of TB, leading to a dramatic increase in TB infections in low- and 
middle-income countries (LMIC) [4]. HIV infection increases the risk for TB (acquisition, 
reactivation, and reinfection), alters its clinical presentation, and reduces survival compared 
to patients with TB who are not living with HIV [5, 6]. For patients with latent TB, HIV is a 
significant risk factor for development of active TB [7, 8], and TB remains the most common 
cause of morbidity in patients living with HIV in resource-limited countries.  
 
In 2014, women between 15-24 years old had a higher incidence of TB than men in areas of 
sub-Saharan Africa with high baseline TB prevalence [2]. In such settings of active TB 
treatment, preventing pregnancy becomes even more important in order for women to attain 
a level of health that will support future healthy pregnancies. Additionally, treatment options 
for TB may be limited during pregnancy because of concerns about teratogenicity. For 
instance, fetal exposure to RIF, although generally considered safe, is associated with 
bleeding disorders [9, 10]. Treatment of TB prior to pregnancy prevents TB exposure in the 
neonate, a condition associated with high infant mortality. Therefore, providing effective 
contraception and understanding potentially important DDIs between antimicrobials and 
contraceptives in populations of women living with either HIV or TB are both of paramount 
importance. 
 


 
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Emergency contraception (EC) use 
Emergency contraception, also referred to as postcoital contraception, is a safe and 
effective form of birth control that prevents pregnancy when used on an episodic basis. Oral 
EC does not interfere with an established pregnancy but works by either preventing or 
delaying ovulation, or by inhibiting fertilization of an egg, depending on the stage of a 
woman’s menstrual cycle and type of EC used. 
 
The use of EC has expanded since becoming available without a prescription in 
pharmacies, both in the United States (US) and internationally. Types of EC include: LNG, 
ulipristal, combined oral contraceptives containing both estrogens and progestins (the 
Yuzpe method), mifepristone, and intrauterine devices that can be impregnated with 
progestins. The most commonly used oral EC is LNG [11], and it is the focus of this study. 
LNG EC tablets are registered in most countries and directly available to women in much of 
sub-Saharan Africa without a prescription [12]. 
 
The World Health Organization (WHO) recommends that all women and girls at risk of an 
unintended pregnancy have access to EC and that EC be routinely included within all 
national family planning programs [12]. Unintended pregnancy rates have been shown to be 
high worldwide, but especially in areas of limited resources where women may be 
disempowered to control their reproductive health. Provision of contraception and access to 
a variety of contraceptive methods are therefore critical to women in resource-limited 
settings. Given the prevalence of HIV and TB in these settings, investigations to expand our 
currently sparse knowledge base on DDIs between commonly used antiretroviral (ARV) 
therapies, TB treatment, and EC are urgently needed. 
 
Populations who may benefit from EC 
EC can be used after unprotected intercourse, contraceptive failure including the incorrect 
use of contraceptives, and sexual assault if it occurs without contraception coverage. EC is 
an essential birth control option for girls and women [12]. 
 
Unplanned and nonconsensual sexual activity has emerged as a critical issue for women 
living with HIV and at risk of HIV-infection. Incidence rates of sexual assault in women living 
with HIV are 1.6/100 person-years in the US [13]. In South Africa, intimate partner violence 
was reported in 20% of pregnant women with HIV attending an antenatal clinic [14]. 
Normative clinical and policy guidance was issued by the WHO [15], but these guidelines do 
not address issues specific to women living with HIV. For example, standard of care practice 
for sexual assault that could lead to pregnancy includes the provision of EC. However, the 
appropriate dosing of EC for the prevention of unintended pregnancies in combination with 
ART or anti-TB therapy is unknown. 
 
Women participating in future clinical trials may also benefit from EC. Members of the HIV 
community frequently cite contraceptive requirements as a barrier to women’s participation 
in clinical trials [16]. A 2016 survey of community members performed for this study found 
that 79% of women surveyed would be willing to use EC after unprotected sex that could 
lead to pregnancy (10% would need more information, including about side effects; 7% did 
not have sex that could lead to pregnancy). As one respondent noted, “I rarely have sex that 
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in order to participate in a clinical trial. I would be willing to use EC after instances of sex 
that could lead to pregnancy.” Of women surveyed, 70% reported they would be more likely 
to participate in a study if EC and condoms were two of the contraceptive options available 
(18% reported no difference, and 11% said less likely). The overwhelming majority of survey 
respondents (96%) were in the US, so these results may not be generalizable to women in 
other countries. For women who are not sexually active at the time of enrollment, the need 
for continuous contraceptive methods can be onerous. For these women, EC, in 
combination with a barrier method, might be a reasonable contraceptive choice that would 
broaden women’s participation in clinical trials evaluating HIV cure, new ART, and new anti-
TB strategies. Data emerging from LMIC show increasing use, awareness, and willingness 
to use contraceptive agents, with one study describing that 85% of women were willing to 
use EC [17]. 
 
Antiretroviral therapy (ART) proposed in this study 
Given that 95% of women living with HIV reside in LMIC [18], ART use for women in these 
regions primarily follows WHO guidelines. WHO guidelines for ART were recently updated to 
include either DTG- or EFV-based ART as preferred alternative first-line ART strategy [19]. 
DTG-based ART use is expanding in LMIC, and the US President’s Emergency Plan for 
AIDS Relief (PEPFAR) programs are actively supporting the transition to DTG-containing 
regimens. Projections for ART drug procurement through 2025 in LMIC demonstrates that 
there will be an approximately even distribution of EFV- and DTG-based ART for first-line 
regimens (42% and 57% of all ART strategies, respectively) [20]. Therefore, this study will 
investigate these two important ART strategies in combination with EC to assess relevant 
DDIs. 
 
2.1.1 Levonorgestrel (LNG) 
 
Levonorgestrel is a progestational agent that inhibits ovulation by interrupting 
follicular development, and inhibits fertilization by altering the tubal transport of 
sperm and/or ova. In addition, it may inhibit implantation by altering the 
endometrium, but it is not effective once the process of implantation has begun [21]. 
LNG is commonly used in combination oral contraceptive pills, as EC, in progestin-
releasing subdermal implants, and intrauterine devices. As EC, LNG should be taken 
within 72 hours after unprotected intercourse to prevent pregnancy. The absolute 
effectiveness of EC is difficult to determine because the rate varies with the timing of 
dosage with respect to unprotected intercourse, ovulation, and with the type of EC 
used. Estimates of LNG efficacy range from 59-94% [22]. In a multicenter 
randomized comparison of LNG versus ulipristal in nearly 1700 women presenting to 
family planning clinics for EC, there were 37 pregnancies with no statistical 
difference observed between the groups. To increase the power of the study, a 
meta-analysis was performed, and data from a total of 2221 women randomized to 
either ulipristal or LNG were compiled. This analysis confirmed that the pregnancy 
rate in both groups was lower than predicted, and that the pregnancy rate for LNG 
was 2.6% [23].      
 
LNG for EC is typically given as a single 1.5 mg dose within 72 hours after 
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hours after administration and is 100% bioavailable after oral administration [21, 24, 
25]. In 30 healthy, female volunteers, the mean (SD) LNG Cmax was 19.1 (9.7) 
ng/mL, area under the curve (AUC)inf was 307.5 (218.5) ng*hr/mL, and half-life was 
27.5 hours [21]. A clinical evaluation of another formulation of LNG (0.75 mg tablets, 
two tablets once) in five healthy volunteers found a geometric mean 44-hour (39-48-
hours) half-life [26]. 
 
The effect of food on LNG absorption has not been evaluated. LNG is 97.5-99% 
protein-bound to sex hormone-binding globulin and albumin, only 2% of LNG is 
present as unbound drug. This, in addition to an inverse association between LNG 
concentrations and body weight [27-29], contributes to the high interpatient variability 
in drug levels. LNG is extensively metabolized to inactive metabolites 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 
LNG concentrations. Approximately 45% of LNG and its metabolites are excreted in 
the urine and 32% in the feces, and the elimination half-life following a single oral 
dose LNG is approximately 17 to 24 hours. LNG is not known to influence exposure 
to ART or TB therapy [21]. 
 
LNG PKs are influenced by body weight as measured by BMI. Two studies have 
evaluated the effect of an overweight or obese BMI on LNG PKs. Edelman et al. 
found 49% lower AUC0-2.5h in women with BMI >35 compared to BMI <25 [30]. 
Pradipan et al. found 52% lower AUC0-24h in women with BMI >30 kg/m2compared to 
BMI <25 kg/m2 [31]. 
 
Studies have not been conducted to determine the PK parameter that is associated 
with LNG EC effectiveness. Variable doses of LNG EC have been evaluated, ranging 
from 0.4 to 1.5 mg, and the studies conducted were not designed to be dose-finding. 
Therefore, the concentration-response relationship is unknown [32]. Although there 
is a proposed threshold for LNG implant effectiveness, the mechanism of 
contraception is not the same between a long-acting contraceptive and EC so this 
concentration cannot be extrapolated to EC. 
 
Safety Profile  
The most common LNG EC side effects include heavier menstrual bleeding (30.9%), 
nausea (13.7%), lower abdominal pain (13.3%), fatigue (13.3%), headache (10.3%), 
dizziness (9.6%), breast tenderness (8.2%), and delay of menses >7 days (4.5%). 
These side effects are typically self-limiting during the treatment period. In contrast to 
other forms of contraception, EC does not have a contraindication with 
thromboembolic complications [21]. 
 
2.1.2 Rifampicin (RIF) 
 
Rifampicin is a semi-synthetic rifamycin derivative that is highly active against 
mycobacteria, most gram-positive bacteria, and some gram-negative bacteria. It is 
bactericidal for both intracellular and extracellular microorganisms. By inhibiting 
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the nucleotide chain in RNA synthesis. It is a key component of TB treatment and 
RIF-containing regimens are associated with reduced mortality compared to non-
RIF-containing regimens. Studies have demonstrated that addition of RIF to a TB 
regimen shortens the duration of treatment with higher cure rates [33]. Menzies et al. 
demonstrated that regimens that contain RIF for only 1 to 2 months of TB treatment 
instead of 6 months have higher failure rates with an increased chance of relapse 
and development of resistance [34]. WHO guidelines recommend that all individuals 
requiring TB therapy receive at least 6 months of RIF [35]. 
 
RIF is a potent inducer of multiple cytochrome P450 enzymes, such as CYP3A and 
CYP2B6. Drug transporters can accelerate clearance of drugs metabolized via the 
cytochrome p450 system, including ART [36, 37, 38], with potential loss of efficacy of 
these drugs. The effect of RIF on LNG PKs has not been evaluated, but several 
studies describe a 50% or greater reduction in exogenous oral progestin (e.g., 
norethindrone) exposure when combined with RIF [39-41]. Because exogenous 
progestins are believed to share the same metabolic pathway via CYP3A, the effect 
of one progestin is expected to be similar across other oral progestins. 
 
Safety Profile  
RIF is well-tolerated in the usual daily dose of 10 mg/kg (maximum 600 mg). It often 
causes harmless red-orange discoloration of tears, sweat, saliva, feces, and urine. 
Fewer than 4% of TB patients experience significant adverse reactions to RIF. 
Gastrointestinal adverse events (AEs) are the most common, and they include 
epigastric distress, anorexia, nausea, vomiting, cramps, and diarrhea. Hepatitis 
rarely occurs in persons who have normal baseline hepatic function. The incidence 
of hepatitis may be increased for older persons and those who have chronic liver 
disease or alcoholism, but remains substantially lower than that for pyrazinamide 
(PZA) or isoniazid (INH). RIF can cause a flu-like syndrome of fever, chills, and 
myalgia (felt to be related to the development of antirifampicin antibodies), although 
this is uncommon using the 600 mg dose given daily. In a very small proportion of 
patients the flu-like syndrome is associated with interstitial nephritis, acute tubular 
necrosis, thrombocytopenia, hemolytic anemia, and shock. There may be changes in 
menstruation such as oligomenorrhea and amenorrhea [42]. 
 
2.1.3 Efavirenz (EFV) 
 
EFV is a potent non-nucleoside reverse-transcriptase inhibitor (NNRTI) that is widely 
used in combination with other ARVs for the treatment of HIV-1 infection.  
 
Steady-state plasma EFV clearance is known to be affected by relatively frequent 
genetic polymorphisms, primarily in CYP2B6 (especially rs3745274 and rs28399499) 
[36, 37, 43-45], and perhaps also in CYP2A6 [46]. Genotyping of CYP2B6 can be 
used to characterize individuals as belonging to slow, intermediate, and extensive 
EFV metabolizer groups. 
 
EFV is known to decrease concentrations of many contraceptive hormones [47], 
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decrease LNG exposure by approximately 50% after release from a contraceptive 
implant in women living with HIV [48]. EFV also decreased oral LNG by 
approximately 60% after a single dose in healthy volunteers (discussed further in 
section 2.2) [24]. 
 
Safety Profile  
The most significant AEs observed in patients receiving EFV were central nervous 
system (CNS) symptoms, psychiatric symptoms, and rash [38]. CNS symptoms 
usually begin during the first one or two days of therapy and generally resolve after 
the first 2 to 4 weeks. Dosing at bedtime (and without food) improves the tolerability 
of these symptoms and is recommended during the first weeks of therapy and in 
patients who continue to experience these symptoms.  
 
Serious psychiatric adverse experiences have been reported, including severe 
depression, suicidal ideation or attempts, aggressive behavior, paranoid reactions, 
and manic reactions.  
 
Rash is usually mild to moderate and occurs within the first 2 weeks of initiating 
therapy. In most persons, rash resolves with continuing EFV therapy within 1 month.  
 
2.1.4 Dolutegravir (DTG) 
 
Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI) that 
binds HIV integrase enzyme, inhibiting transfer of HIV DNA into the DNA of host 
cells. DTG has a rapid and durable virologic response with an optimized background 
treatment, low PK variability, few DDIs, and a high genetic barrier to resistance. DTG 
once daily dosing is recommended in treatment-naïve individuals or in individuals 
with no resistance to other INSTIs [19].  
 
DTG is primarily a substrate of UDP-glycuronosyltransferase (UGT)1A1, with minor 
involvement of CYP3A4. Less than half the oral dose (31%) of DTG is eliminated in 
urine as metabolites, while the majority of the DTG is eliminated unchanged in feces 
(53%). Its elimination half-life is 14 hours. In vitro, DTG is also a substrate of P-
glycoprotein (P-gp) and breast cancer resistance protein (BCRP). DTG is not found 
to induce or inhibit these transporters or UGT and CYP isoenzymes at clinically 
relevant concentrations [49]. 
 
DTG has low DDI potential due to its lack of induction or inhibition of metabolizing 
enzymes and renal transporters. A study of DTG 50 mg twice daily with oral ethinyl 
estradiol and norgestimate found that the oral contraceptive PK profiles were not 
significantly impacted by coadministration with DTG [50]. In vitro, DTG inhibits the 
OCT2 transporter at clinically relevant concentrations, and a reversible increase in 
serum creatinine is has been observed clinically in the first 4 weeks of use (mean 
change: 0.11 mg/dL [-0.60 to 0.62 mg/dL]).  
 


 
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Safety Profile 
DTG is generally well tolerated. In Phase III clinical trials, the most common AEs 
were nausea (14%), headache (13%), and diarrhea (17%). Other AEs included sleep 
disturbances (23%), fatigue (13%), as well as psychological effects like depression 
(6%), and anxiety (3%). 
 
2.2 
Rationale 
 
Unintended pregnancies are associated with increased maternal and infant morbidity and 
mortality, risk of maternal to child transmission of HIV, and socioeconomic disparity in 
women living with HIV. Therefore, a range of available contraceptive choices are of critical 
importance to avoid unintended pregnancies.  
 
Recently, the European Medicines Authority (EMA) and the United Kingdom (UK) guidelines 
on emergency contraception [51, 52] advised that women on CYP inducers, specifically EFV 
and RIF, should receive an adjusted dose of LNG EC (increased from 1.5 mg once to 3.0 
mg once post-coital). Although dose adjustment is an accepted strategy to overcome DDIs, 
it is typically associated with a PK evaluation of the dose adjustment to ensure normal 
exposure is restored with the dose adjustment. In this instance, this recommendation was 
made in the absence of data to confirm this strategy corrects LNG exposure in the presence 
of this DDI. 
 
The primary objective of this study is to provide evidence to support or refute this guideline 
recommendation: does doubling the dose of LNG EC overcome known DDIs with EFV or 
RIF by resulting in similar PK exposure between the dose-adjusted groups and the control 
group. PK is a well-established surrogate marker to evaluate the clinical impact of a DDI. In 
the absence of a known concentration-response relationship that can be used to inform a 
“no effect” relationship, the US Food and Drug Administration (FDA) recommends a 
bioequivalence range (see section 10.0) as an acceptable alternative to assess a DDI [53]. 
Given LNG EC does not have a known threshold for effectiveness that may be used to 
determine the “no effect” relationship (see section 2.1), we have designed this study utilizing 
standard FDA methods for determination of bioequivalence [54] to evaluate the impact of 
this DDI.  
 
Emergency contraception drug-drug interactions (DDIs) 
One of the challenges in using EC in clinical trials including HIV or TB therapy is the 
potential for DDI resulting in impaired EC effectiveness. There is a growing body of 
information documenting DDI between hormonal contraceptive agents and ARVs, as well as 
other drugs commonly used by women living with HIV [47]. LNG is metabolized by the 
CYP3A enzyme system to inactive metabolites. This results in a risk of DDI that may 
decrease LNG exposure, and possibly its effectiveness, with CYP3A inducers (such as EFV 
and/or RIF).  
 
One PK study evaluated standard-dose LNG EC in combination with EFV. The combination 
resulted in a 57% reduction in overall LNG exposure area under the concentration time 
curve, likely related to CYP3A enzyme induction by EFV [24]. Notably, this study was 
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different dose of LNG for EC (0.75 mg q12h x 2 doses) than is currently recommended (1.5 
mg x 1 dose). It was recently demonstrated that the magnitude of the DDI between EFV and 
LNG is influenced by CYP2B6 polymorphisms [55]; therefore, the extent of this DDI may be 
different in diverse ethnic and racial populations.   
 
Supporting the relationship between pregnancy outcomes and low LNG PK exposure, one 
study identified unacceptably high pregnancy rates in Ugandan women using EFV and a 
continuous LNG contraceptive [48]. The relationship between LNG EC exposure and 
efficacy has also been established; obesity reduces LNG exposure and obese women have 
a 4-fold greater risk of contraceptive failure compared to women with normal weight [56]. 
Dose adjustment of LNG to 3.0 mg for EC in obese women results in normalized drug 
exposure without increasing LNG-related AEs [30]. Notably, no serious AEs were reported 
in the study group that received the increased dose of LNG EC [30]. 
 
DTG is not expected to alter LNG PKs. No studies examining LNG with DTG have been 
conducted. However, based on the routes of metabolism and elimination of LNG and DTG 
(sections 2.1.1 and 2.1.4), no clinically significant interaction is expected. A study of DTG 
plus a coformulated oral contraceptive containing a synthetic progestin, norgestimate, plus 
ethinyl estradiol found no clinically significant impact of DTG on norgestimate PKs among 
healthy women [50]. 
 
Considerations for enrollment of women and girls aged 16-17 
This study includes a hormonal contraceptive method for use in women; therefore only 
women will be included. Because it is a hormonal contraceptive method intended to prevent 
pregnancy, pregnant women will not be included. LNG EC is not known to be associated 
with fetal or reproductive risk, but it is a contraceptive method intended to prevent 
pregnancy. Because the study is enrolling volunteers who do not require LNG EC to prevent 
pregnancy (i.e., within 72 hours after unprotected sex that could lead to pregnancy), an 
effective form of contraception (defined in section 4.1.5) is required during the study period 
for women of reproductive potential who engage in sex that could lead to pregnancy.  
 
Adolescent girls aged 16-17 will be included as this age group is at greater risk for HIV 
infection, TB infection, unintended pregnancy, and gender-based violence. Both the 
American Academy of Pediatrics (AAP) and the Society for Adolescent Health and Medicine 
(SAHM) advocate for the use of LNG EC for girls requiring episodic contraception due to sex 
without contraception, contraceptive failure during sex, or gender-based violence [57, 58]. 
Further, both in the US and LMICs, both patient and provider knowledge regarding the use 
of EC is suboptimal, and family planning groups advocate for increased awareness and 
knowledge about the availability and use of EC [57-59]. Inclusion of this at-risk population of 
adolescent girls will achieve this increased awareness, while allowing the study population 
to appropriately represent the characteristics of girls and women for whom this therapy is 
needed. Girls under 16 years of age will not be included, as the PKs of LNG may be 
influenced by changing CYP metabolism during early adolescence. Sites may elect to only 
include adult (according to local age criteria) women if they lack access to enrollment of 
adolescent girls, or are unable to include this age group due to local regulations.  
 


 
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Breastfeeding Women 
Breastfeeding women will be included only after their infants are 6 months old or older. 
Progestin-containing contraceptives are recommended during breastfeeding. During long-
term contraception with progestins, steroid levels in infant plasma are only 1-6% of the 
levels in maternal plasma. Isolated cases of decreased milk production have been reported 
with the use of levonorgestrel; however, cohort evaluations indicate no adverse effects of 
progestin exposure have been found on breastfeeding (quality or quantity of milk) [21, 60, 
61]. However, because this is a volunteer PK study in women who are not using the EC to 
prevent pregnancy, women breastfeeding an infant under 6 months of age will be excluded. 
After 6 months, weaning often starts and the infant will receive a smaller daily volume of 
breast milk. 
 
Acceptability and practicality of EC as an exploratory objective 
The ACTG has a demonstrated commitment to meaningful community engagement and 
increasing the diversity of trial participants. While at least one study of women in LMIC found 
that 85% of women were willing to use EC [17], the acceptability and practicality of 
administering EC in the context of an ACTG study has not yet been evaluated. An 
exploratory objective regarding acceptability and practicality of EC will provide valuable 
information about acceptability. This objective may also identify barriers to administration of 
EC at the site level regarding infrastructure, reimbursement, or education/outreach needs. 
Acceptability and practicality will be assessed via questionnaires for participants and site 
staff. 
 
Postcoital contraception is generally reported to be an acceptable contraceptive option [62]. 
Allowing EC as a contraceptive option may be a viable strategy for increasing the enrollment 
of women of reproductive potential in ACTG trials. This exploratory objective will evaluate if 
postcoital contraception is acceptable in the context of an ACTG trial. 
 
Inclusion of hair samples as an adherence metric in the study 
Since this study will perform PK sampling to assess the impact of increased doses of LNG 
EC to overcome known DDIs between LNG and EFV or RIF, it is imperative to assure 
adequate long-term adherence to the ART or TB drug of interest at the time of study 
procedures. The demonstration of long-term adherence to the ART or TB drug in question 
will assure that these medications are at steady state at the time of PK sampling of the 
administered LNG EC in this protocol.   
 
Self-reported adherence can overestimate drug-taking due to social desirability bias [63]. 
Medication electronic monitoring systems (MEMS) cannot measure actual drug ingestion. 
Plasma levels can be susceptible to “white coat effects,” where adherence improves 
transiently prior to study visits [64]. Moreover, marked day-to-day variation in plasma levels 
can limit their utility in representing typical patterns of adherence [65-69]. For medications 
phosphorylated intracellularly, such as the active moieties of tenofovir (TFV) or emtricitabine 
(FTC), concentrations of intracellular anabolites in dried blood spot (DBS) relay information 
on exposure over longer dosing periods [70]. Hair and DBS measures of TFV and FTC (and 
their anabolites tenofovir diphosphate [TFV-DP] and emtricitabine triphosphate [FTC-TP]) 
are strongly correlated [70]. However, because INSTIs (e.g., DTG) and NNRTIs (e.g., EFV) 
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DBS does not offer any additional advantage to plasma levels with these ARVs. The 
concentration of medications in hair reflects drug uptake from the systemic circulation over 
weeks to months and thereby provide a long-term measure of medication adherence [71].  
 
Hair concentrations of ARVs are the strongest independent predictor of virologic success in 
large prospective cohorts of patients living with HIV [68, 69, 72-77], providing 
pharmacodynamic relevance for the longitudinal exposure data provided by hair samples. 
Hair levels of ARVs are stronger predictors of treatment outcomes than self-reported 
adherence [68, 72, 74-77] or single plasma ARV concentrations [68, 73].  
 
Unlike phlebotomy, hair collection is noninvasive and does not require specific skills, sterile 
equipment, or specialized storage conditions. Hair sample collection merely requires a pair 
of scissors and storage and shipment at room temperature. The laboratory and its 
investigators have published data on high rates of acceptability and feasibility (>95%) of 
collecting hair samples for hair ARV monitoring in Africa [66, 67, 69]. Therefore, hair 
concentrations will provide long-term exposure information to EFV, DTG and INH (as a 
proxy for RIF adherence) in this study. 
 
Pharmacogenetic evaluation 
As described above, pharamacogenetic variation influences drug exposure, and single 
nucleotide polymorphisms (SNPs) in CYP2B6 that influence EFV metabolism were 
associated with the extent of the DDI between EFV and LNG in one report [55]. We plan to 
study the following SNPs in CYP2B6/CYP2A6 for EFV, UGT1A1 for DTG and SLCO1B1 for 
RIF. These SNPs occur in 25-50% of individuals regardless of ancestry allowing the 
identification of associations even with a small sample size.   
 
In addition to these frequent SNPs, other SNPs that are known to be associated with ART or 
LNG will also be evaluated. For EFV, genotyping will include at least four CYP2B6 and 
CYP2A6 SNPs that predict increased plasma EFV exposure, including CYP2B6 516G→T 
(rs3745274), 983T→C (rs28399499), 15582C→T (rs4803419), and CYP2A6, -48T→G 
(rs28399433). These polymorphisms in combination explain approximately 35% of 
interindividual variability in plasma EFV exposure. For RIF, genotyping will include at least 
SLCO1B1 rs4149032 that has been associated with RIF bioavailability, and SLCO1B1 
521T→C (rs4149056) that has been associated with decreased transporter activity. For 
DTG, genotyping will include at least UGT1A1 rs887829 that is associated with higher 
plasma DTG concentrations. For LNG, genotyping will include at least SNPs identified in 
genome-wide studies or PharmGKB for CYP3A4 (rs28371759, rs34670419, rs35599367), 
CYP3A5 (rs4646450, rs776746), CYP1A1 (rs2470893, rs2472297), CYP1A2 (rs1378942, 
rs2069514, rs2472299, rs2472304, rs28399424, rs56107638, rs56276455, rs72547516, 
rs762551) or estrogen phenotypes (rs1864729, rs2414095, rs2445762, rs117585797, 
rs727428). 
 
Rationale Summary 
EC represents a useful second method of contraception for women participating in clinical 
trials, as well as women who are unable or unwilling to receive continuous contraception. 
This study will evaluate the dose adjustment required of LNG EC in combination with EFV-
based ART or RIF-containing TB treatment to provide evidence to support use of LNG EC 


 
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and its appropriate dosing during clinical care and clinical trial situations for women living 
with either HIV or TB. The following four groups of volunteers will be used to evaluate LNG 
EC in combination with important ART and TB strategies in LMIC. 
 
• 
Randomized Group A: EFV-based ART with standard-dose LNG EC 
This group is important to describe the difference in LNG PKs with standard dose and 
double dose (Group B) of LNG EC in the context of EFV. Although one study reports the 
effect of EFV on LNG, this study was done in a predominately Caucasian group of 
healthy volunteers using an alternative dose of EC. The inclusion of Group A will inform 
the extent of this DDI in women living with HIV, and women of diverse genetic and ethnic 
backgrounds, given the US and non-US sites participating in A5375, particularly 
because of known pharmacogenetic differences across populations. In addition, it will 
inform whether doubling the dose of LNG EC from 1.5 mg to 3.0 mg in the presence of 
EFV results in higher LNG exposure. The dose-exposure relationship cannot be 
assessed without two different doses of LNG EC administered in the combination with 
EFV. 
 
• 
Randomized Group B: EFV-based ART with double-dose LNG EC 
According to UK and EMA emergency contraception guidelines, this LNG EC dose is 
already recommended in the absence of data. EFV will remain clinically relevant in LMIC 
for the coming decades [20], so verifying that LNG PK exposure with a double dose of 
LNG EC in combination with EFV is safe and equivalent to LNG exposure in the 
absence of a DDI (Group C) will support women’s contraceptive options. 
 
• 
Assigned Group C: A control group receiving DTG-based ART with standard-dose LNG 
EC 
This group will act as an active control group, because a control group of women living 
with HIV who are not receiving ART is not ethically feasible. DTG was selected because 
it is not expected to have DDIs with LNG, and it is the regimen whose use is expanding 
in LMIC. 
 
• 
Assigned Group D: RIF-containing TB therapy with double-dose LNG EC 
According to UK and EMA emergency contraception guidelines, this dose is already 
recommended in the absence of data. RIF is the cornerstone of TB therapy. Verifying 
that this double dose is safe and results in equivalent LNG exposure in the absence of a 
DDI (Group C) will support women’s contraceptive options. The protocol team 
considered also including a group receiving RIF with standard-dose LNG EC; however, 
because RIF is a similar or more potent CYP inducer than EFV, the expected decrease 
in LNG exposure after standard-dose in combination with RIF is expected to be the 
same or even greater than that of Group A. The effect of dose escalation on LNG 
exposure in the presence of a DDI will already be addressed via comparison of Groups 
A and B. Therefore, to increase efficiency and conserve resources, the study is designed 
to only evaluate whether dose escalation of LNG EC overcomes the expected interaction 
with RIF. 
 


 
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3.0 
STUDY DESIGN 
 
A5375 is a Phase II, open-label, four parallel group, partially randomized, PK study to 
assess if a double dose of LNG EC overcomes known DDI with EFV-based ART and RIF-
containing TB therapy. The safety of double-dose LNG EC versus standard-dose will also 
be compared. 
 
Participants will be volunteers who do not currently require EC for contraception. This study 
will enroll a total of 116 women who are 16 years of age or older. Group assignment will be 
determined by infection status (HIV or TB; participants cannot be coinfected), and, for those 
who are living with HIV, by ART regimen at enrollment. Women living with HIV who are 
taking EFV-based ART will be randomized to Group A (17 participants) or B (33 participants) 
in a 1:2 ratio. Women taking DTG-based ART will be assigned to Group C (33 participants). 
Women who are HIV-negative and in the continuation phase of active TB treatment taking 
RIF and INH will be assigned to Group D (33 participants). 
 
At study entry, participants in Groups A and C will receive a standard (1.5 mg) single dose of 
LNG EC. Participants in Groups B and D will receive a double (3.0 mg) dose of LNG EC. 
Intensive PK monitoring will be conducted pre-dose, and after the LNG EC dose. Women 
are expected to be at the clinical site while the initial 8 hour PK samples are collected and 
may return for the 24 and 48 hour samples. 
 
Information about demographic factors that can affect drug concentrations such as age, 
ethnicity, disease state, and concomitant drug use will be collected on all participants. 
Whole blood will be collected and stored for pharmacogenetic analyses.  
 
Body fat content will be estimated using weight, height, neck, hip, and waist measurements. 
Because LNG exposure is known to be inversely correlated with weight/BMI (i.e., women 
with an obese BMI have lower LNG exposure) [30, 31], women with a BMI ≥30 kg/m2 will be 
limited to no more than five within each of Groups B-D, and no more than three within Group 
A. Therefore, the representation of obese women will be no more than 15% of the study 
sample, and stratification limits by group will help control for imbalance across groups for 
this potential confounder. 
 
All participants will complete self-report questionnaires to assess adherence to TB therapy 
and ART, menstrual history and patterns after LNG EC administration, and to collect 
adverse effects commonly reported with LNG EC (i.e., irregular bleeding patterns). 
Adherence to ART and RIF will also be assessed by collecting hair samples and single 
plasma concentrations at entry. 
 


 
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4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 Postmenarcheal female. 
 
Note: Participant report and clinician’s opinion are acceptable. 
 
4.1.2 The following laboratory values obtained within 30 days prior to study entry by any 
US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) 
certification or its equivalent, or at any network-approved non-US laboratory that 
operates in accordance with Good Clinical Laboratory Practices (GCLP) and 
participates in appropriate external quality assurance (EQA) programs. 
• 
Absolute neutrophil count (ANC) ≥500 cells/mm3    
• 
Platelet count ≥50,000 platelets/mm3  
• 
Hemoglobin ≥8.0 g/dL  
• 
Aspartate transaminase (AST) <5 x upper limit of normal (ULN) 
• 
Alanine aminotransferase (ALT) <5 x ULN  
• 
Creatinine ≤1.5 x ULN   
• 
Total bilirubin ≤2.0 x ULN 
 
4.1.3 Negative serum or urine pregnancy test within 30 days prior to study entry and within 
48 hours prior to entry (if screening occurs more than 48 hours prior to entry) by any 
US clinic or US laboratory that has a CLIA certification or its equivalent, or is using a 
point of care (POC)/CLIA-waived test, or at any network-approved non-US laboratory 
or non-US clinic that operates in accordance with GCLP and participates in 
appropriate EQA programs. The serum or urine pregnancy test must have a 
sensitivity of at least 25 mIU/mL. 
 
4.1.4 Has not had sex that could lead to pregnancy without contraception within 14 days 
prior to study entry as defined in section 4.1.5, according to participant self-report. 
 
4.1.5 Contraception requirements  
 
All participants must agree not to participate in a conception process (e.g., active 
attempt to become pregnant or in vitro fertilization) for the duration of the study.  
Women of reproductive potential, who are participating in sexual activity that could 
lead to pregnancy, must agree to use at least one reliable method of contraception 
while in the study. Acceptable forms of contraceptives include: 
• 
Male condom with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Non-hormonal IUD 
• 
Bilateral tubal ligation 
• 
Male partner vasectomy 
 
4.1.6 Women and girls ≥16 years of age. 


 
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4.1.7 Ability and willingness of the participant to provide informed consent. 
 
4.1.8 BMI (kg/m2) available at entry. See section 6.3.5 for BMI calculation instructions. 
 
Note: A maximum of five participants with BMI ≥30 kg/m2 will be allowed in each 
arm B-D and a maximum of three participants in Arm A. 
 
4.1.9 For women living with HIV: HIV-1 infection, documented by any licensed rapid HIV 
test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time 
prior to study entry and confirmed by a licensed Western blot or a second antibody 
test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, 
plasma HIV-1 RNA viral load. 
 
Note: The term “licensed” refers to a US FDA-approved kit, which is required for all 
IND studies, or for sites located in countries other than the United States, a kit that 
has been certified or licensed by an oversight body within that country and validated 
internally. Non-US sites are encouraged to use US FDA-approved methods for IND 
studies. 
 
WHO and Centers for Disease Control and Prevention (CDC) guidelines mandate 
that confirmation of the initial test result must use a test that is different from the one 
used for the initial assessment. A reactive initial rapid test should be confirmed by 
either another type of rapid assay or an E/CIA that is based on a different antigen 
preparation and/or different test principle (e.g., indirect versus competitive), or a 
Western blot or a plasma HIV-1 RNA viral load. 
 
4.1.10 For women living with HIV: Receiving a stable qualifying concomitant ART regimen 
containing either once-daily DTG 50 mg or EFV 600 mg with no changes in the 
components of their ART for at least 30 days prior to study entry.  
 
4.1.11 For women who are being treated for TB: HIV-negative at screening, documented 
within the prior 6 months by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit and confirmed by a licensed 
Western blot or a second antibody test by a method other than the initial rapid HIV 
and/or E/CIA, or by HIV-1 antigen, or plasma HIV-1 RNA viral load. 
 
Note: The term “licensed” refers to a US FDA-approved kit, which is required for all 
IND studies, or for sites located in countries other than the United States, a kit that 
has been certified or licensed by an oversight body within that country and validated 
internally. Non-US sites are encouraged to use US FDA-approved methods for IND 
studies. 
 
WHO and CDC guidelines mandate that confirmation of the initial test result must 
use a test that is different from the one used for the initial assessment. A reactive 
initial rapid test should be confirmed by either another type of rapid assay or an 
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(e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral 
load. 
 
4.1.12 For women who are HIV-negative and being treated for TB: Receiving RIF and INH 
on a once daily dosing (7 days per week) schedule at study entry, after completion of 
the intensive phase of TB treatment. 
 
Note: Inclusion of ethambutol as part of continuation phase of TB therapy is allowed.  
 
4.1.13 Ability and willingness of participant to be contacted remotely for study visits. 
 
4.2 
Exclusion Criteria  
 
4.2.1 Known allergy/sensitivity or any hypersensitivity to LNG or components of the 
formulation. 
 
4.2.2 Bilateral oophorectomy, hysterectomy, or postmenopausal. 
 
Note: Postmenopausal is defined as amenorrhea for at least 12 consecutive months 
prior to study entry (in the absence of medications known to induce amenorrhea), 
and have a documented follicle stimulated hormone-release factor (FSH) 
measurement >40 mIU/mL or a result in the testing laboratory’s menopausal range. 
If an FSH level is not available, 24 consecutive months of amenorrhea prior to study 
entry (in the absence of medications known to induce amenorrhea). 
 
Note: Clinical assessment and clinician’s opinion are acceptable. 
 
4.2.3  Currently pregnant, within 6 weeks of delivery, or currently breastfeeding an infant 
under 6 months of age. 
 
Note: For recent pregnancy resolution during the first or second trimester, the 
participant is only eligible when the pregnancy test result is negative. 
 
4.2.4 Receipt of LNG within 30 days prior to study entry. 
 
4.2.5 Receipt of depo-medroxyprogesterone for 90 days prior to study entry, or 
norethisterone enanthate (NET-EN) within 60 days prior to study entry, or other 
hormonal contraceptives within 30 days prior to study entry.  
 
4.2.6 Use of any drugs other than RIF and EFV known to: 1) induce CYP3A4 system 
within 30 days prior to study entry, and 2) inhibit the CYP3A4 system within 7 days 
prior to study entry. See Appendix IV for prohibited and precautionary medications. 
 
4.2.7 Active drug or alcohol use or dependence that, in the opinion of the site investigator, 
would interfere with adherence to study requirements. 
 


 
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4.2.8 Acute or serious illness requiring systemic treatment and/or hospitalization within 14 
days prior to study entry. 
 
4.2.9  Other medical, psychiatric, or psychological condition that, in the opinion of the site 
investigator, would interfere with completion of study procedures and or adherence 
to study drug. 
 
4.2.10 For women living with HIV: Currently receiving medications for TB disease. 
 
Note: Isoniazid alone given for TB prophylaxis is allowed.  
 
4.2.11 For women living with HIV: Has missed one or more of the prescribed doses of HIV 
medications within 3 days prior to study entry. 
 
Note: The entry visit may be rescheduled within the screening period once the 
participant has taken all prescribed doses within 3 days prior to study entry. 
 
4.2.12 For women who are HIV-negative and being treated for TB: Has missed one or more 
of the prescribed doses of TB medication within 3 days prior to study entry. 
 
Note: The entry visit may be rescheduled within the screening period once the 
participant has taken all prescribed doses within 3 days prior to study entry. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form 
approved, as appropriate, by their local institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE). Upon receiving final 
approval, sites will submit all required protocol registration documents to the DAIDS 
Protocol Registration Office (PRO) at the Regulatory Support Center (RSC). The 
DAIDS PRO will review the submitted protocol registration packet to ensure that all 
of the required documents have been received. Protocol activation is required before 
each site can enroll any participants. 
 
Site-specific informed consent forms (ICFs) will be reviewed and approved by the 
DAIDS PRO and sites will receive an Initial Registration Notification from the DAIDS 
PRO that indicates successful completion of the protocol registration process. A copy 
of the Initial Registration Notification should be retained in the site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an 
amendment, sites should implement the amendment immediately. Sites are required 
to submit an amendment registration packet to the DAIDS PRO at the RSC. Site-
specific ICF(s) will not be reviewed and approved by the DAIDS PRO, and sites will 
receive an Amendment Registration Notification from the DAIDS PRO that approves 
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protocol registration process. A copy of the final Amendment Registration Notification 
issued by the DAIDS PRO should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual. 
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant (or, when necessary, the parent or 
legal representative if the participant is younger than 18 years of age or under 
guardianship) will be asked to read and sign the approved protocol consent form. For 
those under the age of consent, assent will also be obtained according to the local 
IRB requirements and regulations. 
 
For participants from whom a signed informed consent has been obtained, an ACTG 
Screening Checklist must be entered through the Data Management Center (DMC) 
Subject Enrollment System.  
 
4.3.2 Protocol Activation 
 
Prior to enrollment, sites must complete the Protocol Activation Checklist found on 
the ACTG Member website. This checklist must be approved prior to any screening 
of participants for enrollment.  
 
4.3.3 Randomization/Participant Registration 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the protocol, an ACTG Screening Failure 
Results form must be completed and keyed into the database. 
 
Participants who meet the enrollment criteria will be randomized (if taking EFV-based 
HIV therapy) or registered (if taking DTG-based HIV therapy or RIF-containing TB 
therapy) to the study according to standard ACTG DMC procedures.  
 
4.4 
Co-enrollment Guidelines  
 
• 
US sites are encouraged to co-enroll participants in A5128, “Plan for Obtaining Informed 
Consent to Use Stored Human Biological Materials (HBM) for Currently Unspecified 
Analyses.” Co-enrollment in A5128 does not require permission from the A5375 protocol 
chairs.  
• 
Non-US sites are encouraged to co-enroll participants in A5243, “Plan for Obtaining 
Human Biological Samples at Non-US Clinical Research Sites for Currently Unspecified 
Genetic Analyses.” Co-enrollment in A5243 does not require permission from the A5375 
protocol chairs.  
• 
For specific questions and approval for co-enrollment in other studies, sites should first 
check the PSWP or contact the protocol team via e-mail as described in the Study 
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5.0 
STUDY TREATMENT  
 
Study treatment is defined as levonorgestrel emergency contraception (LNG EC) 1.5 mg or 
3 mg. 
 
5.1 
Regimens, Administration, and Duration 
 
5.1.1 Regimen 
 
At study entry, participants will be randomized or assigned in open-label fashion to 
Group A, B, C, or D, and will receive one standard (1.5 mg) or double (3 mg) dose of 
LNG EC depending on the randomized or assigned group as follows: 
 
Table 5.1.1-1: LNG EC Dose by Group 
Group 
LNG EC Dose 
Randomized 
Group A 
1.5 mg once on Day 0 
Randomized 
Group B 
3  mg once on Day 0 
Assigned 
Group C 
1.5 mg once on Day 0 
Assigned 
Group D 
3  mg once on Day 0 
 
5.1.2  Administration 
 
LNG EC 1.5 mg: Administered orally as one 1.5 mg tablet or two 0.75 mg tablets. 
LNG EC 3 mg: Administered orally as two 1.5 mg tablets or four 0.75 mg tablets. 
The appropriate dose of LNG EC will be administered by mouth in a directly 
observed manner. LNG EC should be administered with food (or within 2 hours of 
food), but there is no calorie or other content requirements for that food intake.  
 
5.1.3 Treatment Duration 
 
Study participants will receive one dose of LNG EC on Day 0 and will be followed 
post-treatment for 4 weeks. 
 
5.2 
Study Product Formulation and Preparation 
 
LNG EC provided through the study will be supplied as 1.5 mg round tablets. The 
tablets are pink and packaged in a blister pack in a carton. Do not use if carton is open or 
blister seal is broken or missing. The product should be stored at room temperature 
between 20-25°C (68-77°F).  
 


 
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LNG EC 1.5 mg or 0.75 mg tablets locally procured by the site and approved for use in 
A5375 by the protocol team must be stored in accordance with the manufacturer’s 
instructions. 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
LNG EC 1.5 mg (New Day™) will be supplied by NorthStar Rx and will be made 
available to sites through the NIAID Clinical Research Products Management Center 
(CRPMC). Upon successful completion of protocol registration procedures, the 
product may be obtained by the site pharmacist by following the instructions provided 
in the manual Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks.  
 
LNG EC 0.75 mg (Pregnon), supplied by Mylan, may be locally sourced by 
clinical research sites that are unable to import study-provided LNG EC. The 
A5375 Site Implementation Plan (SIP) must be completed by each site for 
protocol team notification and authorization of locally sourced LNG EC. 
 
Any study product not provided by the study must comply with the NIAID (DAIDS) 
policy that outlines the process for authorizing the use of study products not 
marketed in the United States in NIAID (DAIDS)-supported and/or -sponsored clinical 
trials. This policy is available on the NIAID (DAIDS) website at 
https://www.niaid.nih.gov/sites/default/files/NonFDAapprovedProducts.pdf. 
 
5.3.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC or other sources, and subsequently dispensed. 
All study products must be stored in the investigational pharmacy. 
 
5.3.3 Final Disposition of Study Product 
 
All unused study products remaining at US clinical research sites after the study is 
completed or terminated must be returned to the NIAID CRPMC (unless otherwise 
directed by the sponsor). Study products may also be returned to the CRPMC for 
other reasons, as requested by the sponsor. Site pharmacists will follow the relevant 
instructions for return of unused study products provided in the manual Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks. 
 
At non-US clinical research sites, the site pharmacist must follow the instructions 
provided in the manual Pharmacy Guidelines and Instructions for DAIDS Clinical 
Trials Networks for the destruction of unused study products. 
 


 
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5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study product is initiated or a dose changed, 
investigators must review the concomitant medication’s and study product’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the ACTG Precautionary and Prohibited 
Medications Database located at http://tprc.pharm.buffalo.edu/home/di_search/. 
 
5.4.1 Required Medications 
 
Required ARV therapy (not provided through study) for participants living with HIV: 
 
• 
Efavirenz (EFV) 600 mg in combination with two or more NRTIs 
 
OR 
 
• 
Dolutegravir (DTG) 50 mg in combination with two or more NRTIs 
 
Required TB treatment (not provided through study) for participants with TB: 
 
• 
Rifampicin (RIF)  
 
AND 
 
• 
Isoniazid (INH)  
 
Note: Pyridoxine (vitamin B6), if recommended by local standard of care with INH, 
will not be supplied through the study and must be obtained locally by the site.  
 
5.4.2 Prohibited Medications 
 
Other hormone therapies, therapy for TB (except Group D), and significant CYP 
inducers or inhibitors other than study therapy. Prohibited medications are listed in 
Appendix IV. 
 
5.4.3 Precautionary Medications 
 
Precautionary medications are listed in Appendix IV.   


 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations (SOE) 
 
Table 6.1-1: Schedule of Participant Evaluations 
Evaluation 
Screening 
Entry 
Post-
Dose 
24 hours 
post-dose 
(±2 hours) 
48 hours 
post-dose 
(±2 hours) 
Post-dose  
(±3 days) 
Clinically 
Indicated 
Visit 
Premature 
Study 
Discontinuation 
-30 Days 
Day 0 
Day 1 
Day 2 
Day 
7 
Day 
14 
Day 
28 
Documentation of HIV Status 
X 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
Gynecological History 
X 
X 
 
 
 
X 
X 
X 
 
X 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
Targeted Physical Exam 
X 
X 
 
 
 
 
 
 
X 
 
BMI 
X 
 
 
 
 
 
 
 
 
 
Body Fat Estimate Measurements 
 
X 
 
 
 
 
 
 
 
 
Signs and Symptoms 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diagnoses 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
 
X 
 
X 
X 
 
 
X 
X 
X 
LNG EC Administration 
 
X 
 
 
 
 
 
 
 
 
Hematology 
X 
 
 
 
Liver Function Tests 
X 
 
 
 
Blood Chemistries 
X 
 
 
 
Pregnancy Test 
X 
X 
 
 
 
 
X 
CD4+/CD8+ for Groups A, B, & C  
X 
 
 
 
HIV-1 RNA for Groups A, B, & C 
X 
 
 
 
PK Sampling 
X 
X 
X 
X 
 
Whole Blood for Pharmacogenetic 
Assessment 
 
X 
 
 
 
 
 
 
 
 
Hair Sampling 
 
 
X 
 
 
 
 
 
 
 
Adherence Assessment (ART and TB 
Drugs) 
X 
X 
 
X 
X 
 
Acceptability and Practicality Questionnaire 
 
X 
 
 
X 
 
X 
X 
 
X 
 


 
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Table 6.1-2: Schedule of Site Evaluations 
Evaluation 
Timepoint 
Site Acceptability and Practicality 
Questionnaire 
Once during site-participation in study 
 
6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 
Screening evaluations must occur after the informed consent is signed and prior 
to the participant starting any study medications, treatments, or interventions. 
 
Screening 
Screening evaluations to determine eligibility must be completed within 30 days 
prior to study entry unless otherwise specified. 
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
for participants who do not enroll and entered into the ACTG database.  
 
6.2.2 Entry Evaluations 
 
Participants must complete all entry evaluations prior to administration of study 
treatment.  
 
Participants must receive treatment under direct observation of study staff within 
7 days of enrollment. 
 
6.2.3 Post-Entry Evaluations 
 
Post-entry evaluations occur after study treatment is administered. 
 
The two final post-dose PK visits should occur 24 hours post-dose ±2 hours, and 
48 hours post-dose ±2 hours. If the visit occurs outside of this window, but within 
72 hours of the LNG EC dose, the sample should still be collected. 
 
The 24 and 48 hours post-dose study visits may only be conducted 
remotely (e.g., telephone, telehealth) in the following situations during the 
COVID-19 outbreak: 
  
• 
A participant is unable to attend a visit because of personal illness, 
COVID illness among others in their home, or local conditions or 
guidelines restricting travel to the clinic; the site must inform the core 
team (actg.corea5375@fstrf.org).  
• 
The site is temporarily unable to conduct non-essential visits in the 
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Regardless of the situation, sites should document which visits were 
conducted remotely, attempt to obtain as much of the visit-specific 
required information as possible, based on the SOE, and record it on the 
relevant eCRF. The impacted visits and rationale must be reported and 
documented, following instructions provided by the team or network 
leadership.  
 
Follow-up assessments at 7, 14, and 28 days post entry are conducted by 
remote contact interview and should occur within the ±3 days window.  
 
If clinically indicated (refer to section 6.3.5), participants will be requested to 
return to the clinic for a visit. 
 
Study Completion Evaluations 
The week 4 evaluations will be performed as the final study visit. A study 
discontinuation eCRF must be keyed for all participants at the time of premature 
discontinuation, or at week 4 for participants who complete the study, including 
participants who miss the final visit.  
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Randomized or Registered Participants Who Do Not Start Study 
Treatment 
Participants who are enrolled but do not complete the study treatment will be 
taken off the study. No further evaluations are required. These participants will be 
replaced. All eCRFs must be keyed for the period up to and including the entry 
visit. 
 
Premature Study Discontinuation 
Women who do not complete the post-dose 8-hour PK study visit to assess LNG 
concentrations are not evaluable for the primary outcome and will be 
discontinued from the study and replaced. If the participant does not return for 
the 24- and 48-hour evaluations or is not reached for the follow-up evaluations on 
Days 7, 14, and 28, this will be considered a missed visit and the participant will 
remain on study. 
 
Participants who prematurely discontinue from the study will have the premature 
discontinuation evaluations performed by remote contact interview or at the clinic 
prior to being taken off the study, as noted in the Schedule of Evaluations (SOE).   
 
6.3 
Instructions for Evaluations 
 
 
Each study site and laboratory involved in this study will comply with the DAIDS 
policy on Requirements for Laboratories Performing Testing for DAIDS-Supported 
and/or Sponsored Clinical Trials, which is available at 
https://www.niaid.nih.gov/sites/default/files/laboratorypolicy1.pdf. 
 


 
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All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
website for information about what must be included in the source document: 
https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf. 
 
All stated evaluations are to be recorded on the eCRF unless otherwise specified. Refer 
to section 7.0 for information on the Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events (DAIDS AE Grading Table), and AE reporting of 
adverse events requirements. 
 
6.3.1 Documentation of HIV-1 
 
Sections 4.1.9 and 4.1.11 specify assay requirements for HIV-1 documentation.  
 
6.3.2 Medical History 
 
The medical history must include all signs and symptoms regardless of grade 
and all diagnoses identified by the ACTG criteria for clinical events and other 
diagnoses regardless of grade within the past 30 days prior to study entry. In 
addition, the following diagnoses should be recorded regardless of when the 
diagnosis was made: 
• 
AIDS-defining conditions 
• 
Bone fractures (verbal history accepted) 
• 
Coronary heart disease 
• 
Cancer (exclusive of basal cell skin cancer) 
• 
Diabetes 
• 
Tuberculosis 
• 
Chronic hepatitis C 
• 
Chronic hepatitis B 
 
Any pregnancy and/or pregnancy outcome within 1 year prior to study 
entry must be recorded. 
 
Any allergies to any medications and their formulations must also be 
documented.  
 
6.3.3 Gynecological History 
 
Baseline Gynecological History 
Obstetric history, age of menarche, cycle length, and frequency will be obtained 
at the screening visit.  
 
The menstrual history over the past 6 months will cover the participant’s 
perception of her usual frequency of menstrual cycles, how long the menstrual 
bleeding usually lasts, and whether she usually has spotting between menstrual 
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Interval Gynecological History 
The participant will be asked about spotting between menstrual cycles and the 
last menstrual period (date of first day of bleeding) will be collected at the clinic at 
the entry visit, and by remote contact interview post-entry, per the SOE. 
Questionnaires are posted on the DMC Portal in the Forms Management Utility. 
 
Contraceptive History 
At study entry, record all contraceptive methods currently utilized or 
utilized within the 120 days prior to study entry, including non-hormonal 
methods, as listed in section 4.1.5 (Contraception requirements) of the 
protocol. 
 
6.3.4 Medication History 
 
A medication history must be present, including start and stop dates. The table 
below lists the medications that must be included in the history.  
 
The medication history evaluation will be assessed at the screening and entry 
pre-treatment visits and recorded on the eCRFs at the entry pre-treatment visit. 
 
Table 6.3.4-1: Medication History 
Medication Category 
Complete History or Timeframe 
Antiretroviral therapy 
1 year prior to study entry 
Immune-based therapy 
1 year prior to study entry 
Tuberculosis therapy 
1 year prior to study entry 
Blinded study treatment 
30 days prior to study entry 
Prescription drugs for treatment of 
opportunistic infections 
30 days prior to study entry 
Prescription drugs for prophylaxis of 
opportunistic infections 
30 days prior to study entry 
Prescription drugs (other) 
30 days prior to study entry 
Alternative therapies 
30 days prior to study entry 
Dietary supplements 
30 days prior to study entry 
Sex-hormone medications or sex-
hormone analogues or antagonists* 
1 year prior to study entry 
except as noted below 
Barrier methods for contraception 
1 year prior to study entry 
Other – in vitro fertilization (IVF) 
30 days prior to study entry 
*Includes: hormone-releasing IUDs (e.g., Mirena inserted in the last 5 years); 
oral, injectable, implanted, or patch contraceptives; vaginal ring, creams, or 
inserts; estrogen, progesterone, or testosterone therapy; leuprolide or other 
synthetic gonadotropin-releasing hormone; tamoxifen, raloxifene, aromatase 
inhibitors or any other androgen, estrogen, spironolactone, emergency 
contraception, or progesterone analogue or antagonist therapy. 
 


 
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6.3.5 Clinical Assessments 
 
Targeted Physical Examination 
A targeted physical exam is to include vital signs (height [collected only at 
screening], weight, temperature, pulse, respiration rate, and blood pressure). A 
targeted physical exam will be conducted: 
• 
As indicated in the SOE. 
• 
If clinically indicated by any previously identified or new symptom possibly 
related to study treatment, study procedures, SAE, or pregnancy that the 
participant has experienced since the last visit or at this visit. 
 
Post entry, see section 8.2 for collection requirements for pregnancy. 
 
BMI 
BMI calculated using height and weight collected at screening. Refer to the BMI 
Index calculator located on the FSTRF web site. 
 
Body Fat Estimate Measurements 
Collect as indicated in the SOE. Waist, hip, and neck measurements are 
required. Height will be recorded at screening. Please see the study-specific 
manual of procedures (MOPS) for body measurement instructions. 
 
Signs and Symptoms 
At entry, all grades of signs and symptoms that occurred within 30 days prior to 
study entry must be recorded. 
 
Post-entry, information may be collected by remote contact interview or during a 
site visit via participant questionnaire (see section 6.3.13) including: nausea, 
stomach/abdominal pain, vomiting, tiredness, headache, dizziness, breast pain, 
vaginal bleeding (related to menstruation), and menstrual discomfort.  
 
Refer to section 7.2 for AE collection requirements. 
 
Diagnoses 
Record all diagnoses identified by the ACTG criteria for clinical events and other 
diseases, as indicated in the SOE. Post-entry, information may be collected by 
remote contact interview or during a site visit. 
 
Refer to section 7.2 for AE collection requirements.   
 
Concomitant Medications 
The following new and discontinued concomitant medications must be recorded 
as indicated in the SOE: 
• 
Sex-hormone medications or sex-hormone analogues or antagonists (see 
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• 
ART medication modifications (Groups A-C only): Record all ARV medication 
modifications, including initial doses, participant-initiated modifications, 
physician modifications, and/or protocol-mandated modifications, inadvertent 
and deliberate interruptions of more than 7 days since last recorded per the 
SOE, and record any permanent discontinuation of ART treatment. 
• 
TB medication modifications (Group D only): Record all TB medication 
modifications, including initial doses, participant-initiated modifications, 
physician modifications, and/or protocol-mandated modifications, inadvertent 
and deliberate interruptions of more than 7 days since last recorded per the 
SOE, and record any permanent discontinuation of TB treatment. 
 
Post-entry, information may be collected by remote contact interview or during a 
site visit. 
 
LNG EC Administration 
Record the study treatment administration, including date and time of 
administration, and if the participant vomited the dose within 2 hours of 
administration. Refer to section 6.2.2 for the timing of dose administration. 
 
6.3.6 Laboratory Evaluations 
 
Record and key all laboratory values regardless of grade. Laboratory evaluations 
will be collected per the SOE. 
 
Hematology 
Hemoglobin, hematocrit, white blood cell (WBC) count, ANC, and platelet count. 
 
Liver Function Tests 
Total bilirubin, AST (SGOT), ALT (SGPT), and albumin. 
 
Blood Chemistries 
Electrolytes (sodium, potassium, chloride, and bicarbonate), creatinine, and 
blood urea nitrogen (BUN). 
 
Pregnancy Test 
Serum or urine β-HCG (urine test must have a sensitivity of ≤25 mIU/mL) by any 
US clinic or US laboratory that has a CLIA certification or its equivalent, or is 
using a POC/CLIA-waived test, or at any network-approved non-US laboratory or 
non-US clinic that operates in accordance with GCLP and participates in 
appropriate EQA programs. 
 
There must be a negative pregnancy test within 30 days prior to study entry and 
within 48 hours prior to study entry, if screening occurs >48 hours prior to entry. If 
LNG EC is administered more than 24 hours after study entry, the pregnancy test 
must be repeated if the test was not done within 48 hours prior to LNG EC 
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Note: The pregnancy test within 48 hours of study entry may be done on the day 
of entry, but must be performed before enrollment and before any enrollment 
procedures are completed. 
 
Perform as clinically indicated, as specified in section 6.1. Record pregnancy and 
pregnancy outcome per section 8.2.   
 
6.3.7 Immunologic Studies 
 
CD4+/CD8+ for Groups A, B, & C 
Obtain absolute CD4+/CD8+ count and percentages at entry from a laboratory 
that possesses a CLIA certification or equivalent (US sites) or IQA certification 
(non-US sites). 
 
Note: If a CD4+/CD8+ count has been drawn for clinical care within the last 45 
days, it may be used. This laboratory does not have to provide documentation of 
GCLP or EQA. 
 
6.3.8 Virologic Studies 
 
Plasma HIV-1 RNA for Groups A, B, & C 
At entry, HIV-1 RNA must be performed by a laboratory that possesses a CLIA 
certification or equivalent (US sites) or VQA certification (non-US sites). 
 
Note: If plasma HIV-1 RNA has been drawn for clinical care within the last 45 
days, it may be used. This laboratory does not have to provide documentation of 
GCLP or EQA. 
 
6.3.9 Pharmacokinetic Sampling  
 
Plasma will be obtained for LNG concentrations. Participants will have blood 
sampling within 30 minutes prior to LNG EC administration, and then 0.5, 1, 1.5, 
2, 3, 4, 6, 8, 24, and 48 hours after administration of LNG EC. Participants may 
leave the clinical site after the 8 hour sample, and return for the 24- and 48-hour 
samples.  
 
From the same samples collected for LNG analysis, measurement of EFV 
(Groups A and B), DTG (Group C), and RIF (Group D) concentrations will occur. 
EFV will be assessed from a sample collected 12-20 hours after the last dose of 
EFV. DTG or RIF will be assessed from a plasma sample collected 20-28 hours 
after the last dose of DTG or RIF. To accommodate this timing, EFV should be 
administered in the evening prior to the entry PK visit and if RIF or DTG are 
given in the morning, collect pre-dose LNG sample prior to administered DTG or 
RIF. See the MOPS for further instructions on timing. 
 
The three doses of EFV, DTG, or RIF prior to the entry PK sampling period 
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during the Day 0 PK visit should be documented. On Day 1 and Day 2, 
document any EFV, DTG, or RIF dose administered since the previous visit.   
 
Additional details regarding LNG, ART, or RIF PK, please see section 11.3, the 
MOPS, and the laboratory processing chart (LPC) found on the A5375 PSWP.   
 
6.3.10 Whole Blood for Pharmacogenetic Assessment 
 
A single whole blood sample will be obtained from all study participants for 
human genotyping of polymorphisms that have been associated with metabolism 
and/or transport of the study drugs, including EFV (e.g., CYP2B6), RIF (e.g., 
SLCO1B1), and LNG. See the LPC on the A5375 PSWP for details regarding 
processing and shipping. 
 
If the whole blood for drug metabolism genotype is not obtained at entry, this 
sample may be obtained at any later visit. 
 
6.3.11 Hair Sampling 
 
Hair samples will be collected per the SOE from participants to measure 
concentrations of EFV (Groups A and B), DTG (Group C), and INH (as a 
surrogate of adherence to RIF in Group D), to evaluate adherence to ART or 
anti-TB therapy at the time of LNG EC administration. Participants may opt-out 
of the hair collection procedure and remain enrolled in the study. 
 
Please see section 11.3, the MOPS, and the LPC found on the A5375 PSWP for 
more details regarding hair sampling.   
 
6.3.12 Adherence Assessment (ART and TB drugs) 
 
Adherence to ART or TB drugs will be assessed per the SOE using the ACTG 
self-report questionnaires completed by the participant or completed with the 
help of site staff (counselor- or nurse-driven). Adherence to the relevant ART or 
TB drug at study entry will be further verified by collecting a plasma and hair 
specimen on that day for measuring ARV or INH/RIF concentrations. For sites 
with clinics located at a different location from the TB and ARV clinic, study staff 
will be encouraged to work closely with TB and ARV providers for monitoring of 
adherence to medication. 
 
The adherence eCRF is posted on the DMC Portal in the Forms Management 
Utility. 
 
6.3.13 Acceptability and Practicality Questionnaire 
 
The acceptability and practicality questionnaire will collect information about the 
participant’s experience of side effects known to be associated with LNG EC 
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relationship status, level of education, prior experience with EC, sex that could 
lead to pregnancy, and pregnancy intention. 
 
At entry, the acceptability and practicality questionnaire will be collected via 
participant interview and entered on the questionnaire. An entry, the Current 
Symptoms portion of this questionnaire should be collected prior to LNG 
dose receipt. 
 
NOTE: The discomfort/bothersome scale in the Current Symptoms 
questionnaire is NOT equivalent to the DAIDS grading table for reportable 
adverse events (please refer to protocol section 7.2), which has particular 
and more rigorous criteria the event must fulfill to be reported. 
 
Post-entry, the acceptability and practicality questionnaire may be collected by 
remote contact interview or during a site visit. 
 
Questionnaires are posted on the DMC Portal in the Forms Management Utility. 
 
6.3.14 Site Acceptability and Practicality Questionnaire 
 
Each participating site will complete a Site Acceptability and Practicality 
Questionnaire per the Schedule of Site Evaluations (Table 6.1-2). 
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
 
7.1 
Definition of Adverse Events 
 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or diagnosis that occurs in a study participant during the 
conduct of the study REGARDLESS of the attribution (i.e., relationship of event to  
medical treatment/study product/device or procedure/intervention). This includes any 
occurrence that is new in onset or aggravated in severity or frequency from the baseline 
condition.  
 
7.2 
Adverse Event Collection Requirements for this Protocol 
 
AEs must be recorded on the eCRFs if any of the following criteria have been met: 
• 
All Grade ≥3 AEs considered potentially or definitely related to LNG 
• 
All Grade ≥2 nausea 
• 
All Grade ≥2 diarrhea  
• 
All Grade ≥2 menorrhagia or metrorrhagia 
• 
Ectopic pregnancy (see EAE reporting requirements section 7.3.2) 
• 
All AEs meeting Serious Adverse Event (SAE) definition or Expedited Adverse Event 
(EAE) reporting requirement 
 
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Note B:  Events meeting EAE reporting requirements should also be entered into the 
DAIDS Adverse Experience Reporting System (DAERS), an Internet-based 
reporting system. 
 
All AEs that are reported must have their severity graded. To grade AEs, sites must refer 
to the DAIDS AE Grading Table, corrected Version 2.1, July 2017.  
 
In addition, Addendum 1, Female Genital Grading Table for Use in Microbicide Studies, 
Version 1.0 – November 2007, will be used for vaginal symptoms and abnormal uterine 
bleeding unrelated to pregnancy.  
 
Both grading tables are available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables. 
 
Serious Adverse Events (SAEs) 
An SAE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above. 
 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS 
 
7.3.1 Expedited Reporting of Adverse Events to DAIDS 
 
Requirements, definitions and methods for expedited reporting of Adverse 
Events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual, which is 
available on the RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/manual-expedited-reporting-adverse-events-daids. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based 
reporting system, must be used for EAE reporting to DAIDS. In the event of 
system outages or technical difficulties, EAEs may be submitted using the DAIDS 
EAE Form. This form is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. 
 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Please note that site queries may also be sent 
from within the DAERS application itself. 
 
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Office at DAIDSRSCSafetyOffice@tech-res.com. 
 
7.3.2 Reporting Requirements for this Study 
 
• 
The suspected, unexpected serious adverse reaction (SUSAR) Reporting 
Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be used 
for this study. 
• 
The study agent for which expedited reporting is required is: levonorgestrel 
emergency contraception (LNG EC). 
• 
In addition to the EAE Reporting Category identified above, other AEs that 
must be reported in an expedited manner are:  
o Ectopic pregnancies. 
 
7.3.3 Grading Severity of Events 
 
The DAIDS AE Grading Table corrected Version 2.1, July 2017, must be used.  
 
In addition, Addendum 1, Female Genital Grading Table for Use in Microbicide 
Studies, Version 1.0 – November 2007, will be used for vaginal symptoms and 
abnormal uterine bleeding unrelated to pregnancy. 
 
Note: normal menses are not a reportable event.  
 
Both grading tables are available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables. 
 
7.3.4 Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is as per the DAIDS EAE 
manual.  
• 
After the protocol-defined EAE reporting period, unless otherwise noted, only 
SUSARs, as defined in Version 2.0 of the DAIDS EAE Manual, will be 
reported to DAIDS if the study staff become aware of the events on a passive 
basis (from publicly available information). 
 
7.4 
Study Monitoring 
 
The protocol core team will monitor the conduct and safety of the study via regular 
summaries of accrual, study discontinuation, data completeness, and AEs, as appropriate.  
 
The DAIDS Clinical Representatives will review and assess select EAE reports for 
potential impact on study participant safety and protocol conduct as per DAIDS policies, 
guidance documents, and SOPs, as applicable. Additionally, the DAIDS Clinical 
Representative will review aggregated adverse event summaries by open-label group as 
distributed in the core team monitoring report described above, which will be 
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The study will undergo interim review at least annually by an ACTG-appointed Study 
Monitoring Committee (SMC). The first interim review will occur no more than 1 year 
after the enrollment of the first study participant or 3 months after 25 women have 
completed the study, whichever occurs earlier. An interim review may also be convened 
if a concern is identified by the DAIDS Clinical Representative, the study chairs, or study 
statistician in consultation with the team. See section 10.0 for statistical and other 
considerations related to interim monitoring. 
 
Detailed plans for study monitoring will be outlined in a Study Monitoring Plan developed 
by the Statistical and Data Management Center (SDMC) prior to enrollment of the first 
participant. 
 
8.0 
CLINICAL MANAGEMENT  
 
8.1 
Toxicity  
 
Toxicities will be evaluated and managed by the site staff in close consultation with the 
participants’ primary care clinicians. Ongoing communication between the ACTG site 
staff and the participants’ clinicians is encouraged. If a toxicity is identified, the ACTG 
site staff is encouraged to communicate with primary care providers as soon as possible. 
 
If TB medication or ART is held for toxicity by the primary care physician, participants 
must inform the site staff. Information about these treatment modifications/interruptions 
must be recorded on the source document and eCRF. 
 
Grades 1 and 2: Can be managed as per standard of care by the study doctor or local 
physician. 
  
Grades 3 and 4: Participants must be stabilized and referred immediately to obtain 
treatment at local hospital, if required.  
 
Vaginal Bleeding: Grade ≥2 must be closely monitored and managed as per standard of 
care. 
 
Diarrhea: Grade 2 should be managed per standard of care by the study doctor or local 
physician. Participants with Grades 3 and 4 diarrhea must be stabilized and referred. 
 
8.2 
Pregnancy  
 
Pregnancy and pregnancy outcome will be recorded on the eCRFs. Pregnancies that 
occur on study should be reported prospectively to The Antiretroviral Pregnancy 
Registry. More information is available at www.apregistry.com. Telephone: 800-258-
4263; Fax: 800-800-1052. (For studies conducted at sites outside the United States, 
report to The Antiretroviral Pregnancy Registry—Telephone: 910-679-1598; Fax: 44-
1628-789-666 or 910-256-0637.) 
 


 
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Pregnancy Outcomes and Reporting 
If a woman has completed the study or chooses to discontinue from the study before the 
end of the pregnancy, then site staff should request permission to contact her regarding 
pregnancy outcomes at the end of pregnancy. If the information is obtained, pregnancy 
outcomes will be submitted on an eCRF at the end of the pregnancy.  
 
8.3 
Breastfeeding 
 
Breastfeeding is discouraged at sites where alternative feeding options are feasible and 
available. Sites should follow local guidelines to prevent mother-to-child transmission 
during breastfeeding.  
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Premature Treatment Discontinuation 
 
Because the study treatment is a single dose, this section does not apply. See section 
9.2 for Study Discontinuation. 
 
9.2 
Premature Study Discontinuation 
 
• 
Participant fails to complete PK specimen draws over the 8-hour period following 
study treatment 
• 
Participant fails to initiate/take study treatment within 7 days of enrollment  
• 
Participant has a positive pregnancy test prior to LNG EC administration 
• 
Request by the participant to withdraw  
• 
Request of the primary care provider if she or he thinks the study is no longer in the 
best interest of the participant 
• 
At the discretion of the IRB/EC, FDA, NIAID, Office for Human Research Protections 
(OHRP), other government agencies as part of their duties, or investigator  
 
Note: If the participant discontinues before evaluations for the primary outcome have 
been completed, the participant will be replaced. 
 
10.0 
STATISTICAL CONSIDERATIONS  
 
10.1 
General Design Issues 
 
A5375 is a Phase II, prospective, partially randomized, open-label, multi-center 
controlled clinical trial designed to investigate the appropriate dosing of “single dose” 
levonorgestrel (LNG – intended to be used as EC), among women who are taking 
medications that might have PK interactions with LNG, such as particular anti-HIV ART 
regimens or an anti-TB regimen. This parallel group, DDI PK study has two directly 
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women on DTG-containing ART regimens and women on RIF-containing TB regimens 
will be directly assigned to Groups C and D, respectively; and women on EFV-containing 
ART regimens will be randomized in a 1:2 ratio to Groups A and B, respectively.   
 
Study treatment is LNG EC given once following entry evaluation completion in a directly 
observed manner: Groups A and C will receive standard dose of LNG 1.5 mg, and 
Groups B and D will receive double dose of LNG 3.0 mg. Absence of blinding does not 
affect study integrity via bias due to a number of study design factors including the 
following: directly observed administration of a study treatment that consists of only a 
single dose (i.e., one time versus longitudinal intervention), and the primary study 
outcome is an objectively assessed PK parameter (AUC). The key study evaluation is an 
intensive, 8-hour PK sampling around this one dose of study treatment. Length of study 
follow-up is 4 weeks for each participant, but follow-up subsequent to the 48-hour PK 
assessment will be performed remotely. 
 
Women on the qualifying targeted concomitant medication regimens must not be 
pregnant, within 6 weeks postpartum, breastfeeding an infant under 6 months of age, or 
currently using other hormonally based contraception. 
 
The primary completion date for each woman is one day after study treatment 
administration. 
 
10.2 
Outcome Measures 
 
10.2.1 Primary Outcome Measure 
 
10.2.1.1 Area under the Curve over 8 hours (AUC0-8h) for LNG. 
 
10.2.2 Secondary Outcome Measures  
 
10.2.2.1 Safety: Occurrence of any SAE potentially or definitely related to LNG, 
or occurrence of reportable AEs potentially or definitely associated with 
LNG EC use (see section 7.2 for list of targeted AEs) during study 
follow-up. 
 
10.2.2.2 PK estimates of LNG including the following: maximum concentration 
(Cmax), minimum concentration (Cmin), oral clearance (CL/F), volume of 
distribution (Vd), half-life (T1/2), time to minimum concentration 
(Tmin), and area under the Curve over 24 hours (AUC0-24h), 48 hours 
(AUC0-48h), and AUCinf (infinity) of LNG.  
 
10.2.3 Exploratory Outcome Measures  
 
10.2.3.1 Concentration of targeted concomitant medication (e.g., DTG, EFV, 
and INH) in hair sample collected at entry as measure of long-term 
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10.2.3.2  Specific plasma concentration of targeted concomitant medication 
(e.g., trough of DTG or RIF, mid-dose concentration of EFV). 
 
10.2.3.3  Human genetic variants/polymorphisms that are known to affect PK of 
EFV, DTG, RIF, or LNG (e.g., CYP2B6, SLCO1B1). 
 
10.2.3.4 
Acceptability and practicality of LNG based on participant self-report 
via study-specific questionnaires. 
 
10.3 
Randomization and Stratification 
 
Enrollment to the study is deterministic (not-randomized) for participants who are 
currently taking either DTG based ART regimens, or RIF-containing anti-TB regimens; 
these women are directly assigned to Groups C and D, respectively. Participants on 
EFV-containing ART regimens will be randomized between Groups A (1.5 mg LNG) and 
B (3.0 mg LNG) in a 1:2 ratio using permuted block randomization that is dynamically 
balanced within each institution. To guard against potential confounding due to body 
weight or BMI of the participant, enrollment will be limited by BMI in the following 
manner. Women with BMI ≥30 kg/m2 will be limited to no more than five within Groups B-
D and no more than three within Group A. Therefore, the overall representation of obese 
women in the study sample will be limited to no more than 15%. The results of either 
randomization or enrollment to treatment group will be unblinded to participants, and 
clinical research site staff. 
 
10.4 
Sample Size and Accrual [53, 78-80] 
 
Given that a therapeutic target for minimum exposure required or average exposure 
expected for single dose use of LNG as emergency contraception (EC) is unknown, this 
study is estimating whether adjusted dosing of LNG under a known DDI achieves similar 
exposure to LNG single dose as measured by the geometric mean ratio (GMR) of the 
AUC of LNG concentrations over the 8 hours post dose. The study design was 
developed under the constraints of requiring a parallel groups design (rather than a 
crossover design using healthy controls), practicalities of number of available 
participants to enroll and complete the study in a reasonable timeframe, and how the 
features of this highly variable drug (LNG) result in both power to test for bioequivalence 
as defined by a specified interval about equivalence, and precision of GMR estimates by 
the width of the 90% confidence interval.  
 
The effective sample sizes of 30 women in Groups B-D and 15 women in Group A were 
chosen to provide adequate statistical precision about the estimated GMR, which 
compares arms in order to address the primary study objectives [54]. See below for the 
total sample size enrollment, which includes how these effective samples sizes are 
inflated slightly to accommodate missing primary outcome data.   
 


 
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Table 10.4-1: Sample size per arm (prior to inflation for replacements) 
 
Assumptions: Sample size required to give 80% probability (power) to conclude 
bioequivalence defined as the 90% CI for the GMR being entirely within the No-effect 
Bounds (NEB). Various NEBs are provided for BE given that bounds of (80%, 125%) 
may be considered too conservative for highly variable drugs with a wide therapeutic 
ranges in PK exposure. [Note: Calculations use 5% significance level with two, one-
sided tests (TOSTs) testing procedure.] 
 
Sample Sizes per Arm 
in Table 
Coefficient of Variation Estimates* 
0.45 
0.70 
0.90 
Alternative Hypothesis  
(True GMR): 
100% 
95% 
90% 
100% 
95% 
90% 
100% 
95% 
90% 
NEB : (67%,150%) 
20 
22 
27 
43 
45 
57 
63 
67 
84 
NEB : (70%,143%) 
26 
28 
37 
55 
59 
79 
81 
87 
117 
NEB : (75%,133%) 
40 
45 
72 
85 
97 
154 
126 
144 
228 
 
*Note: CV for AUC(0-24hr) ranged from 0.45 to 0.90 in the individual arms of PK study of 
LNG-EC and St. John’s Wort (Time period 1 when LNG-EC given alone, ref ct.gov 
NCT00131885). Package insert for LNG CV(AUC24hr)=0.7. Data not available for CV of 
AUC or LNG-EC under shorter time frames. 
 
Summary of Table 10.4-1. Because primary outcome of current study is AUC(0-8hr), it is 
assumed that the CV for this study may be on the lower range of published AUCs(LNG) 
over 24 hours. Furthermore, the sample sizes for CV ≥ 0.7 result in study sizes beyond 
feasibility for execution. NEBs of (80%, 125%) are not given in the table as the required 
sample would be too large, even under assumed CV=0.45. 
 
Table 10.4-2: Statistical Power assuming n=30 per arm (prior to inflation for 
replacements) 
 
Assumptions: same as Table 10.4-1 above [NEB = No-effect bounds] 
 
Statistical Power 
Estimates in Table 
Coefficient of Variation 
0.45 
0.70 
0.90 
Alternative Hypothesis  
(True GMR): 
100% 
95% 
90% 
100% 
95% 
90% 
100% 
95% 
90% 
NEB : (67%,150%) 
95% 
93% 
85% 
58% 
56% 
50% 
29% 
28% 
25% 
NEB : (70%,143%) 
88% 
84% 
72% 
40% 
38% 
33% 
12% 
12% 
10% 
NEB : (75%,133%) 
63% 
58% 
45% 
9% 
9% 
7% 
0% 
0% 
0% 
 
Summary of Table 10.4-2 Assuming CV(AUC0-8hr) = 0.45, and other design 
assumptions above, BE bounds of either (67%, 150%) or (70%, 143%) provide high 
statistical power, even under modest departures from equivalence alternative (e.g., true 
GMR of between 90% and 100%). The study design is not well powered for NEBs 
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(i.e., true GMRs of less than 90%). Please see references [53, 78-80] that show 
precedence for using NEBs of (70%, 143%) in similar situations. 
 
Table 10.4-3: Some CI estimates under various alternatives (sample size 30 per arm 
before inflation for replacements and same assumptions above)—simulation results. 
 
Because the study analysis plan is focused on estimation of the GMR of AUC(LNG) and 
90% CI about the estimated (observed) GMR, the following table is provided to augment 
the sample size/power tables above. 
 
Alternative 
Hypothesis 
(True GMR) 
CV=0.45 
CV = 0.75 
Q1 
Observed 
GMR 
Q3 
Observed 
GMR 
Median 
Observe
d GMR 
Typical 90% 
CI (median 
LCB and UCB) 
Q1 
Obser
ved 
GMR 
Q3 
Obser
ved 
GMR 
Median 
Observ
ed 
GMR 
Typical 90% 
CI (median 
LCB and 
UCB) 
100% 
93% 
108% 
100% 
(83%, 120%) 
90% 
115% 
100% 
(75%, 133%) 
95% 
87% 
103% 
95% 
(79%, 115%) 
83% 
108% 
95% 
(72%, 127%) 
90% 
84% 
96% 
89% 
(74%, 107%) 
81% 
102% 
90% 
(68%, 120%) 
85% 
79% 
93% 
85% 
(71%, 102%) 
74% 
95% 
84% 
(63%, 112%) 
 
Alternative  
Hypothesis  
(True GMR) 
CV=0.90 
Q1 Observed 
GMR 
Q3 Observed  
GMR 
Median 
Observed GMR 
Typical 90% CI 
(median LCB and 
UCB) 
100% 
88% 
116% 
102% 
(73%, 141%) 
95% 
83% 
110% 
96% 
(69%, 134%) 
90% 
76% 
103% 
89% 
(64%, 124%) 
85% 
74% 
97% 
86% 
(61%, 119%) 
 
Summary of Table 10.4-3. Under modest departures from equivalence, the 90% CI 
about estimated GMRs observed to be 85% or closer to equivalence (100%) are 
expected to be bounded above the BE LCB of 70%. 
 
The effective sample size for randomized Group A (15) is based on the secondary 
objective for a superiority hypothesis (rather than equivalence testing as in the primary 
study objectives), comparing the randomized Groups A and B (n=30). Here, the ratio is 
B/A so that the anticipated raw scale ratios are >100 and the significance level has been 
adjusted to 0.05 so that a 2-sided 95% CI is calculated and compared to see if the 
confidence interval excludes 100. There is at least 80% power to conclude a difference 
between the randomized groups for LNG AUC when the true difference between groups 
is that the increased dose has at least 47% larger AUC of LNG than the standard-dose 
(or estimated ratio 147.5). A 95% CI for this estimated ratio would be (112, 194). 
 
A participant is considered to be evaluable for the primary objective if the participant 
completes the 8 hour PK sampling after LNG EC administration. The participant 
replacement criteria are described in section 9.0. Participants who are not evaluable for 
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Considering the sample size calculations above, and to protect against 10% loss of the 
primary outcomes after study accrual is closed, (e.g., problems related to laboratory 
analysis), the adjusted sample size for this four-group study is 116 female participants—
33 each in Groups B-D, and 17 in Group A. (In another ACTG contraception study, 
A5093, the loss of the primary outcomes of week 12 was 9.8% [6 of 61 participants] due 
to either sample specimen loss or assay results not available.) 
 
Complete accrual to all study groups is anticipated to take between 1 year to 18 months. 
However, it is not assumed for this accrual to be uniform over this time period. Due to 
differences in regulatory approvals in different locations, it is anticipated that accrual 
during the first 6 months of the study may by exclusively from US sites. But it is 
anticipated that accrual will be rapid following the approval of the study at non-US CRSs. 
As an example, in a recent ACTG PK study investigating DDIs between ART and 
another contraceptive (A5316: NCT01903031), accrual within the first 6 months 
following first enrollment was only within the US and accounted for only 20% of total 
study accrual. However, in the following 6 month period when sites from an additional 6 
countries were available, over 55% of the total study sample was accrued (and thus 77% 
of total study accrual occurred within 1 year). Therefore, it is anticipated that only 20% of 
the total sample size (or 23) women might be enrolled during the first 6 months following 
first participant enrollment, and that the remaining accrual will occur in the subsequent 6-
12 months (which assumes enrollment of 8-16 women per month over this time period). 
Please see below for contingencies regarding a possible additional interim review if the 
total accrual at 12 months following first enrollment is <50% of the total sample size (i.e., 
fewer than 58 women). 
 
10.5 
Data and Safety Monitoring  
 
10.5.1 Interim Monitoring Guidelines 
 
This study will be formally monitored at least annually by an ACTG-appointed 
SMC (via the standing committee for the ARTS TSG). The first interim review will 
occur no more than one year after the enrollment of the first participant or 3 
months after 25 women have completed the study, whichever occurs earlier. An 
additional SMC review may be triggered if the accrual at one year is less than 
50% of total expected accrual (e.g., fewer than 58 of 116 women across all 4 
arms). This additional review, under the contingency of very slow accrual, would 
provide an opportunity for the SMC to review the available estimate of coefficient 
of variation of the AUC of LNG(0-8hrs) in order to see if the calculated CV varies 
greatly from the CV estimate used above to support the study size/design. Due to 
the two-stage testing workflow to achieve PK parameter estimates from blood 
samples, and the desire not to increase the study budget by requiring expedited 
shipping or testing, the timeframe for this additional review could be 6 months or 
longer. 
 
Outside of this additional review contingency plan, there are no plans to initiate 
PK testing prior to completion of a primary objective, and thus no planned early 
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An unplanned interim review will be triggered if, at any time, any participant 
experiences an SAE that is attributed to LNG (by adjudication by the core team 
and DAIDS clinical representative), or if more than five women need to be 
replaced (as per the guidelines for replacement as described in section 9.2) in 
the overall study sample. An SMC review can also be requested at any time at 
the request of the team or sponsor.   
 
Note: Eligibility and enrollment issues that cause participant replacement 
will not be included as an SMC trigger. The participant replacement interim 
review trigger will be determined based strictly on criteria stated in section 
9.2 (Premature Study Discontinuation) of the protocol. 
 
Any/all SMC reviews will include administrative/trial conduct data as well as 
safety data according to the safety-related outcomes enumerated above. 
 
Routine monitoring reports are distributed to core team and are detailed in the 
study monitoring plan (SMP): screening, accrual, data delinquency, study status, 
data and sample completeness, with attention to intensive PK sampling for the 
primary efficacy outcome. The routine safety monitoring report is distributed to 
the DAIDS Clinical Representative and a subset of the core team (to include the 
study chairs) every 3 months. 
 
Further details about monitoring of this study are available in the SMP. 
 
10.6 
Analyses 
 
If accrual to study groups is such that one primary objective is able to be addressed 
before the other due to unequal accrual rates, then the team will plan to perform final 
analyses that include completely accrued groups, even if accrual is still occurring to 
groups required for the other primary objective. This is because it is anticipated that 
each primary objective can be published independently. 
 
10.6.1 Primary Efficacy Analysis 
 
The primary efficacy outcome of AUC of LNG PK over 8 hours will be calculated 
using the trapezoidal rule (i.e., noncompartmental technique) as described in 
section 11.3 below, using all observed data. As women not taking LNG will not 
have PK samples drawn, and any woman not having complete data to assess 8 
hour AUC for any reason will be replaced, these observed data will be per-
protocol and will have already excluded women for non-adherence to LNG or 
other protocol deviations that prevent primary outcome assessment. If participant 
self-reported short term non-adherence to the other targeted medications (either 
ARVs or RIF) were such that the PK samples should not have been collected, 
but were collected in error, then these women will also be replaced, and samples 
will not be sent for PK testing. Please see section 11.0 of the protocol for more 
information on the derivation of the primary efficacy outcome. 
 


 
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Each of the two primary objectives will be analyzed as follows. Assessing if 
increased dose of LNG overcomes DDI with EFV will be assessed by a 
comparison of randomized Group B to directly assigned Group C. Assessing if 
increased dose of LNG overcomes DDI with RIF will be assessed by a 
comparison of directly assigned Group D to directly assigned Group C. 
Therefore, in each of these primary objectives, the direct assignment Group C 
(i.e., women on DTG ARV regimen with standard-dose LNG) serves as the 
control group. Neither of these parallel group comparisons is based on 
randomization, and thus prior to primary analysis, the distribution of potential 
baseline confounding factors will be examined between pairwise groups for 
imbalance. A key factor is race; BMI is not expected to have significant 
imbalance due to enrollment limits placed on each group for women with BMI ≥ 
30 kg/m2. 
 
Descriptive analysis will include the following: a) plots of the concentrations of 
LNG over time for will be provided to inform the derivation of the primary AUC 
outcome and other PK parameters (secondary outcomes); b) plots of the 
summary statistics of concentrations over time by treatment group; c) descriptive 
statistics of the primary outcome, including mean, standard deviation, median, 
interquartile range, minimum, and maximum of the primary outcome, will be 
presented by each study group.  
 
The between group statistic that compares AUC(0-8hr of LNG) is the geometric 
mean ratio (GMR). The geometric mean and 95% confidence interval about the 
geometric mean of the primary outcome will be provided by each group. The 
GMR between Groups B and C (for the EFV objective) and between Groups D 
and C (for the RIF objective) will be presented. The 90% confidence intervals 
about the two pairwise GMRs will be compared to the FDA reference standard 
for bioequivalence in order to determine if LNG AUC is similar between AUC of 
LNG increased dose versus standard dose in each of the primary objective 
comparisons. Note that because of the high variability of the PKs of LNG, the 
bioequivalence interval will be (70%, 143%). 
 
10.6.2 Primary Safety Analysis 
 
Occurrence of the safety outcomes (i.e., number of participants meeting a safety 
outcome) as defined above will be enumerated and summarized by individual 
study group. Safety outcomes may be summarized separately by severity grade 
or type (category or MedDRA grouping) of adverse event. 
 
The secondary objective of comparing safety between standard and increased 
doses will be achieved by a comparison of the relative number of participants 
with safety outcome in Groups A+C (or collectively the standard-dose groups) 
versus the relative number of participants with this outcome in Groups B+D (or 
collectively the increased dose groups). The statistical hypothesis test for this 
comparison will be a Fisher’s exact test. This comparison may also be repeated 
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are analyzed separately: (1) randomized Group A versus randomized Group B, 
which is a randomized comparison and is restricted to HIV+ women taking EFV 
(2) assigned Group C versus assigned Group D.  
 
Since this study is not powered to compare occurrence of AEs between LNG 
double dose versus single dose, inference related to comparisons above will 
focus on describing the magnitude and range of plausible values of observed 
differences between groups, and will not conclude similarity based on the 
absence of significant differences by Fisher’s exact test. 
 
10.6.3 Secondary Outcomes Analysis 
 
The secondary objective of comparing increased dose of LNG EC to standard-
dose among women on EFV (randomized comparison), will use analyses parallel 
to the primary outcome analysis as described above. However, since the 
hypothesis for this objective is superiority (rather than equivalence), the statistical 
inference for examination of the confidence interval about the GMR will focus 
whether this interval includes or excludes 1 (in which a significance difference 
can be concluded). Conclusions will focus on the estimations and plausible 
values of the GMR between LNG doses within this EFV comparison. Note this 
comparison is not subject to confounding because it is randomized comparison.  
A similar, non-randomized comparison will be performed between randomized 
Group A and control, directly assigned Group C. 
 
Analyses for other PK parameters of LNG will follow an analysis plan parallel to 
the primary outcome as described above.  Note that derivation of these PK 
parameter outcomes are according to specifications in section 11.0 below. 
 
Other adverse events (that do not meet the primary safety outcome) and side 
effects between single dose and double dose may be compared either separately 
by group, or collapsed over group by LNG dosing (single vs. double). 
 
Further details are outlined in the study’s Statistical Analysis Plan (SAP). 
 
10.6.4 Exploratory Outcomes Analysis 
 
All host genotypes will be treated as ordinal variables (as 3 levels for individual 
SNPs, and either 3 or 12 levels for composite CYP2B6/CYP2A6 genotypes). For 
each SNP or genotype, associations with PK concentrations with the AUC of 
LNG will be evaluated. The primary focus will be on SNPs/genotypes with very 
strong a priori evidence for effect on drug exposure (i.e., CYP2B6/CYP2A6 SNPs 
for efavirenz, UGT1A1 for dolutegravir). For example, we will explore whether 
CYP2B6/CYP2A6 genotypes that are known to predict higher plasma efavirenz 
concentrations are also associated with lower levonorgestrel concentrations.  
 


 
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Side effects, tolerance, and acceptability of LNG will be summarized across 
participants grouped by LNG dose. 
 
Further details are outlined in the study’s Exploratory Statistical Analysis Plan.  
 
11.0 
PHARMACOLOGY PLAN 
 
11.1 
Pharmacology Objectives 
 
See section 1.0 for study objectives. 
 
11.2 
Pharmacology Study Design 
 
This is a pharmacology study, thus, the pharmacology study design is specified in the 
overall study design described in section 6.3.9. 
 
11.3 
Primary and Secondary Data, Modeling, and Data Analysis 
 
LNG analysis 
The PK parameters for LNG include: maximum concentration (Cmax), time to maximum 
concentration (Tmax), minimum concentration (Cmin), time to minimum concentration 
(Tmin), oral clearance (CL/F), volume of distribution (Vd), elimination half-life (T1/2), and 
area under the concentration-time curve over 8 hours (AUC0-8h), 24 hours (AUC0-24h), 48 
hours (AUC0-48h), and to infinity (AUCinf). Standard noncompartmental techniques will be 
used to determine these PK parameters using the software package Phoenix WinNonLin 
(Certara®). The AUC (including the primary outcome) will use the linear up/log down 
version of the trapezoidal rule.  This version of the trapezoidal rule uses linear 
interpolation between untransformed data up to Cmax, and between log-transformed data 
from Cmax through Clast [81, 82]. Cmax will be taken as the maximum observed 
concentration. Tmax is the time at which Cmax occurs. Cmin will be taken as the minimum 
observed concentration after the observed dose. Apparent oral clearance will be 
calculated as CL/F = dose/AUC0-24 or CL/F = dose/AUC0-48. The T1/2 will be determined 
using regression analysis when possible.  
 
ART or RIF exposure in plasma 
EFV, DTG, or RIF will be quantitated from aliquots of the same samples collected to 
assess LNG according to section 6.3.9. The concentrations will be at a single time point; 
therefore, no PK parameters will be calculated.  
 
For participants receiving EFV: EFV will be measured in a plasma sample collected 12-
20 hours after the last dose of EFV. Efavirenz should be administered in the evening 
prior to PK visits. 
 
For participants receiving DTG or RIF: DTG or RIF will be measured in a plasma 
sample collected 20-28 hours after the last dose of DTG or RIF. If DTG or RIF is being 
administered in the morning, the pre-LNG dose sample at entry should be collected 
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See MOPS for further discussion of dose timing in relation to PK sampling at entry. 
 
Hair analysis 
Hair levels will be evaluated as continuous variables, possibly using logarithmic 
transformation if their distribution is skewed. Values below the detection limit will be 
counted as equal to the detection limit. We will examine scatterplots and calculate 
Spearman correlation coefficients for hair levels with plasma concentrations, we will also 
examine the correlation between SNPs in the genes implicated in EFV metabolism (e.g., 
CYP2B6) and hair concentrations of EFV. 
 
Pharmacogenetic analyses 
For all study participants who provide DNA for genetic testing, assays will be performed 
for polymorphisms in genes relevant to study drugs and concomitant medications (e.g., 
CYP2B6/CYP2A6 SNPs for efavirenz, UGT1A1 for dolutegravir). Associations will be 
explored between selected genetic polymorphisms and outcome measures as described 
in section 10.0. 
 
11.4 
Anticipated Outcomes 
 
These PK studies will provide information on plasma concentrations of LNG when used 
as EC in participants taking EFV or RIF. The PK data for LNG will fill gaps in our 
knowledge, about possible EC options in women receiving EFV-based ART and RIF-
based TB treatments.   
 
12.0 
DATA COLLECTION AND MONITORING  
 
12.1 
Records to Be Kept 
 
Electronic case report form (eCRF) screens will be made available to sites for data entry. 
Participants must not be identified by name on any data submitted to the DMC. 
Participants will be identified by the patient identification number (PID) and study 
identification number (SID) provided by the ACTG DMC upon randomization/registration. 
 
12.2 
Role of Data Management 
 
12.2.1 Instructions concerning entering study data on eCRFs will be provided by the 
ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
12.2.2 It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 


 
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12.3 
Clinical Site Monitoring and Record Availability 
 
12.3.1 Site monitors under contract to the NIAID will visit participating clinical research 
sites to review the individual participant records, including consent forms, eCRFs, 
supporting data, laboratory specimen records, and medical records (physicians’ 
progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection 
of study participants, compliance with the protocol, and accuracy and 
completeness of records. The monitors also will inspect sites’ regulatory files to 
ensure that regulatory requirements are being followed and sites’ pharmacies to 
review product storage and management. 
 
12.3.2 The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, eCRFs) and pertinent hospital or clinic records readily 
available for inspection by the local IRB, the site monitors, the FDA, the NIAID, 
the OHRP, other local, US, and international regulatory entities for confirmation 
of the study data. 
 
13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent documents (Appendices I-III) and any 
subsequent modifications will be reviewed and approved by the IRB or EC responsible 
for oversight of the study. A signed consent form will be obtained from the participant (or 
parent, legal guardian, or person with power of attorney for participants who cannot 
consent for themselves, such as those below the legal age of consent). The consent 
form will describe the purpose of the study, the procedures to be followed, and the risks 
and benefits of participation. A copy of the consent form will be given to the participant, 
parent, or legal guardian, and this fact will be documented in the participant’s record. 
 
13.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, FDA, NIAID, 
OHRP, or other local, US, and international regulatory entities as part of their duties. 
 
13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
or other country-specific government agencies as part of their duties to ensure that 
research participants are protected. 
 


 
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14.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. 
 
15.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the CDC and the 
National Institutes of Health. 
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  


 
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16.0 
REFERENCES 
 
1. Joint United Nations Programme on HIV/AIDS. Global AIDS Update 2016. Geneva: 
UNAIDS; 2016. 
2. Joint United Nations Programme on HIV/AIDS. When women lead, change happens. 
Geneva: UNAIDS; 2017. 
3. World Health Organization. Global Tuberculosis Report 2015. Geneva: WHO; 2015. 
4. U.S. Agency for International Development. Fact Sheet: The Twin Epidemics: HIV and 
TB Co-infection. U.S. Agency for International Development (USAID); 2014. [Online]. 
Available: https://www.usaid.gov/news-information/fact-sheets/twin-epidemics-hiv-and-
tb-co-infection. [Accessed: 06-Oct-2017]. 
5. De Cock KM, Soro B, Coulibaly IM, Lucas SB. Tuberculosis and HIV infection in sub-
Saharan Africa. JAMA 1992;268:1581-7. 
6. Wilkinson D, Moore DA. HIV-related tuberculosis in South Africa--clinical features and 
outcome. S Afr Med J 1996;86:64-7. 
7. Swaminathan S, Ramachandran R, Baskaran G, et al. Risk of development of 
tuberculosis in HIV-infected patients. Int J Tuberc Lung Dis 2000;4:839-44. 
8. Narain JP, Raviglione MC, Kochi A. HIV-associated tuberculosis in developing countries: 
epidemiology and strategies for prevention. Tuber Lung Dis 1992;73:311-21. 
9. Kobayashi K, Haruta T, Maeda H, Kubota M, Nishio T. Cerebral hemorrhage associated 
with vitamin K deficiency in congenital tuberculosis treated with isoniazid and rifampin. 
Pediatr Infect Dis J 2002;21:1088-90. 
10. Rifadin (rifampin) [package insert]. Bridgewater, NJ: Sanofi-Aventis, US LLC; 2017. 
11. Batur P, Cleland K, McNamara M, Wu J, Pickle S; EC Survey Group, Emergency 
contraception: A multispecialty survey of clinician knowledge and practices. 
Contraception 2016;93:145-52. 
12. World Health Organization. Emergency Contraception. Geneva: WHO; 2017. [Online]. 
Available: http://www.who.int/mediacentre/factsheets/fs244/en/. [Accessed: 03-Nov-
2017]. 
13. Decker MR, Benning L, Webere KM, et al. Physical and sexual violence predictors. Am J 
Prev Med 2016;51:731-42. 
14. Bernstein M, Phillips T, Zerbe A, et al. Intimate partner violence experienced by HIV-
infected pregnant women in South Africa: a cross-sectional study. BMJ Open 
2016;6:e011999. 
15. World Health Organization. Responding to intimate partner violence and sexual violence 
against women. WHO clinical and policy guidelines. Geneva: WHO; 2013. 
16. Global Community Advisory Board; ACTG Community Science Subcommittee; Wei C. 
Recruitment and retention of women in ACTG trials: a guidebook of best practices. 
Women's Enrollment Initiative; 2014. 


 
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17. Lukhaimane TA, Adam Y. Women’s willingness to use emergency contraception: 
Experience at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa. 
S Afr Med J 2015;105:266-7. 
18. World Health Organization. Immunization, Vaccines and Biologicals: HIV/AIDS. Geneva: 
WHO; 2008. [Online]. Available: http://www.who.int/immunization/topics/hiv/en/. 
[Accessed: 03-Nov-2017]. 
19. World Health Organization. Updated recommendations on first-line and second-line 
antiretroviral regimens and post-exposure prophylaxis and recommendations on early 
infant diagnosis of HIV: interim guidance. Geneva: WHO; 2018. 
20. Gupta A, Juneja S, Vitoria M, et al. Projected uptake of new antiretroviral (ARV) 
medicines in adults in low- and middle-income countries: a forecast analysis 2015-2025. 
PLoS One 2016;11:e0164619. 
21. Plan B One-Step Tablet (levonorgestrel) [package insert]. Pomona, NY: Duramed 
Pharmaceuticals (Barr Pharmaceuticals); 2009. 
22. Polis CB, Schaffer K, Blanchard K, Glasier A, Harper CC, Grimes DA. Advance provision 
of emergency contraception for pregnancy prevention: a meta-analysis. Obstet Gynecol 
2007;110:1379-88. 
23. Glasier AF, Cameron ST, Fine PM, et al. Ulipristal acetate versus levonorgestrel for 
emergency contraception: a randomised non-inferiority trial and meta-analysis. Lancet 
2010;375:555-62. 
24. Carten ML, Kiser JJ, Kwara A, Mawhinney S, Cu-Uvin S. Pharmacokinetic interactions 
between the hormonal emergency contraception, levonorgestrel (Plan B), and efavirenz. 
Infect Dis Obstet Gynecol 2012;2012:137192. doi: 10.1155/2012/137192. Epub 2012 
Feb 28. 
25. Hansen LB, Saseen JJ, Teal S.B. Levonorgestrel-only dosing strategies for emergency 
contraception. Pharmacotherapy 2007;27:278-84.  
26. Johansson E, Brache V, Alvarez F, et al. Pharmacokinetic study of different dosing 
regimens of levonorgestrel for emergency contraception in healthy women. Hum Reprod 
2002;17:1472-6. 
27. Sivin I, Lahteenmaki P, Mishell DR Jr, et al. First week drug concentrations in women 
with levonorgestrel rod or Norplant capsule implants. Contraception 1997;56:317-21. 
28. Sivin I, Lahteenmaki P, Ranta S, et al. Levonorgestrel concentrations during use of 
levonorgestrel rod (LNG ROD) implants. Contraception 1997;55:81-5. 
29. Sivin I, Wan L, Ranta S, et al. Levonorgestrel concentrations during 7 years of 
continuous use of Jadelle contraceptive implants. Contraception 2001;64:43-9. 
30. Edelman AB, Cherala G, Blue SW, Erikson DW, Jensen JT. Impact of obesity on the 
pharmacokinetics of levonorgestrel-based emergency contraception: single and double 
dosing. Contraception 2016;94:52-7. 
31. Praditpan P, Hamouie A, Basaraba CN, et al. Pharmacokinetics of levonorgestrel and 
ulipristal acetate emergency contraception in women with normal and obese body mass 
index. Contraception 2017;95:464-9. 


 
63 
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32. European Medicines Agency, Emergency contraceptives, INN-levonorgestrel, ulipristal 
acetate, Assessment report. 2014. [Online]. Available: 
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Emergen
cy_contraceptives_31/WC500176385.pdf. [Accessed: 19-Jun-2018]. 
33. Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by 
the British Medical Research Council tuberculosis units, 1946-1986, with relevant 
subsequent publications. Int J Tuberc Lung Dis 1999;3(10 Suppl 2):S231-S279.  
34. Menzies D, Benedetti A, Paydar A, et al. Effect of duration and intermittency of rifampin 
on tuberculosis treatment outcomes: a systematic review and meta-analysis. PLoS Med 
2009;6:e1000146. 
35. World Health Organization. Treatment of Tuberculosis Guidelines. Geneva: WHO; 2009. 
36. Wang J, Sonnerborg A, Rane A, et al. Identification of a novel specific CYP2B6 allele in 
Africans causing impaired metabolism of the HIV drug efavirenz. Pharmacogenet 
Genomics 2006;16:191-8. 
37. Rotger M, Colombo S, Furrer H, et al.; Swiss HIV Cohort Study. Influence of CYP2B6 
polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and 
nevirapine in HIV-infected patients. Pharmacogenet Genomics 2005;15:1-5. 
38. Sustiva (efavirenz) [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2017. 
39. LeBel M, Masson E, Guilbert E, et al. Effects of rifabutin and rifampicin on the 
pharmacokinetics of ethinylestradiol and norethindrone. J Clin Pharmacol 1998;38:1042-
50. 
40. Barditch-Crovo P, Trapnell CB, Ette E, et al. The effects of rifampin and rifabutin on the 
pharmacokinetics and pharmacodynamics of a combination oral contraceptive. Clin 
Pharmacol Ther 1999;65:428-38. 
41. Back DJ, Breckenridge AM, Crawford FE, et al. The effect of rifampicin on 
norethisterone pharmacokinetics. Eur J Clin Pharmacol 1979;15:193-7. 
42. Arora VK, Bedi RS, Arora R. Rifampicin induced menstrual disturbances. Indian J Chest 
Dis Allied Sci 1987;29:63-4. 
43. Haas DW, Ribaudo HJ, Kim RB, et al. Pharmacogenetics of efavirenz and central 
nervous system side effects: an Adult AIDS Clinical Trials Group Study. AIDS 
200418:2391-400. 
44. Haas DW, Smeaton LM, Shafer RW, et al. Pharmacogenetics of long‐term responses to 
antiretroviral regimens containing efavirenz and/or nelfinavir: an adult AIDS Clinical 
Trials Group Study. J Infect Dis 2005;192:11:1931-42. 
45. Rotger M, Tegude H, Colombo S, et al. Predictive value of known and novel alleles of 
CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals. Clin Pharmacol 
Ther 2007;81:557-66. 
46. di Iulio J, Fayet A, Arab-Alameddine M, et al. In vivo analysis of efavirenz metabolism in 
individuals with impaired CYP2A6 function. Pharmacogenet Genomics 2009;19:300-9. 


 
64 
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47. Scarsi KK, Darin KM, Chappell CA, Nitz SM, Lamorde M. Drug-drug interactions, 
effectiveness, and safety of hormonal contraceptives in women living with HIV. Drug Saf 
2016;39:1053-72. 
48. 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. 
49. Reese MJ, Savina PM, Generaux GT, et al. In vitro investigations into the roles of drug 
transporters and metabolizing enzymes in the disposition and drug interactions of 
dolutegravir, a HIV integrase inhibitor. Drug Metab Dispos 2013;41:353-61. 
50. Song IH, Borland J, Chen S, Wajima T, Peppercorn AF, Piscitelli SC. Dolutegravir has 
no effect on the pharmacokinetics of oral contraceptives with norgestimate and ethinyl 
estradiol. Ann Pharmacother 2015;49:784-89. 
51. Medicines and Healthcare products Regulatory Agency. Levonorgestrel-containing 
emergency hormonal contraception: advice on interactions with hepatic enzyme 
inducers and contraceptive efficacy - GOV.UK. 2016. [Online]. Available: 
https://www.gov.uk/drug-safety-update/levonorgestrel-containing-emergency-hormonal-
contraception-advice-on-interactions-with-hepatic-enzyme-inducers-and-contraceptive-
efficacy. [Accessed: 22-Sep-2017]. 
52. European Medicines Agency. European Medicines Agency - Human medicines - 
Levonelle 1500 microgram tablets and associated names. 2016. [Online]. Available: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Levone
lle_1500_microgram_tablets_and_associated_names/human_referral_000405.jsp&mid=
WC0b01ac05805c516f. [Accessed: 19-Sep-2017]. 
53. U.S. Department of Health and Human Services, Food and Drug Administration, and 
Center for Drug Evaluation and Research (CDER). Clinical Drug Interaction Studies — 
Study Design, Data Analysis, and Clinical Implications Guidance for Industry. 2017. 
[Online]. Available: 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default
.htm. [Accessed: 19-Jun-2018]. 
54. U.S. Department of Health and Human Services, Food and Drug Administration, and 
Center for Drug Evaluation and Research (CDER). Guidance for Industry Bioavailability 
and Bioequivalence Studies Submitted in NDAs or INDs — General Considerations 
Guidance for Industry. 2014. [Online]. Available: 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default
.htm. [Accessed: 19-Jun-2018]. 
55. Neary M, Lamorde M, Olagunju A, et al. The effect of gene variants on levonorgestrel 
pharmacokinetics when combined with antiretroviral therapy containing efavirenz or 
nevirapine. Clin Pharmacol Ther 2017;102:529-36. 
56. Glasier A, Cameron ST, Blithe D, et al. Can we identify women at risk of pregnancy 
despite using emergency contraception? Data from randomized trials of ulipristal acetate 
and levonorgestrel. Contraception 2011;84:363-7. 


 
65 
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57. Society of Adolescent Health and Medicine. Position paper. Emergency contraception 
for adolescents and young adults: guidance for health care professionals. J Adolesc 
Health 2016;58:245-8. 
58. American Academy of Pediatrics. Policy statement. Emergency contraception. Pediatrics 
2012;130:1174-82. 
59. Palermo T, Bleck J, Westley E. Knowledge and use of emergency contraception: a 
multicountry analysis. Int Perspect Sex Reprod Health 2014;40:79-86.  
60. Drugs and lactation database (LactMed) [Internet]. Bethesda (MD): National Library of 
Medicine (US); Specialized Information Services Division. [cited 2018 Sep 18]. Available 
from: https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm 
61. Hale TW, Rowe H. Medications and mothers’ milk. 17th ed. New York: Springer 
Publishing Company; 2016. 
62. Willetts SJ, MacDougall M, Cameron ST. A survey regarding acceptability of oral 
emergency contraception according to the posited mechanism of action. Contraception 
2017;96:81-8. 
63. Stirratt MJ, Dunbar-Jacob J, Crane HM, et al. Self-report measures of medication 
adherence behavior: recommendations on optimal use. Transl Behav Med 2015;5:470-
82. 
64. Podsadecki TJ, Vrijens BC, Tousset EP, Rode RA, Hanna GJ. “White coat compliance” 
limits the reliability of therapeutic drug monitoring in HIV-1-infected patients. HIV Clin 
Trials 2008;9:238-46. 
65. Nettles RE, Kieffer TL, Parsons T, et al. Marked intraindividual variability in antiretroviral 
concentrations may limit the utility of therapeutic drug monitoring. Clin Infect Dis 
2006;42:1189-96. 
66. Hickey MD, Salmen CR, Tessler RA, et al. Antiretroviral concentrations in small hair 
samples as a feasible marker of adherence in rural Kenya. J Acquir Immune Defic Syndr 
2014;66:311-5. 
67. Baxi SM, Liu A, Bacchetti P, et al. Comparing the novel method of assessing PrEP 
adherence/exposure using hair samples to other pharmacologic and traditional 
measures. J Acquir Immune Defic Syndr 2015:68:13-20. 
68. Prasitsuebsai W, Kerr SJ, Truong KH, et al. Using lopinavir concentrations in hair 
samples to assess treatment outcomes on second-line regimens among Asian children. 
AIDS Res Hum Retroviruses 2015;31:1009-14. 
69. Koss CA, Natureeba P, Mwesigwa J. Hair concentrations of antiretrovirals predict viral 
suppression in HIV-infected pregnant and breastfeeding Ugandan women. AIDS 
2015;29:825-30. 
70. Castillo-Mancilla JR, Zheng JH, Rower JE, et al. Tenofovir, emtricitabine, and tenofovir 
diphosphate in dried blood spots for determining recent and cumulative drug exposure. 
AIDS Res Hum Retroviruses 2013;29:384-90. 
71. Gandhi M, Greenblatt RM. Hair it is: the long and short of monitoring antiretroviral 
treatment. Ann Intern Med 2002;137:696-7. 


 
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72. Gandhi M, Ameli N, Bacchetti P, et al.; Women's Interagency HIV Study (WIHS). 
Protease inhibitor levels in hair strongly predict virologic response to treatment. AIDS 
2009;23:471-8. 
73. van Zyl GU, van Mens TE, McIlleron H, et al. Low lopinavir plasma or hair 
concentrations explain second-line protease inhibitor failures in a resource-limited 
setting. J Acquir Immune Defic Syndr 2011;56:333-9. 
74. Gandhi M, Ameli N, Bacchetti P, et al. Atazanavir concentration in hair is the strongest 
predictor of outcomes on antiretroviral therapy. Clin Infect Dis 2011;52:1267-75. 
75. Baxi SM, Greenblatt RM, Bacchetti P, et al. Nevirapine concentration in hair samples is 
a strong predictor of virologic suppression in a prospective cohort of HIV-infected 
patients. PLoS One 2015;10:e0129100. 
76. Chawana TD, Gandhi M, Nathoo K, et al.; Adolescent Treatment Failure (ATF) Study 
Team. Defining a cut-off for atazanavir in hair samples associated with virological failure 
among adolescents failing second-line antiretroviral treatment. J Acquir Immune Defic 
Syndr 2017;76:55-9. 
77. Pintye J, Bacchetti P, Teeraananchai S, et al. Brief Report: Lopinavir hair concentrations 
are the strongest predictor of viremia in HIV-infected Asian children and adolescents on 
second-line antiretroviral therapy. J Acquir Immune Defic Syndr 2017;76:367-71. 
78. Majeed S, West S, Jiang S, et al. Confirmation of the drug-drug interaction (DDI) 
potential between cobicistat-boosted antiretroviral regimens and hormonal 
contraceptives. [Oral Abstract #O_05/#5.] 18th International Workshop on Clinical 
Pharmacology of Antiviral Therapy, June 14-17 2017, Chicago, IL; 2017. 
79. Begley R, Anderson K, Watkins T, et al. Lack of drug-drug interaction between filgotinib, 
a JAK-1 selective inhibitor, and a representative hormonal contraceptive medication, 
levonorgestrel/ethinyl estradiol. [ACR Meeting Abstracts 1459]. 2017 ACR/ARHP Annual 
Meeting, November 3-8, 2017. San Diego, CA; 2017. 
80. Davit BM, Chen ML, Conner DP, et al. Implementation of a reference-scaled average 
bioequivalence approach for highly variable generic drug products by the US Food and 
Drug Administration. AAPS J 2012;14:915-24.  
81. Gabrielsson J, Weiner D. Pharmacokinetic and pharmacodynamic data analysis:  
concepts and applications. 3rd ed. Stockholm: Swedish Pharmaceutical Press; 2002.  
82. Pharsight Corporation. WinNolin® User’s Guide. Version 5.3. St. Louis: Pharsight 
Corporation. Available: 
https://support.certara.com/forums/index.php?app=core&module=attach&section=attach
&attach_id=3024. [Accessed: 16-Aug-2018]. 
 
 


 
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APPENDIX I: SAMPLE INFORMED CONSENT 
 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
For protocol: A5375  
 
An Open-Label, Phase II Pharmacokinetic Study to Evaluate Double-Dose Levonorgestrel 
Emergency Contraception in Combination with Efavirenz-Based Antiretroviral Therapy or 
Rifampicin-Containing Anti-Tuberculosis Therapy 
 
FINAL Version 2.0, 10/30/20 
 
SHORT TITLE FOR THE STUDY: Optimize LNG EC 
 
SUMMARY 
 
PURPOSE: 
Emergency contraception is birth control that prevents pregnancy. 
Girls and women use it after having unprotected sex. Levonorgestrel 
(LNG) emergency contraception is commonly known as Plan B® 
One-Step, or the Morning After Pill. This study will test if a higher 
dose of LNG needs to be used to prevent pregnancy in girls and 
women who are taking some types of anti-HIV or anti-TB 
medications. This study will also test if a higher dose of LNG is safe.  
 
STUDY 
TREATMENT: 
You will take a dose of LNG emergency contraception by mouth. 
LNG emergency contraception will be provided by the study. 
 
The United States Food and Drug Administration (US FDA) has 
approved LNG for prevention of pregnancy. 
 
NUMBER OF 
PARTICIPANTS: 
There will be 116 participants in this study. There will be 17 
participants in Group A, and 33 participants in each of Groups B, C, 
and D. 
 
LENGTH 
OF STUDY: 
The study will last about 4 weeks. During this time, you will need to 
come to the clinic for about 3 visits. 
 
REQUIRED 
ACTIVITIES: 
Blood and Urine Collections 
At most visits, some blood will be collected from a vein in your arm. 
You may be asked to provide a urine sample. 
  
At the entry visit, you will be asked to remain at the clinic all day for 
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intensive PK sampling, you will have blood drawn several times over 
a period of 8 hours to measure the amount of LNG in your blood. To 
avoid many needle sticks, a small tube (intravenous device) may be 
placed into a vein in your arm and left in place during your stay. You 
will be able to move around and should not have any significant pain 
or discomfort once the tube is in place.  
 
RISKS: 
The following side effects have been associated with using LNG: 
nausea, lower stomach pain, tiredness, headache, dizziness, breast 
pain, vomiting, and diarrhea. Some individuals will have menstrual 
changes such as spotting or bleeding before their next period. Some 
individuals may have a heavier or lighter next period, or a period 
that is early or late. 
 
Taking blood may cause some discomfort, bleeding, or bruising 
where the needle enters the body, lightheadedness, and in rare 
cases, fainting or infection. 
 
BENEFITS: 
You will receive no benefit from being in this study. 
 
OTHER CHOICES:  Instead of being in this study, you have the option of continuing with 
your current treatment or starting a new treatment under the care of 
your regular doctor or other health care provider. 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are a girl at least 16 years 
of age or a woman and: 
 
1. You are living with human immunodeficiency virus (HIV-1) and you have been taking a 
combination of antiretroviral drugs (ARV) that includes either efavirenz (EFV) or dolutegravir 
(DTG) 
 
OR 
 
2. You are living with tuberculosis (TB) infection, and you have completed the intensive phase 
of TB therapy and are now completing the continuation phase of TB treatment that requires 
taking isoniazid (INH) and rifampicin (RIF) daily. 
 
This study is sponsored by the National Institutes of Health (NIH). The doctor in charge of this 
study at this site is: (insert name of Principal Investigator). Before you decide if you want to be a 
part of this study, we want you to know about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 


 
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WHY IS THIS STUDY BEING DONE? 
 
Emergency contraception is birth control that prevents pregnancy. Girls and women use it after 
having unprotected sex. Levonorgestrel (LNG) emergency contraception is commonly known as 
Plan B® One-Step, or the Morning After Pill. This study will test if a higher dose of LNG needs to 
be used to prevent pregnancy in girls and women who are taking some types of anti-HIV or anti-
TB medications. This study will also test if a higher dose of LNG is safe.  
 
The United States Food and Drug Administration (US FDA) has approved LNG for prevention of 
pregnancy.  
 
LNG works mainly by stopping the release of an egg from the ovary. It may also work by 
preventing fertilization of an egg, or by preventing attachment to the uterus. Girls and women 
can use emergency contraception to prevent pregnancy if regular birth control was used 
incorrectly or fails, or no birth control was used. LNG will not disrupt an existing pregnancy and 
using LNG does not affect your ability to have a baby in the future. After you take LNG as part of 
this study, you may attempt to get pregnant again as soon as your next menstrual cycle (after 
your next period), if you want to. 
 
Efavirenz (EFV) is a medication commonly used to treat HIV. Rifampicin (RIF) is a medication 
commonly used to treat tuberculosis. Both of these medications lower the amount of LNG in 
your blood by about half. This may make LNG not work as well as it normally would. It is 
unknown if the current dose of LNG emergency contraception, in combination with EFV or RIF, 
is enough to prevent a pregnancy. To learn if a higher dose is needed to prevent pregnancy, 
you will take either a regular dose or a double dose of LNG emergency contraception. 
 
Dolutegravir (DTG) is an anti-HIV medication that does not lower the amount of LNG in your 
blood. It is being used as a comparison to the other groups.   
 
In this study, you will not be taking LNG for contraception (to prevent pregnancy), you will be 
volunteering to take it so that we can evaluate the impact of your other medications on the 
amount of LNG in your blood. You will take a dose of LNG emergency contraception by mouth. 
After you take the dose of LNG, the amount of LNG that is in your blood will be measured. This 
study will also take a hair sample that will tell researchers how often you have taken EFV, INH, 
and DTG over the past few weeks.  
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Information Collected at Screening 
There is some information that we collect on everyone who is screened for an ACTG 
study. As part of your screening visit, some demographic (for example, age, gender, 
race), clinical (for example, disease condition, diagnosis), and laboratory (for example, 
routine lab tests for safety) information will be collected from you.  
 
  


 
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We will collect this information even if you do not enroll in this study. This information is 
collected so that ACTG researchers may determine whether there are patterns and/or 
common reasons why people do not join a study. 
 
If you decide to take part in this research study, you will be asked to sign this consent form. A 
screening visit will be done to make sure you are eligible to join the study. If you are found 
eligible, you will have one entry visit that will last 9-10 hours, a 1 hour visit 24 hours after entry, 
and a 1 hour visit 48 hours after entry. You will be asked to take a questionnaire over the phone 
1 week, 2 weeks, and 4 weeks after entry.  
 
If you do not enroll into the study 
If you decide not to take part in this study or if you do not meet the eligibility requirements, we 
will still use some of your information. As part of this screening visit, some demographic (for 
example, age, gender, race), clinical (for example, disease condition, diagnosis), and laboratory 
(for example, pregnancy test) information is being collected from you so that ACTG researchers 
may help determine whether there are patterns or common reasons why people do not join a 
study. 
 
If you enter the study 
• 
At the study entry visit, you will be assigned to a study group. There are four study groups. 
Two will receive a standard dose of LNG, and two will receive twice the standard dose of 
LNG. You will not be able to choose your study group, but you will know what study group 
you are in.  
• 
If you are taking EFV for HIV treatment, you will be randomly assigned (like a coin flip) to 
one of two possible doses of LNG. Some women will take a standard dose of LNG, other 
women will take twice the standard dose of LNG. More women will be assigned to take twice 
the standard dose, so it is more likely that you will be in this group.  
• 
If you are taking DTG for HIV treatment, you will be assigned to receive a standard dose of 
LNG. 
• 
If you are taking RIF for TB treatment, you will be assigned to receive twice the standard 
dose of LNG. 
 
You will have blood samples taken during the study to measure the amount of LNG in your 
blood.  
 
You will have a small sample of hair cut from your head so that we can measure levels of the 
anti-TB or anti-HIV drugs in this small hair sample. You may decline this procedure. 
 
You will be asked questions about how well you take your anti-HIV or anti-TB medications and if 
you have any concerns about taking LNG. 
 
You will be asked to use a reliable form of non-hormonal birth control every time you have sex 
that could lead to pregnancy until the study is completed. You may not enter the study if you 
have had sex that could lead to pregnancy within 14 days prior to starting the study. 
 
 


 
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CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION 
ARE USED FOR? 
 
Some of your blood will be stored and used for study-required pharmacologic, 
pharmacogenetic (testing of material passed from parent to child that determines the 
makeup of the body and mind that can affect your response to the study drugs), and 
virologic testing.  
 
Identifiers will be removed from your samples and from any private information that has 
been collected about you. This means that no one looking at the labels or at other 
information will be able to know that the samples or information came from you.  
 
Your blood and/or hair specimens may be used for commercial profit. If this happens, 
there is no plan to share any money with you.  
 
The tests described above are required by this study. If you do not agree to the storage 
or testing that has been described above, you should not join this study.  
 
Please refer to Attachment I-A to consent for use of your samples in other studies. 
 
A5375 Study Visits 
The study staff can answer any questions you have about individual study visits, and how long 
they will last, or about the tests that will occur. The table below can be used as a quick 
reference for you, along with the explanations that follow. 
 
Table 1: Study Schedule 
Evaluation or 
Procedure 
Screening 
Entry 
Visit 
Study Visits 
Follow-Up Calls 
Clinically 
Indicated 
Visit 
Early Study 
Discontinuation 
Day 0 
Day 1 
Day 2 
Day 7 
Day 14 
Day 28 
1 hour 
9-10 
hours 
1 hour 
1 hour 
30 
minutes 
30 
minutes 
30 
minutes 
1 hour 
30 minutes 
Documentation of 
HIV Status 
√ 
 
 
 
 
 
 
 
 
Medical/ 
Medication History 
√ 
√ 
 
 
 
 
 
 
 
Questions About 
Your Menstrual 
Cycle 
√ 
√ 
 
 
√ 
√ 
√ 
 
√ 
Diagnoses 
Questions 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Medication 
Questions 
 
√ 
√ 
√ 
 
 
√ 
√ 
√ 


 
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Evaluation or 
Procedure 
Screening 
Entry 
Visit 
Study Visits 
Follow-Up Calls 
Clinically 
Indicated 
Visit 
Early Study 
Discontinuation 
Day 0 
Day 1 
Day 2 
Day 7 
Day 14 
Day 28 
1 hour 
9-10 
hours 
1 hour 
1 hour 
30 
minutes 
30 
minutes 
30 
minutes 
1 hour 
30 minutes 
Acceptability and 
Practicality 
Questionnaire 
 
√ 
 
√ 
 
√ 
√ 
 
√ 
Adherence 
Assessment 
√ 
√ 
√ 
√ 
 
 
 
 
 
Physical Exam 
√ 
√ 
 
 
 
 
 
√ 
 
Blood Collection 
√ 
√ 
 
 
 
 
 
 
 
Pregnancy Testing 
√ 
√ 
 
 
 
 
 
√ 
 
Hair Collection 
 
√ 
 
 
 
 
 
 
 
LNG EC 
Administration 
 
√ 
 
 
 
 
 
 
 
Pharmacokinetic 
Sampling 
 
√ 
√ 
√ 
 
 
 
 
 
 
Screening 
If you would like to be in this study, after you have read and signed this informed consent form, 
you will come to the clinic for a screening visit to make sure you meet the requirements for 
joining the study. This visit will take about 1 hour [Site to insert site-specific information about 
duration of study visit]. Up to 18 mL (1.4 tablespoons) of blood will be drawn at this visit.  
• 
Your HIV infection status will be confirmed. If there is no record available, another HIV test 
will be done. You may have to sign a separate consent form before this is done. 
• 
You will be asked questions about your medical and medication history and any medications 
you are currently taking. You will be asked about your menstrual period. 
• 
You will be asked about adherence to your anti-HIV or anti-TB medications (how correctly 
you are taking your medications). 
• 
You will have a physical exam. 
• 
You will have blood drawn for routine lab tests for safety. You will be told the results of these 
tests when they become available.  
• 
You will give a urine sample or have blood drawn to see if you are pregnant. This test must 
show that you are not pregnant for you to enroll in the study. You will be told the result of the 
test when it becomes available. 
 
Entry Visit (Day 0) 
If you are eligible for the study and you choose to enroll, you will come back to the clinic for an 
entry visit. This visit will last about 9 or 10 hours [Site to insert site-specific information about 
duration of study visit]. Up to 75 mL (5.8 tablespoons) of blood will be drawn at this visit. 
• 
You will be asked about:  your medical history and any medications you are taking, birth 
control that you are taking or have taken in the last 4 months, your menstrual period 


 
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and if there has been a change in your menstrual period since the screening visit, and 
adherence to your anti-HIV or anti-TB medications. 
• 
You will have a physical exam, including measuring your neck, waist, and hips. 
• 
If you are HIV positive, you will have blood drawn to test how much HIV is in your blood, and 
to test how many CD4 cells (infection-fighting cells) are in your blood. You will be told the 
results of these tests when they become available. 
• 
You will have blood drawn and stored for a genetic test (a test of your DNA [genes] to better 
understand how fast your body removes the study drugs from your blood). Genetic testing 
looks at differences in people’s genes. Your body, like all living things, is made up of cells, 
and cells contain deoxyribonucleic acid, also known as “DNA.” DNA is like a string of 
information put together in a certain order. Parts of the string make up “genes.” Genes 
contain instructions on how to make your body work and fight disease. The testing in this 
study will only look at certain genes that are known to have an effect on how your body uses 
hormones. The tests will not look at any other genes. You will not receive the results of 
these tests. 
• 
You will give a urine sample or have blood drawn to see if you are pregnant. This test must 
show that you are not pregnant for you to remain in the study. You will be told the result of 
the test when it becomes available. 
• 
You will have a small sample of hair (about 50 strands) cut from your head to measure 
levels of the HIV or TB drugs in this hair sample. Humans lose about 100 hairs from their 
head every day naturally, so this amount of hair removal should not be noticeable. If you 
decide not to provide a hair sample, you can still be in the study. Results of this testing will 
not be available to you since hair levels are still a research tool. 
• 
You will take a dose of LNG emergency contraception by mouth.  
• 
You will be asked to remain at the clinic all day for an intensive pharmacokinetic (PK) blood 
sampling. For this intensive PK sampling, you will have blood drawn over 8 hours to 
measure the amount of LNG in your blood. To avoid many needle sticks, a small tube 
(intravenous device) may be placed into a vein in your arm and left in place during your 
stay. You will be able to move around and should not have any significant pain or discomfort 
once the tube is in place. Blood will be taken before you take the LNG emergency 
contraception dose, and then at 30 minutes, 1, 1.5, 2, 3, 4, 6, and 8 hours after you take the 
LNG emergency contraception dose.  
• 
You will be asked if you have any problems or concerns after taking the LNG emergency 
contraception dose.  
 
Study Visits (Days 1 and 2) 
After the entry visit, you will come back to the clinic for two more study visits. The first will be 1 
day after your entry visit, and the second will be 2 days after your entry visit. These study visits 
will last about 1 hour. Up to 6 mL (0.4 tablespoons) of blood will be drawn at this visit. 
• 
You will have about blood drawn for PK blood sampling. 
• 
You will be asked about: your adherence to medications, changes in your medications and 
diagnoses, the acceptability and practicality of emergency contraception, and any problems 
or concerns you have after taking the LNG emergency contraception dose.  
During the COVID-19 outbreak, the Day 1 and Day 2 study visits may be conducted over 
the phone. If the visit is conducted over the phone, a member of the study staff will call 
you. Visits that are conducted over the phone will not include blood draws.  


 
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Follow-up 
A member of the study staff will call you 7 days after study entry to ask you about your 
menstrual period. You will also be asked about changes in your diagnoses. 
 
A member of the study staff will call you 14 and 28 days after study entry to ask you about: 
changes in your diagnoses and (on day 28 only) your medications, your menstrual period, the 
acceptability and practicality of emergency contraception, and any problems or concerns you 
have after taking the LNG emergency contraception dose.  
 
Clinically Indicated Visit 
If you become pregnant or have an adverse event, you may be asked to return to the clinic for a 
physical exam and pregnancy test, and to discuss any changes in your medications or 
diagnoses. 
 
Early Study Discontinuation (Leaving the Study Early)  
If you leave the study early, you will be asked questions about your menstrual period, changes 
in your medications or diagnoses, questions to determine the acceptability and practicality of 
emergency contraception, and questions about any problems or concerns you have after taking 
the LNG emergency contraception dose. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 116 women and girls who are 16 years of age or older will take part in this study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 4 weeks.  
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
 
• 
The study is stopped or cancelled  
• 
You are not able to attend the study visits as required by the study 
• 
You have a positive pregnancy test before you take the LNG dose for the study 
• 
Your primary care doctor requests that you be taken off the study 
 
After the study: 
 
After you have completed your study participation, the study will not be able to continue to 
provide you with the LNG you received on the study. If similar drugs/agents would be of benefit 
to you, the study staff will discuss how you may be able to obtain them. 
 


 
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WHAT ARE THE RISKS OF THE STUDY? 
 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these drugs. These lists include the 
more serious or common side effects with a known or possible relationship. If you have 
questions concerning the additional study drug side effects please ask the medical staff at your 
site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drugs. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
 
Risks of Levonorgestrel (LNG, Plan B® One-Step) 
The following side effects have been associated with the use of LNG: 
• 
Nausea 
• 
Lower stomach (abdominal) pain 
• 
Tiredness 
• 
Headache 
• 
Dizziness 
• 
Breast pain 
• 
Vomiting 
• 
Diarrhea 
 
Some women will have menstrual changes such as spotting or bleeding before their next period. 
Some women may have a heavier or lighter next period, or a period that is early or late.  
• 
If your period is more than a week late, you should get a pregnancy test 
 
Risks of Drawing Blood 
Taking blood may cause some discomfort, bleeding, or bruising where the needle enters the 
body, lightheadedness, and in rare cases, fainting or infection. 
 
Risks of Hair Collection 
There is a small risk of cutting or nicking the scalp during the hair collection, although this is 
extremely rare. 
 
Risks of Social Harm 
It is possible that participating in this study will make it difficult for you to keep your HIV or TB 
status, or information about your sexual activity, secret from people close to you. This may 
include your parent or guardian if you are under 18 years old. This may lead to unwelcome 
discussions about or reactions to your HIV or TB status. Please talk with the study staff if you 
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ARE THERE RISKS RELATED TO PREGNANCY? 
 
It is not known if the drug or drug combinations in this study harm unborn babies. If you are 
having sex that could lead to pregnancy, you must agree not to become pregnant until you 
complete the study. You may not enter the study if you have had sex that could lead to 
pregnancy within 14 days prior to starting the study. 
 
You and your partner must use reliable birth control that you discuss with the study staff. You 
must continue to use birth control while in the study. You may choose one of the birth control 
methods below:  
• 
Male condom with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Non-hormonal IUD 
• 
Bilateral tubal ligation 
• 
Male partner vasectomy 
  
If you can become pregnant, you must have a pregnancy test before you enter this study. The 
test must show that you are not pregnant. If you think you may be pregnant at any time during 
the study, tell your study staff right away. The study staff will talk to you about your choices. A 
pregnancy test may not detect a very early pregnancy, which is why the study team asks that 
you not enter the study if you have had sex that could lead to pregnancy within 14 days of study 
entry.   
 
If you become pregnant while on study, the study staff would like to obtain information from you 
about the outcome of the pregnancy (even if it is after your participation in the study ends). If 
you are taking anti-HIV drugs when you become pregnant, your pregnancy will be reported to 
an international database that collects information about pregnancies in women taking anti-HIV 
drugs. This report will not use your name or other information that could be used to identify you. 
 
Breastfeeding 
Breastfeeding women will be included only after their infants are at least 6 months old. Birth 
control like LNG is allowed during breastfeeding. During long-term use of drugs like LNG, called 
progestins, the amount of progestin in infant blood is only 1-6% of the amount in maternal blood. 
No side effects of progestins have been found on breastfeeding (quality or quantity of milk), or 
on the health or development of the infant due to this low progestin exposure. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
You will receive no benefit from being in this study. Information learned from this study may help 
other women who have HIV or TB. 
 
 


 
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WHAT ABOUT CONFIDENTIALITY? 
 
For Sites in the US 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have gotten a Certificate of Confidentiality 
from the US Federal Government. This certificate means that researchers cannot be forced to 
tell people who are not connected with this study, such as the court system, about your 
participation. Also, any publication of this study will not use your name or identify you 
personally.  
 
Your records may be reviewed by the ACTG, the US Office for Human Research Protections 
(OHRP), or other local, US, and international regulatory entities as part of their duties, (insert 
name of site) institutional review board (IRB) (a committee that protects the rights and safety of 
participants in research), National Institutes of Health (NIH), study staff, study monitors, and 
their designees. Having a Certificate of Confidentiality does not prevent you from releasing 
information about yourself and your participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by US 
law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time.  
 
For Sites outside the US 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. Any 
publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the ACTG, the US Office for Human Research Protections 
(OHRP), or other local, US, and international regulatory entities as part of their duties, (insert 
name of site) institutional review board (IRB) or Ethics Committee (a committee that protects the 
rights and safety of participants in research), National Institutes of Health (NIH), study staff, 
study monitors, and their designees.  
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by US 
law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time.  
 
 
WHAT ARE THE COSTS TO ME? 
 
Taking part in this study may lead to added costs to you and your insurance company. In some 
cases it is possible that your insurance company will not pay for these costs because you are 
taking part in a research study.  
 


 
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There is no cost to you for LNG, study-related visits, physical examinations, laboratory tests, or 
other study procedures.  
 
Anti-HIV and anti-TB medicines will not be provided by the study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
You may be reimbursed for your time and travel expenses as part of your participation in this 
study. (Site to insert site-specific information about payment.)  
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of your being in this study, you will be given immediate 
treatment for injuries and be referred for further treatment, if necessary.  
[Sites: Please modify (if necessary) and insert one of these two statements, as 
appropriate to your site. If your site is required to carry Clinical Trials Insurance (CTI), 
this must be indicated in the informed consent.] 
• 
This site has clinical trials insurance. This insurance will allow the site to provide you 
with monetary compensation if you suffer harm as a result of participating in this 
research study.  
• 
The cost for this treatment will be charged to you or your insurance company. There 
is no program for compensation either through this institution or the NIH.  
You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
• 
Name of the investigator or other study staff 
• 
Telephone number of above  
 


 
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For questions about your rights as a research participant, contact: 
 
• 
Name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
Telephone number of above 
 


 
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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered, and you agree to take part in this study, please sign your name below. 
 
 
 
____________________________ 
__________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
 
____________________________ 
__________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
 
____________________________ 
__________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 
 
 


 
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ATTACHMENT I-A: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES 
 
When samples are no longer needed for this study, the ACTG may want to use them in 
other studies and share them with other researchers. These samples are called “extra 
samples.” The ACTG will only allow your extra samples to be used in other studies if 
you agree to this. If you have any questions, please ask. 
 
Identifiers will be removed from your samples and from any information that has been 
collected about you. This means that no one looking at the labels or at other information 
will know that the samples or information came from you.  
 
Extra samples are stored in a secure central place called a repository. Your samples 
will be stored in the ACTG repository located in the United States. 
 
There is no limit on how long your extra samples will be stored.  
[Site: Revise the previous sentence to insert limits if your regulatory authority imposes 
them.] 
 
When a researcher wants to use your samples and information, their research plan must 
be approved by the ACTG. Also, the researcher’s institutional review board (IRB) or 
ethics committee (EC) will review their plan. [Site: If review by your institution’s 
IRB/EC/RE is also required, insert a sentence stating this.] IRBs/ECs protect the rights 
and well-being of people in research. If the research plan is approved, the ACTG will 
send your samples to the researcher’s location. This means that researchers who are not 
part of the protocol team may use your samples without asking you again for your 
consent.  
 
You will not be paid for your samples. Also, a researcher may make a new scientific 
discovery or product based on the use of your samples. If this happens, there is no 
plan to share any money with you.  
 
You may withdraw your consent for research on your extra samples at any time, and the 
specimens will be discarded. 
 
Please choose the response that matches what you want by putting your initials in the 
space provided. Please ask the staff any questions that you have before you indicate 
your selection. 
 


 
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Research without Human Genetic Testing  
If you agree, your extra samples may be stored (with usual protection of your identity) 
and used for ACTG-approved HIV-related research that does not include human genetic 
testing. 
 
____ (initials) I understand and I agree to this storage and possible use of my samples  
 
OR 
____ (initials) I understand but I do not agree to this storage and possible use of my 
samples 
 
Research with Human Genetic Testing  
 
The ACTG has two different studies that collect samples for genetic testing. 
 
If you live in the US, this study is called ACTG A5128, Plan for Obtaining Informed 
Consent to Use Stored Human Biological Materials (HBM) for Currently Unspecified 
Analyses. 
 
If you live outside of the US, this study is called ACTG A5243, Plan for Obtaining Human 
Biological Samples at Non-US Clinical Research Sites for Currently Unspecified Genetic 
Analyses. 
 
Your site might ask you if you would like to participate in one of these studies if it is 
being done where you live. If you would like to participate, you will sign a separate 
consent form. 
 
Your extra samples will not be used for human genetic testing unless you sign a 
consent for A5128 or A5243.  
 
 
 


 
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APPENDIX II: SAMPLE PARENTAL INFORMED CONSENT 
 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
For protocol: A5375  
 
An Open-Label, Phase II Pharmacokinetic Study to Evaluate Double-Dose Levonorgestrel 
Emergency Contraception in Combination with Efavirenz-Based Antiretroviral Therapy or 
Rifampicin-Containing Anti-Tuberculosis Therapy 
 
FINAL Version 2.0, 10/30/20 
 
SHORT TITLE FOR THE STUDY: Optimize LNG EC 
 
SUMMARY 
 
PURPOSE: 
Emergency contraception is birth control that prevents pregnancy. 
Girls and women use it after having unprotected sex. Levonorgestrel 
(LNG) emergency contraception is commonly known as Plan B® 
One-Step, or the Morning After Pill. This study will test if a higher 
dose of LNG needs to be used to prevent pregnancy in girls and 
women who are taking some types of anti-HIV or anti-TB 
medications. This study will also test if a higher dose of LNG is safe.  
 
STUDY  
TREATMENT: 
Your child will take a dose of LNG emergency contraception by 
mouth. LNG emergency contraception will be provided by the study. 
 
The United States Food and Drug Administration (US FDA) has 
approved LNG for prevention of pregnancy. 
 
NUMBER OF  
PARTICIPANTS: 
There will be 116 participants in this study. There will be 17 
participants in Group A, and 33 participants in each of Groups B, C, 
and D. 
 
LENGTH  
OF STUDY: 
The study will last about 4 weeks. During this time, your child will 
need to come to the clinic for about 3 visits. 
 
REQUIRED 
ACTIVITIES: 
Blood and Urine Collections 
At most visits, some blood will be collected from a vein in your 
child’s arm. Your child may be asked to provide a urine sample. 
  
At the entry visit, your child will be asked to remain at the clinic all 
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intensive PK sampling, your child will have blood drawn several 
times over a period of 8 hours to measure the amount of LNG in her 
blood. To avoid many needle sticks, a small tube (intravenous 
device) may be placed into a vein in your child’s arm and left in 
place during her stay. She will be able to move around and should 
not have any significant pain or discomfort once the tube is in place.  
 
RISKS: 
The following side effects have been associated with using LNG: 
nausea, lower stomach pain, tiredness, headache, dizziness, breast 
pain, vomiting, and diarrhea. Some individuals will have menstrual 
changes such as spotting or bleeding before their next period. Some 
individuals may have a heavier or lighter next period, or a period 
that is early or late. 
 
Taking blood may cause some discomfort, bleeding, or bruising 
where the needle enters the body, lightheadedness, and in rare 
cases, fainting or infection. 
 
BENEFITS: 
Your child will receive no benefit from being in this study. 
 
OTHER CHOICES: 
Instead of being in this study, your child has the option of 
continuing with her current treatment or starting a new treatment 
under the care of her regular doctor or other health care provider. 
 
INTRODUCTION 
 
You are being asked to let your child take part in this research study because your child is a girl 
who is at least 16 years of age and: 
 
1. Your child is living with human immunodeficiency virus (HIV-1) and she has been taking a 
combination of antiretroviral drugs (ARV) that includes either efavirenz (EFV) or dolutegravir 
(DTG) 
 
OR 
 
2. Your child is living with tuberculosis (TB) infection, and she has completed the intensive 
phase of TB therapy and is now completing the continuation phase of TB treatment that 
requires taking isoniazid (INH) and rifampicin (RIF) daily. 
 
This study is sponsored by the National Institutes of Health (NIH). The doctor in charge of this 
study at this site is: (insert name of Principal Investigator). Before you decide if you want to let 
your child be a part of this study, we want you to know about the study.  
 
This is a consent form for your child to participate in the study. It gives you information about 
this study. The study staff will talk with you about this information. You are free to ask questions 
about this study at any time. If you agree to let your child take part in this study, you will be 


 
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asked to sign this consent form. You will get a copy to keep. We will also talk to your child about 
the study and ask her if she agrees to participate in the study. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
Emergency contraception is birth control that prevents pregnancy. Girls and women use it after 
having unprotected sex. Levonorgestrel (LNG) emergency contraception is commonly known as 
Plan B® One-Step, or the Morning After Pill. This study will test if a higher dose of LNG needs to 
be used to prevent pregnancy in girls and women who are taking some types of anti-HIV or anti-
TB medications. This study will also test if a higher dose of LNG is safe.  
 
The United States Food and Drug Administration (US FDA) has approved LNG for prevention of 
pregnancy.  
 
LNG works mainly by stopping the release of an egg from the ovary. It may also work by 
preventing fertilization of an egg, or by preventing attachment to the uterus. Girls and women 
can use emergency contraception to prevent pregnancy if regular birth control was used 
incorrectly or fails, or no birth control was used. LNG will not disrupt an existing pregnancy and 
using LNG does not affect your child’s ability to have a baby in the future. After your child takes 
LNG as part of this study, she may attempt to get pregnant again as soon as her next menstrual 
cycle (after her next period), if she wants to. 
 
Efavirenz (EFV) is a medication commonly used to treat HIV. Rifampicin (RIF) is a medication 
commonly used to treat tuberculosis. Both of these medications lower the amount of LNG in the 
blood by about half. This may make LNG not work as well as it normally would. It is unknown if 
the current dose of LNG emergency contraception, in combination with EFV or RIF, is enough to 
prevent a pregnancy. To learn if a higher dose is needed to prevent pregnancy, your child will 
take either a regular dose or a double dose of LNG emergency contraception. 
 
Dolutegravir (DTG) is an anti-HIV medication that does not lower the amount of LNG in the 
blood. It is being used as a comparison to the other groups.   
 
In this study, your child will not be taking LNG for contraception (to prevent pregnancy), your 
child will be volunteering to take it so that we can evaluate the impact of your child’s other 
medications on the amount of LNG in your child’s blood. Your child will take a dose of LNG 
emergency contraception by mouth. After your child takes the dose of LNG, the amount of LNG 
that is in your child’s blood will be measured. This study will also take a hair sample that will tell 
researchers how often your child has taken EFV, INH, and DTG over the past few weeks.  
 
 
WHAT DOES MY CHILD HAVE TO DO IF SHE IS IN THIS STUDY? 
 
Information Collected at Screening 
There is some information that we collect on everyone who is screened for an ACTG 
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race), clinical (for example, disease condition, diagnosis), and laboratory (for example, 
routine lab tests for safety) information will be collected from your child.  
 
We will collect this information even if your child does not enroll in this study. This 
information is collected so that ACTG researchers may determine whether there are 
patterns and/or common reasons why people do not join a study. 
 
If you decide to let your child take part in this research study, you will be asked to sign this 
consent form. A screening visit will be done to make sure your child is eligible to join the study. 
If your child is found eligible, she will have one entry visit that will last 9-10 hours, a 1 hour visit 
24 hours after entry, and a 1 hour visit 48 hours after entry. Your child will be asked to take a 
questionnaire over the phone 1 week, 2 weeks, and 4 weeks after entry.  
 
If your child does not enroll into the study 
If you or your child decide not to take part in this study or if your child does not meet the 
eligibility requirements, we will still use some of your child’s information. As part of this 
screening visit, some demographic (for example, age, gender, race), clinical (for example, 
disease condition, diagnosis), and laboratory (for example, pregnancy test) information is being 
collected from your child so that ACTG researchers may help determine whether there are 
patterns or common reasons why people do not join a study. 
 
If your child enters the study 
• 
At the study entry visit, your child will be assigned to a study group. There are four study 
groups. Two will receive a standard dose of LNG, and two will receive twice the standard 
dose of LNG. Your child will not be able to choose her study group, but she will know what 
study group she is in. 
• 
If your child is taking EFV for HIV treatment, she will be randomly assigned (like a coin flip) 
to one of two possible doses of LNG. Some women will take a standard dose of LNG, other 
women will take twice the standard dose of LNG. More women will be assigned to take twice 
the standard dose, so it is more likely that your child will be in this group.  
• 
If your child is taking DTG for HIV treatment, she will be assigned to receive a standard dose 
of LNG. 
• 
If your child is taking RIF for TB treatment, she will be assigned to receive twice the 
standard dose of LNG. 
 
Your child will have blood samples taken during the study to measure the amount of LNG in her 
blood.  
 
Your child will have a small sample of hair cut from her head so that we can measure levels of 
the anti-TB or anti-HIV drugs in this small hair sample. Your child may decline this procedure. 
 
Your child will be asked questions about how well she takes her anti-HIV or anti-TB medications 
and if she has any concerns about taking LNG. 
 
Your child will be asked to use a reliable form of non-hormonal birth control every time your 
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the study if she has had sex that could lead to pregnancy within 14 days prior to starting the 
study. 
 
 
CAN I CHOOSE THE TYPES OF RESEARCH THAT MY CHILD’S SAMPLES AND 
INFORMATION ARE USED FOR? 
 
Some of your child’s blood will be stored and used for study-required pharmacologic, 
pharmacogenetic (testing of material passed from parent to child that determines the 
makeup of the body and mind that can affect your response to the study drugs), and 
virologic testing.  
 
Identifiers will be removed from your child’s samples and from any private information 
that has been collected about her. This means that no one looking at the labels or at 
other information will be able to know that the samples or information came from your 
child.  
 
Your child’s blood and/or hair specimens may be used for commercial profit. If this 
happens, there is no plan to share any money with you or your child. 
 
The tests described above are required by this study. If you do not agree to the storage 
or testing that has been described above, your child should not join this study.  
 
Please refer to Attachment II-A to consent for use of your child’s samples in other 
studies. 
 
 
 


 
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A5375 Study Visits 
The study staff can answer any questions you have about individual study visits, and how long 
they will last, or about the tests that will occur. The table below can be used as a quick 
reference for you, along with the explanations that follow. 
 
Appendix II Table 1: Study Schedule 
Evaluation or 
Procedure 
Screening 
Entry 
Visit 
Study Visits 
Follow-Up Calls 
Clinically 
Indicated 
Visit 
Early Study 
Discontinuation 
Day 0 
Day 1 
Day 2 
Day 7 
Day 14 
Day 28 
1 hour 
9-10 
hours 
1 hour 
1 hour 
30 
minutes 
30 
minutes 
30 
minutes 
1 hour 
30 minutes 
Documentation of 
HIV Status 
√ 
 
 
 
 
 
 
 
 
Medical/ 
Medication History 
√ 
√ 
 
 
 
 
 
 
 
Questions About 
Your Menstrual 
Cycle 
√ 
√ 
 
 
√ 
√ 
√ 
 
√ 
Diagnoses 
Questions 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Medication 
Questions 
 
√ 
√ 
√ 
 
 
√ 
√ 
√ 
Acceptability and 
Practicality 
Questionnaire 
 
√ 
 
√ 
 
√ 
√ 
 
√ 
Adherence 
Assessment 
√ 
√ 
√ 
√ 
 
 
 
 
 
Physical Exam 
√ 
√ 
 
 
 
 
 
√ 
 
Blood Collection 
√ 
√ 
 
 
 
 
 
 
 
Pregnancy Testing 
√ 
√ 
 
 
 
 
 
√ 
 
Hair Collection 
 
√ 
 
 
 
 
 
 
 
LNG EC 
Administration 
 
√ 
 
 
 
 
 
 
 
Pharmacokinetic 
Sampling 
 
√ 
√ 
√ 
 
 
 
 
 
 
Screening 
If you agree to let your child be in this study, after you have read and signed this informed 
consent form, your child will come to the clinic for a screening visit to make sure your child 
meets the requirements for joining the study. This visit will take about 1 hour [Site to insert site-
specific information about duration of study visit]. Up to 18 mL (1.4 tablespoons) of blood will be 
drawn at this visit.  
• 
Your child’s HIV infection status will be confirmed. If there is no record available, another 
HIV test will be done. You may have to sign a separate consent form before this is done. 


 
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• 
Your child will be asked questions about her medical and medication history and any 
medications she is currently taking. Your child will be asked about her menstrual period. 
• 
Your child will be asked about adherence to her anti-HIV or anti-TB medications (how 
correctly she is taking her medications). 
• 
Your child will have a physical exam. 
• 
Your child will have blood drawn for routine lab tests for safety. [Site to insert site-specific 
information about sharing test results with adolescents and parents/guardians.]  
• 
Your child will give a urine sample or have blood drawn to see if she is pregnant. This test 
must show that she is not pregnant for her to enroll in the study. [Site to insert site-specific 
information about sharing test results with adolescents and parents/guardians.] 
 
Entry Visit (Day 0) 
If your child is eligible for the study and you choose to let her enroll, she will come back to the 
clinic for an entry visit. This visit will last about 9 or 10 hours [Site to insert site-specific 
information about duration of study visit]. Up to 75 mL (5.8 tablespoons) of blood will be drawn 
at this visit. 
• 
Your child will be asked questions about: her medical history and any medications she is 
taking, birth control that she is taking or has taken in the last 4 months, her menstrual 
period and if there has been a change in her menstrual period since the screening visit, and 
adherence to her anti-HIV or anti-TB medications. 
• 
Your child will have a physical exam, including measuring her neck, waist, and hips. 
• 
If your child is HIV positive, she will have a blood drawn to test how much HIV is in her 
blood, and to test how many CD4 cells (infection-fighting cells) are in her blood. [Site to 
insert site-specific information about sharing test results with adolescents and 
parents/guardians.]  
• 
Your child will have blood drawn and stored for a genetic test (a test of your child’s DNA 
[genes] to better understand how fast her body removes the study drugs from your blood). 
Genetic testing looks at differences in people’s genes. Our bodies, like all living things, are 
made up of cells, and cells contain deoxyribonucleic acid, also known as “DNA.” DNA is like 
a string of information put together in a certain order. Parts of the string make up “genes.” 
Genes contain instructions on how to make our bodies work and fight disease. The testing in 
this study will only look at certain genes that are known to have an effect on how our bodies 
use hormones. The tests will not look at any other genes. Your child will not receive the 
results of these tests. 
• 
Your child will be asked to give a urine sample or have blood drawn to see if she is 
pregnant. This test must show that she is not pregnant for her to remain in the study. [Site to 
insert site-specific information about sharing test results with adolescents and 
parents/guardians.] 
• 
Your child will have a small sample of hair (about 50 strands) cut from her head to measure 
levels of the HIV or TB drugs in this hair sample. Humans lose about 100 hairs from their 
head every day naturally, so this amount of hair removal should not be noticeable. If your 
child decides not to provide a hair sample, she can still be in the study. Results of this 
testing will not be available to your child since hair levels are still a research tool. 
• 
Your child will take a dose of LNG emergency contraception by mouth.  
• 
Your child will be asked to remain at the clinic all day for an intensive pharmacokinetic (PK) 
blood sampling. For this intensive PK sampling, she will have blood drawn over 8 hours to 


 
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measure the amount of LNG in your blood. To avoid many needle sticks, a small tube 
(intravenous device) may be placed into a vein in her arm and left in place during her stay. 
Your child will be able to move around and should not have any significant pain or 
discomfort once the tube is in place. Blood will be taken before she takes the LNG 
emergency contraception dose, and then at 30 minutes, 1, 1.5, 2, 3, 4, 6, and 8 hours after 
she takes the LNG emergency contraception dose.  
• 
Your child will be asked if she has any problems or concerns after taking the LNG 
emergency contraception dose.  
 
Study Visits (Days 1 and 2) 
After the entry visit, your child will come back to the clinic for two more study visits. The first will 
be 1 day after her entry visit, and the second will be 2 days after her entry visit. These study 
visits will last about 1 hour. Up to 6 mL (0.4 tablespoons) of blood will be drawn at this visit. 
• 
Your child will have blood drawn for PK blood sampling. 
• 
Your child will be asked about: her adherence to medications, changes in her medications or 
diagnoses, the acceptability and practicality of emergency contraception, and any problems 
or concerns she has after taking the LNG emergency contraception dose.  
During the COVID-19 outbreak, the Day 1 and Day 2 study visits may be conducted over 
the phone. If the visit is conducted over the phone, a member of the study staff will call 
your child. Visits that are conducted over the phone will not include blood draws.  
 
Follow-up 
A member of the study staff will call your child 7 days after study entry to ask her about her 
menstrual period, and about changes in her diagnoses. 
 
A member of the study staff will call your child 14 and 28 days after study entry to ask her about: 
changes in her diagnoses and (on day 28 only) her medications, her menstrual period, the 
acceptability and practicality of emergency contraception, and any problems or concerns she 
has after taking the LNG emergency contraception dose.  
 
Clinically Indicated Visit 
If your child becomes pregnant or has an adverse event, she may be asked to return to the 
clinic for a physical exam and pregnancy test, and to discuss any changes in her medications or 
diagnoses. 
 
Early Study Discontinuation (Leaving the Study Early)  
If your child leaves the study early, she will be asked about: changes in her medications or 
diagnoses, her menstrual period, the acceptability and practicality of emergency contraception, 
and any problems or concerns she has after taking the LNG emergency contraception dose. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 116 women and girls who are 16 years of age or older will take part in this study. 
 
 


 
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HOW LONG WILL YOUR CHILD BE IN THIS STUDY? 
 
Your child will be in this study for about 4 weeks.  
 
 
WHY WOULD THE DOCTOR TAKE YOUR CHILD OFF THIS STUDY EARLY? 
 
The study doctor may need to take your child off the study early without your permission if: 
 
• 
The study is stopped or cancelled  
• 
Your child has a positive pregnancy test before she takes the LNG dose for the study 
• 
Your child is not able to attend the study visits as required by the study 
• 
Your child’s primary care doctor requests that she be taken off the study 
 
After the study: 
 
After your child has completed her study participation, the study will not be able to continue to 
provide your child with the LNG she received on the study. If similar drugs/agents would be of 
benefit to your child, the study staff will discuss how your child may be able to obtain them. 
 
 
WHAT ARE THE RISKS OF THE STUDY TO YOUR CHILD? 
 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these drugs. These lists include the 
more serious or common side effects with a known or possible relationship. If you have 
questions concerning the additional study drug side effects please ask the medical staff at your 
site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drugs. For your child’s safety, you must tell the study doctor or nurse about 
all medications your child is taking before she starts the study and also before she starts any 
new medications while on the study. Also, you must tell the study doctor or nurse before your 
child enrolls in any other clinical trials while on this study. 
 
Risks of Levonorgestrel (LNG, Plan B® One-Step) 
The following side effects have been associated with the use of LNG: 
• 
Nausea 
• 
Lower stomach (abdominal) pain 
• 
Tiredness 
• 
Headache 
• 
Dizziness 
• 
Breast pain 
• 
Vomiting 
• 
Diarrhea 
 


 
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Some women will have menstrual changes such as spotting or bleeding before their next period. 
Some women may have a heavier or lighter next period, or a period that is early or late.  
• 
If your child’s period is more than a week late, she should get a pregnancy test 
 
Risks of Drawing Blood 
Taking blood may cause some discomfort, bleeding, or bruising where the needle enters the 
body, lightheadedness, and in rare cases, fainting or infection. 
 
Risks of Hair Collection 
There is a small risk of cutting or nicking the scalp during the hair collection, although this is 
extremely rare. 
 
Risks of Social Harm 
It is possible that participating in this study will make it difficult for your child to keep her HIV or 
TB status, secret from people close to her. This may lead to unwelcome discussions about or 
reactions to your child’s HIV or TB status. Please talk with the study staff if you have any 
concerns about this. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
It is not known if the drug or drug combinations in this study harm unborn babies. If your child is 
are having sex that could lead to pregnancy, she must agree not to become pregnant until she 
completes the study. Your child may not enter the study if she has had sex that could lead to 
pregnancy within 14 days prior to starting the study. 
 
Your child and her partner must use reliable birth control that she discusses with the study staff. 
Your child must continue to use birth control while in the study. Your child may choose one of 
the birth control methods below:  
• 
Male condom with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Non-hormonal IUD 
• 
Bilateral tubal ligation 
• 
Male partner vasectomy 
  
If your child can become pregnant, she must have a pregnancy test before she enters this 
study. The test must show that she is not pregnant. If your child thinks she may be pregnant at 
any time during the study, she must tell the study staff right away. The study staff will talk to 
your child about her choices. A pregnancy test may not detect a very early pregnancy, which is 
why the study team asks that your child not enter the study if she has had sex that could lead to 
pregnancy within 14 days of study entry.   
 
If your child becomes pregnant while on study, the study staff would like to obtain information 
from her about the outcome of the pregnancy (even if it is after her participation in the study 
ends). If your child is taking anti-HIV drugs when she becomes pregnant, her pregnancy will be 
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taking anti-HIV drugs. This report will not use your child’s name or other information that could 
be used to identify her. 
 
Breastfeeding 
Breastfeeding women will be included only after their infants are at least 6 months old. Birth 
control like LNG is allowed during breastfeeding. During long-term use of drugs like LNG, called 
progestins, the amount of progestin in infant blood is only 1-6% of the amount in maternal blood. 
No side effects of progestins have been found on breastfeeding (quality or quantity of milk), or 
on the health or development of the infant due to this low progestin exposure. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
Your child will receive no benefit from being in this study. Information learned from this study 
may help other women and girls who have HIV or TB. 
 
  
WHAT ABOUT CONFIDENTIALITY? 
 
For Sites in the US 
We will do everything we can to protect your child’s privacy. In addition to the efforts of the study 
staff to help keep your child’s personal information private, we have gotten a Certificate of 
Confidentiality from the US Federal Government. This certificate means that researchers cannot 
be forced to tell people who are not connected with this study, such as the court system, about 
your participation. Also, any publication of this study will not use your child’s name or identify 
your child personally.  
 
Your child’s records may be reviewed by the ACTG, the US Office for Human Research 
Protections (OHRP), or other local, US, and international regulatory entities as part of their 
duties, (insert name of site) institutional review board (IRB) (a committee that protects the rights 
and safety of participants in research), National Institutes of Health (NIH), study staff, study 
monitors, and their designees. Having a Certificate of Confidentiality does not prevent you from 
releasing information about your child and your child’s participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by US 
law. This website will not include information that can identify your child. At most, the website 
will include a summary of the results. You can search this website at any time.  
 
For Sites outside the US 
Efforts will be made to keep your child’s personal information confidential. We cannot guarantee 
absolute confidentiality. Your child’s personal information may be disclosed if required by law. 
Any publication of this study will not use your child’s name or identify your child personally. 
 


 
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Your child’s records may be reviewed by the ACTG, the US Office for Human Research 
Protections (OHRP), or other local, US, and international regulatory entities as part of their 
duties, (insert name of site) institutional review board (IRB) or Ethics Committee (a committee 
that protects the rights and safety of participants in research), National Institutes of Health 
(NIH), study staff, study monitors, and their designees.  
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by US 
law. This website will not include information that can identify your child. At most, the website 
will include a summary of the results. You can search this website at any time.  
 
 
WHAT ARE THE COSTS TO ME? 
 
Taking part in this study may lead to added costs to you and your insurance company. In some 
cases it is possible that your insurance company will not pay for these costs because your child 
is taking part in a research study.  
 
There is no cost to you for LNG, study-related visits, physical examinations, laboratory tests, or 
other study procedures.  
 
Anti-HIV and anti-TB medicines will not be provided by the study. 
 
 
WILL MY CHILD RECEIVE ANY PAYMENT? 
 
Your child may be reimbursed for her time and travel expenses as part of her participation in 
this study. (Site to insert site-specific information about payment to adolescents.)  
 
 
WHAT HAPPENS IF YOUR CHILD IS INJURED? 
 
If your child is injured as a result of your being in this study, your child will be given 
immediate treatment for injuries and be referred for further treatment, if necessary.  
[Sites: Please modify (if necessary) and insert one of these two statements, as 
appropriate to your site. If your site is required to carry Clinical Trials Insurance (CTI), 
this must be indicated in the informed consent.] 
• 
This site has clinical trials insurance. This insurance will allow the site to provide 
your child with monetary compensation if your child suffers harm as a result of 
participating in this research study.  
• 
The cost for this treatment will be charged to you/your child or your child’s insurance 
company. There is no program for compensation either through this institution or the 
NIH.  
You will not be giving up any of your legal rights by signing this consent form. 
 
 


 
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WHAT ARE YOUR CHILD’S RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to let your child take part 
in this study or to remove your child from this study at any time. Your child may choose to 
leave the study at any time. Your decision will not have any impact on your child’s 
participation in other studies conducted by NIH and will not result in any penalty or loss of 
benefits to which your child is otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your child’s 
health, welfare, or willingness to stay in this study. If you want the results of the study, let the 
study staff know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
• 
Name of the investigator or other study staff 
• 
Telephone number of above  
 
For questions about your child’s rights as a research participant, contact: 
 
• 
Name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
Telephone number of above 
 


 
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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered, and you agree to let your child to take part in this study, please sign your name 
below. 
 
 
 
____________________________ 
__________________________________ 
Child Participant’s Name (print) 
Child Participant’s Date of Birth 
 
 
____________________________ 
__________________________________ 
Parent/Legal Guardian Name (print) 
Parent/Legal Guardian Signature and Date 
(As appropriate) 
 
 
____________________________ 
__________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
 
____________________________ 
__________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 
 
 


 
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ATTACHMENT II-A: PARENTAL CONSENT FOR USE OF SAMPLES IN OTHER STUDIES 
 
When samples are no longer needed for this study, the ACTG may want to use them in 
other studies and share them with other researchers. These samples are called “extra 
samples.” The ACTG will only allow your child’s extra samples to be used in other 
studies if you agree to this. If you have any questions, please ask. 
 
Identifiers will be removed from your child’s samples and from any information that has 
been collected about your child. This means that no one looking at the labels or at other 
information will know that the samples or information came from your child.  
 
Extra samples are stored in a secure central place called a repository. Your child’s 
samples will be stored in the ACTG repository located in the United States. 
 
There is no limit on how long your child’s extra samples will be stored.  
[Site: Revise the previous sentence to insert limits if your regulatory authority imposes 
them.] 
 
When a researcher wants to use your child’s samples and information, their research 
plan must be approved by the ACTG. Also, the researcher’s institutional review board 
(IRB) or ethics committee (EC) will review their plan. [Site: If review by your institution’s 
IRB/EC/RE is also required, insert a sentence stating this.] IRBs/ECs protect the rights 
and well-being of people in research. If the research plan is approved, the ACTG will 
send your child’s samples to the researcher’s location. This means that researchers who 
are not part of the protocol team may use your child’s samples without asking you or 
your child again for consent.  
 
You will not be paid for your child’s samples. Also, a researcher may make a new 
scientific discovery or product based on the use of your child’s samples. If this 
happens, there is no plan to share any money with you or your child.  
 
You may withdraw your consent for research on your extra samples at any time, and the 
specimens will be discarded. 
 
Please choose the response that matches what you want by putting your initials in the 
space provided. Please ask the staff any questions that you have before you indicate 
your selection. 
 
Research without Human Genetic Testing  
If you agree, your child’s extra samples may be stored (with usual protection of your 
child’s identity) and used for ACTG-approved HIV-related research that does not include 
human genetic testing. 
 
____ (initials) I understand and I agree to this storage and possible use of my child’s 
samples  
 


 
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OR 
____ (initials) I understand but I do not agree to this storage and possible use of my 
child’s samples 
 
Research with Human Genetic Testing  
The ACTG has two different studies that collect samples for genetic testing. 
 
If you live in the US, this study is called ACTG A5128, Plan for Obtaining Informed 
Consent to Use Stored Human Biological Materials (HBM) for Currently Unspecified 
Analyses. 
 
If you live outside of the US, this study is called ACTG A5243, Plan for Obtaining Human 
Biological Samples at Non-US Clinical Research Sites for Currently Unspecified Genetic 
Analyses. 
 
Your site might ask you if you would like your child to participate in one of these 
studies if it is being done where you live. If you would like your child to participate, you 
will sign a separate consent form. 
 
Your child’s extra samples will not be used for human genetic testing unless you sign a 
consent for A5128 or A5243.  
 
 
 
 


 
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APPENDIX III: SAMPLE ASSENT FORM 
 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
For protocol: A5375  
 
An Open-Label, Phase II Pharmacokinetic Study to Evaluate Double-Dose Levonorgestrel 
Emergency Contraception in Combination with Efavirenz-Based Antiretroviral Therapy or 
Rifampicin-Containing Anti-Tuberculosis Therapy 
 
FINAL Version 2.0, 10/30/20 
 
 
SHORT TITLE FOR THE STUDY: Optimize LNG EC 
 
 
SUMMARY 
 
PURPOSE: 
Emergency contraception is birth control that prevents pregnancy. 
Girls and women use it after having unprotected sex. Levonorgestrel 
(LNG) emergency contraception is commonly known as Plan B® 
One-Step, or the Morning After Pill. This study will test if a higher 
dose of LNG needs to be used to prevent pregnancy in girls and 
women who are taking some types of anti-HIV or anti-TB 
medications. This study will also test if a higher dose of LNG is safe.  
 
STUDY 
TREATMENT: 
You will take a dose of LNG emergency contraception by mouth. 
LNG emergency contraception will be provided by the study. 
 
The United States Food and Drug Administration (US FDA) has 
approved LNG for prevention of pregnancy. 
 
NUMBER OF 
PARTICIPANTS: 
There will be 116 women and girls who are 16 years of age or older 
in this study. There will be 17 people in Group A, and 33 people in 
each of Groups B, C, and D. 
 
LENGTH 
OF STUDY: 
The study will last about 4 weeks. During this time, you will need to 
come to the clinic for about 3 visits. 
 
REQUIRED 
ACTIVITIES: 
Blood and Urine Collections 
At most visits, some blood will be collected from a vein in your arm. 
You may be asked to provide a urine sample. 
  


 
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At the entry visit, you will be asked to remain at the clinic all day for 
an intensive pharmacokinetic (PK) blood sampling. For this 
intensive PK sampling, you will have blood drawn several times over 
a period of 8 hours to measure the amount of LNG in your blood. To 
avoid many needle sticks, a small tube (intravenous device) will be 
placed into a vein in your arm and left in place during your stay. You 
will be able to move around and should not have any significant pain 
or discomfort once the tube is in place.  
 
RISKS: 
The following side effects have been associated with using LNG: 
nausea, lower stomach pain, tiredness, headache, dizziness, breast 
pain, vomiting, and diarrhea. Some individuals will have menstrual 
changes such as spotting or bleeding before their next period. Some 
individuals may have a heavier or lighter next period, or a period 
that is early or late. 
 
Taking blood may cause some discomfort, bleeding, or bruising 
where the needle enters the body, lightheadedness, and in rare 
cases, fainting or infection. 
 
BENEFITS: 
You will receive no benefit from being in this study. 
 
OTHER CHOICES:  Instead of being in this study, you have the option of continuing with 
your current treatment or starting a new treatment under the care of 
your regular doctor or other health care provider. 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are a girl at least 16 years 
of age and: 
 
1. You are living with human immunodeficiency virus (HIV-1) and you have been taking a 
combination of antiretroviral drugs (ARV) that includes either efavirenz (EFV) or dolutegravir 
(DTG) 
 
OR, 
 
2. You are living with tuberculosis (TB) infection, and you have completed the intensive phase 
of TB therapy and are now completing the continuation phase of TB treatment that requires 
taking isoniazid (INH) and rifampicin (RIF) daily. 
 
Your parent/guardian will be informed about this study and asked to sign a separate form giving 
their consent for you to take part. As a participant in this study, we would like you to know about 
the study too, and to be given a chance to ask any questions you may have about it. You will be 
asked to sign this assent form. You will get a copy to keep. 
 
 


 
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WHY IS THIS STUDY BEING DONE? 
 
Emergency contraception is birth control that prevents pregnancy. Girls and women use it after 
having unprotected sex. Levonorgestrel (LNG) emergency contraception is commonly known as 
Plan B® One-Step, or the Morning After Pill. This study will test if a higher dose of LNG needs to 
be used to prevent pregnancy in girls and women who are taking some types of anti-HIV or anti-
TB medications. This study will also test if a higher dose of LNG is safe.  
 
The United States Food and Drug Administration (US FDA) has approved LNG for prevention of 
pregnancy.  
 
LNG works mainly by stopping the release of an egg from the ovary. It may also work by 
preventing fertilization of an egg, or by preventing attachment to the uterus. Girls and women 
can use emergency contraception to prevent pregnancy if regular birth control was used 
incorrectly or fails, or no birth control was used. LNG will not disrupt an existing pregnancy and 
using LNG does not affect your ability to have a baby in the future. After you take LNG as part of 
this study, you may attempt to get pregnant again as soon as your next menstrual cycle (after 
your next period), if you want to. 
 
Efavirenz (EFV) is a medication commonly used to treat HIV. Rifampicin (RIF) is a medication 
commonly used to treat tuberculosis. Both of these medications lower the amount of LNG in 
your blood by about half. This may make LNG not work as well as it normally would. It is 
unknown if the current dose of LNG emergency contraception, in combination with EFV or RIF, 
is enough to prevent a pregnancy. To learn if a higher dose is needed to prevent pregnancy, 
participants will take either a regular dose or a double dose of LNG emergency contraception. 
 
Dolutegravir (DTG) is an anti-HIV medication that does not lower the amount of LNG in your 
blood. It is being used as a comparison to the other groups.   
 
In this study, you will not be taking LNG for contraception (to prevent pregnancy), you will be 
volunteering to take it so that we can evaluate the impact of your other medications on the 
amount of LNG in your blood. You will take a dose of LNG emergency contraception by mouth. 
After you take the dose of LNG, the amount of LNG that is in your blood will be measured. This 
study will also take a hair sample that will tell researchers how often you have taken EFV, INH, 
and DTG over the past few weeks. You can refuse to give a hair sample. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
People who take part in this study will be asked to be part of it for 4 weeks. A screening visit will 
be done to make sure you are eligible to join the study. If you are found eligible, you will have 
one entry visit that will last 9-10 hours, a 1 hour visit 24 hours after entry, and a 1 hour visit 48 
hours after entry. You will be asked to take a questionnaire over the phone 1 week, 2 weeks, 
and 4 weeks after entry.  
 
The study staff can tell you more about the study visits and what exactly will be done at the 
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and the possible effects of these medicines. They will also tell you about health problems that 
they would like you to report to them. You are welcome to ask any questions you may have at 
any time. 
 
We would also like you to know that information collected in this study will be kept confidential 
(private) and only those people who are doing the study and are overseeing the study will be 
able to see your information. [Sites should also include a statement here describing the extent 
to which information reported by children/adolescents will be shared with their 
parents/guardians]. 
 
Taking part in this study is your choice. This means you can say yes or no to being part of the 
study. No matter what decision you make, and even if your decision changes, nothing bad will 
happen to you or your family. You will not lose medical care, legal rights, or any benefits that 
you are otherwise entitled to. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these drugs. These lists include the 
more serious or common side effects with a known or possible relationship. If you have 
questions concerning the additional study drug side effects please ask the medical staff at your 
site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drugs. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
 
Risks of Levonorgestrel (LNG, Plan B® One-Step) 
The following side effects have been associated with the use of LNG: 
• 
Nausea 
• 
Lower stomach (abdominal) pain 
• 
Tiredness 
• 
Headache 
• 
Dizziness 
• 
Breast pain 
• 
Vomiting 
• 
Diarrhea 
 
Some women will have menstrual changes such as spotting or bleeding before their next period. 
Some women may have a heavier or lighter next period, or a period that is early or late.  
• 
If your period is more than a week late, you should get a pregnancy test 
 


 
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Risks of Drawing Blood 
Taking blood may cause some discomfort, bleeding, or bruising where the needle enters the 
body, lightheadedness, and in rare cases, fainting or infection. 
 
Risks of Hair Collection 
There is a small risk of cutting or nicking the scalp during the hair collection, although this is 
extremely rare. 
 
Risks of Social Harm 
It is possible that participating in this study will make it difficult for you to keep your HIV or TB 
status, or information about your sexual activity, secret from people close to you. This may 
include your parent or guardian. This may lead to unwelcome discussions about or reactions to 
your HIV or TB status. Please talk with the study staff if you have any concerns about this. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
It is not known if the drug or drug combinations in this study harm unborn babies. If you are 
having sex that could lead to pregnancy, you must agree not to become pregnant until you 
complete the study. You may not enter the study if you have had sex that could lead to 
pregnancy within 14 days prior to starting the study. 
 
You and your partner must use reliable birth control that you discuss with the study staff. You 
must continue to use birth control while in the study. You may choose one of the birth control 
methods below:  
• 
Male condom with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Non-hormonal IUD 
• 
Bilateral tubal ligation 
• 
Male partner vasectomy 
  
If you can become pregnant, you must have a pregnancy test before you enter this study. The 
test must show that you are not pregnant. If you think you may be pregnant at any time during 
the study, tell your study staff right away. The study staff will talk to you about your choices. A 
pregnancy test may not detect a very early pregnancy, which is why the study team asks that 
you not enter the study if you have had sex that could lead to pregnancy within 14 days of study 
entry.   
 
If you become pregnant while on study, the study staff would like to obtain information from you 
about the outcome of the pregnancy (even if it is after your participation in the study ends). If 
you are taking anti-HIV drugs when you become pregnant, your pregnancy will be reported to 
an international database that collects information about pregnancies in women taking anti-HIV 
drugs. This report will not use your name or other information that could be used to identify you. 
 


 
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Breastfeeding 
Breastfeeding women will be included only after their infants are at least 6 months old. Birth 
control like LNG is allowed during breastfeeding. During long-term use of drugs like LNG, called 
progestins, the amount of progestin in infant blood is only 1-6% of the amount in maternal blood. 
No side effects of progestins have been found on breastfeeding (quality or quantity of milk), or 
on the health or development of the infant due to this low progestin exposure. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
You will receive no benefit from being in this study. Information learned from this study may help 
other women who have HIV or TB. 
 
 


 
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SIGNATURE PAGE 
 
If you have read this form (or had it read and explained to you), all your questions have been 
answered, and you agree to take part in this study, please sign your name below. 
 
 
 
_____________________________________ 
Child Participant’s Name and Surname (print) 
 
 
 
_____________________________________  
Child Participant’s Date of Birth  
 
 
 
_____________________________________  
Child Participant’s Signature and Date 
 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Assent Discussion (print)  
 
 
 
____________________________ 
_________________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 
 
 
 


 
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APPENDIX IV: PROHIBITED AND PRECAUTIONARY MEDICATIONS 
Some drugs on these lists that can be used topically may be allowed on a case-by-case 
basis, after discussion with and approval by the protocol team via e-mail as described in 
the Study Management section. 
 
1.0 PROHIBITED MEDICATIONS 
 
1.1 Other Hormones  
 
All Groups: Efavirenz, Dolutegravir, Rifampicin 
• 
Delestrogen 
• 
Depotestrogen 
• 
Desogestrel 
• 
Drospirenone 
• 
Estradiol cypionate 
• 
Estradiol Valerate 
• 
Estrogens, Conjugated 
• 
Estrogens, Esterfied 
• 
Ethinyl Estradiol 
• 
Ethynodiol Diacetate 
• 
Etonogestrel 
• 
Gestodene 
• 
Hydroxyprogesterone 
• 
Levonorgestrel 
• 
Medroxyprogesterone 
• 
Norelgestromin 
• 
Norethindrone 
• 
Norgestimate 
• 
Norgestrel 
• 
Progesterone 
• 
Testosterone 
 
1.2 
Other Concomitant Medications  
 
Group A and B: Efavirenz 
• 
Amodiaquine 
• 
anticonvulsants (carbamezepine, Eslicarbazepine, felbamate, fosphenytoin, 
Lamotrigine, Oxcarbazepine, Perampanel, phenytoin)  
• 
Astemizole 
• 
Azole Antifungals (Fluconazole, itraconazole, ketoconazole, posaconazole, 
voriconazole)  
• 
barbiturates (phenobarbital, primidone) 
• 
Bepridil 
• 
cat's claw 


 
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• 
Cisapride 
• 
dexamethasone 
• 
Dihydroergotamine 
• 
Enzalutamide 
• 
Ergotamine 
• 
Griseofulvin 
• 
integrase strand transfer inhibitors (including dolutegravir, elvitegravir, raltegravir, 
bictegravir) 
• 
Macrolides (Clarithromycin, erythromycin) 
• 
maraviroc 
• 
Midazolam 
• 
Mitotane 
• 
Other Nonnucleoside reverse transcriptase inhibitors (including nevirapine, 
rilpivirine, delavirdine, doravirine) 
• 
Protease inhibitors (HIV or HCV) 
• 
Rifamycins (including rifampin, rifapentine & rifabutin) 
• 
St John's Wort 
• 
Terfenadine 
 
Group C: Dolutegravir 
• 
African potato 
• 
anticonvulsants (carbamezepine, Eslicarbazepine, felbamate, fosphenytoin, 
Lamotrigine, Oxcarbazepine, Perampanel, phenytoin) 
• 
Azole Antifungals (Fluconazole, itraconazole, ketoconazole, posaconazole, 
voriconazole)  
• 
barbiturates (phenobarbital, primidone) 
• 
Dofetilide 
• 
Enzalutamide 
• 
Macrolides (Clarithromycin, erythromycin) 
• 
maraviroc 
• 
Mitotane 
• 
Nonnucleoside reverse transciptase inhibitors (including efavirenz, nevirapine, 
rilpivirine, delavirdine, doravirine) 
• 
Other integrase strand transfer inhibitors (including elvitegravir, raltegravir, 
bictegravir) 
• 
protease inhibitors (HIV or HCV) 
• 
Rifamycins (including rifampin, rifapentine & rifabutin) 
• 
St John's Wort 
 
Group D: Rifampicin 
• 
anticonvulsants (carbamezepine, Eslicarbazepinefelbamate, fosphenytoin, 
Lamotrigine, Oxcarbazepine, Perampanel, phenytoin) 
• 
Azole Antifungals (Fluconazole, itraconazole, ketoconazole, posaconazole, 
voriconazole)  
• 
barbiturates (phenobarbital, primidone) 


 
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• 
Enzalutamide 
• 
Halothane 
• 
integrase strand transfer inhibitors (including dolutegravir, elvitegravir, raltegravir, 
bictegravir) 
• 
Macrolides (Clarithromycin, erythromycin) 
• 
maraviroc 
• 
Mitotane 
• 
Nonnucleoside reverse transciptase inhibitors (including efavirenz, nevirapine, 
rilpivirine, delavirdine, doravirine) 
• 
Other Rifamyacins (rifabutin & rifapentine) 
• 
protease inhibitors (HIV or HCV) 
• 
St. John's Wort 
 
2.0 
PRECAUTIONARY MEDICATIONS 
 
Groups A and B: Efavirenz 
• 
Aprepitant 
• 
Artemether/lumefantrine  
• 
Atovaquone/proguanil 
• 
Azole antifungals (itraconazole, posaconazole) 
• 
Bosentan 
• 
clopidogrel 
• 
diltiazem 
• 
Fosaprepitant 
• 
garlic 
• 
ginkgo biloba 
• 
GLP-1 agonists (exenatide, lixisenatide) 
• 
hops 
• 
Lesinurad 
• 
malabar nut tree 
• 
Mycophenolate 
• 
nefazodone 
• 
pioglitazone 
• 
Proguanil 
• 
Prucalopride 
• 
quercetin 
• 
Telithromycin 
• 
ticlopidine 
• 
Topiramate 
• 
Triazolam 
 
Group C: Dolutegravir 
• 
antacids - follow product labeling for instructions on separation with DTG 
• 
Aprepitant 
• 
Artemether/lumefantrine  


 
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• 
buffered medications -  follow product labeling for instructions on separation with 
DTG 
• 
divalent cations (e.g., Ca++, Fe++) - follow product labeling for instructions on 
separation with DTG 
• 
Fosaprepitant 
• 
garlic 
• 
GLP-1 agonists (exenatide, lixisenatide) 
• 
Lesinurad 
• 
malabar nut tree 
• 
MVI -  follow product labeling for instructions on separation with DTG 
• 
Mycophenolate 
• 
Prucalopride 
• 
sucralfate -  follow product labeling for instructions on separation with DTG 
• 
Topiramate 
 
Group D: Rifampicin 
• 
antacids  - follow product labeling for instructions on separation with RIF 
• 
Aprepitant 
• 
Artemether/lumefantrine  
• 
cotrimoxazole 
• 
Fosaprepitant 
• 
GLP-1 agonists (exenatide, lixisenatide) 
• 
Lesinurad 
• 
Mycophenolate 
• 
probenecid 
• 
Prucalopride 
• 
Topiramate 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPROVALS 
 


 
 
 
 
ACTG A5375 
 
Primary Statistical Analysis Plan 
Version 3.0 
 
An Open-Label, Phase II Pharmacokinetic Study to Evaluate 
Double-Dose Levonorgestrel Emergency Contraception in 
Combination with Efavirenz-Based Antiretroviral Therapy or 
Rifampicin-Containing Anti-Tuberculosis Therapy 
Protocol Version 2.0 
 
ClinicalTrials.gov Identifier: NCT03819114 
 
May 24, 2021
 
This is the ACTG A5375 SAP Version 3.0 with names of authors, names of 
publication writing team members, and analysis timelines redacted. 


A5375 – Primary Statistical Analysis Plan Version 3.0 
May 24, 2021 
 
 
Page 1 of 14 
 
1 
INTRODUCTION ........................................................................................................................ 1 
1.1 
Purpose ............................................................................................................................ 1 
1.2 
Version History Table ..................................................................................................... 2 
2 
STUDY OVERVIEW ................................................................................................................... 3 
2.1 
Study Design ................................................................................................................... 3 
2.1.1 
Primary Hypotheses: ............................................................................................ 5 
2.1.2 
Secondary Hypotheses: ....................................................................................... 5 
2.2 
Study Objectives ............................................................................................................. 5 
2.2.1 
Primary Objectives ............................................................................................... 5 
2.2.2 
Secondary Objectives .......................................................................................... 5 
2.2.3 
Exploratory Objectives ......................................................................................... 6 
2.3 
Overview of Sample Size Considerations .................................................................... 6 
2.4 
Overview of Formal Interim Monitoring ........................................................................ 6 
2.4.1 
Timing of reviews ................................................................................................. 6 
2.4.2 
Scope of reviews .................................................................................................. 7 
3 
OUTCOME MEASURES ........................................................................................................... 7 
3.1 
Primary Outcome Measures .......................................................................................... 7 
3.2 
Secondary Outcome Measures ..................................................................................... 9 
3.2.1 
Safety ................................................................................................................... 9 
3.2.2 
Secondary LNG PK Parameters ........................................................................ 10 
3.3 
Other Outcome Measures ............................................................................................ 11 
4 
STATISTICAL PRINCIPLES ................................................................................................... 12 
4.1 
General Considerations ............................................................................................... 12 
4.1.1 
Analysis sets ...................................................................................................... 12 
4.1.2 
Other general considerations ............................................................................. 12 
4.2 
Analysis Approaches ................................................................................................... 13 
4.2.1 
Calculating Geometric Means, GMRs and associated confidence intervals ..... 13 
4.2.2 
Primary PK analysis ........................................................................................... 13 
5 
REPORT CONTENTS ............................................................................................................. 14 
 
 
1 
Introduction 
1.1 
Purpose  
This Primary Statistical Analysis Plan (SAP) describes the primary and secondary outcome 
measures and any additional outcome measures of the ACTG A5375 study that will be included 
in the primary manuscript, and which address, at a minimum, the major primary and secondary 
objectives of the study. The Primary SAP outlines the general statistical approaches that will be 
used in the analysis of the study. It has been developed to facilitate discussion of the statistical 


A5375 – Primary Statistical Analysis Plan Version 3.0 
May 24, 2021 
 
 
Page 2 of 14 
analysis components among the study team, and to provide agreement between the study team 
and statisticians regarding the statistical analyses to be performed and presented in the Primary 
Analysis Report. It also describes the results for the primary and secondary outcome measures 
that will be posted on ClinicalTrials.gov.  
Detailed outlines of tables, figures, and coding descriptions that will be included in the Primary 
Analysis Report are included in the Analysis Implementation Plan (AIP).  
Analyses for the Primary Analysis Report will be finalized once the last participant has completed 
the study, all queries have been resolved, and the study database closure/data lock has been 
completed. 
1.2 
Version History Table 
Version 
Changes Made 
Rationale 
Effective Date 
1 
Original Version 
 
09/10/2019 
2 
Addition of SMC letter recommendation 
about PK replacement and edits based on 
team discussion/consensus  
Edits to PK data imputations based on 
assay limits 
Review/update of SAP 
done in preparation for 
study closure based on 
said timeline 
07/24/2020 
3.0 
Minor formatting changes, correction of 
typo, and other minor updates to align with 
protocol version 2. 
Attachment 2 : timeline was updated to 
reflect current forecasting near time of 
primary analysis initiation 
Removal of contingency language to 
perform primary analysis in 2 stages based 
on observed prompt completion of accrual. 
Reversing ratio for secondary comparison 
of groups A versus B so that Group A is in 
the denominator of the GMR. 
Refining definition of other outcome 
measure – single timed concentration of 
RIF and associated metabolites, to reflect 
testing of earlier post RIF dose samples 
due to accelerated clearance of RIF. And 
updating the thresholds for exclusion of 
participants in secondary analyses due to 
inadequate perpetrator drug 
concentrations. 
Review triggered by 
finalization and release 
of protocol version 2 
(dated 10/30/2020) 
05/24/2021 


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Page 3 of 14 
Addition of sensitivity analysis to the 
primary PK (for the assumption of equal 
variance between groups), as well as 
supplementary analyses to explore the 
robustness of primary PK analyses: a) 
exclusion of participants with inadequate 
measured exposure to perpetrator drug , 
and b) calculation of adjusted GMRs to 
account for imbalance in prognostic factors 
between comparison groups. 
2 
Study Overview 
2.1 
Study Design  
Copied from v2 (10/30/2020) Protocol Schema: 
DESIGN  
A5375 is a phase II, open-label, four parallel group, partially randomized, 
pharmacokinetic (PK) study to evaluate if a double dose of 
levonorgestrel (LNG) emergency contraception (EC) overcomes known 
drug-drug interactions (DDIs) with efavirenz (EFV)-based antiretroviral 
therapy (ART) or rifampicin (RIF)-containing tuberculosis (TB) therapy. 
The safety of double-dose LNG EC versus standard-dose will also be 
compared.  
 
Participants will be volunteers who do not currently require EC for 
contraception. Eligible participants will receive a single dose (1.5 mg) or 
a double dose (3.0 mg) of LNG EC based on their group assignment, 
which will be determined by their infection (HIV or TB; participants 
cannot be coinfected), and, for those who are living with HIV, by their 
ART regimen at enrollment (see Schema Figure 1). Women living with 
HIV who are taking EFV-based ART will be randomized to Group A or B 
(1:2 ratio). Women taking dolutegravir (DTG)-based ART will be 
assigned to Group C. Women who are HIV-negative and in the 
continuation phase of TB treatment taking RIF and isoniazid (INH) will be 
assigned to Group D.  
DURATION 
All participants will be followed for 4 weeks. 
SAMPLE SIZE 
116 participants; 17 in Group A, 33 in each of Groups B, C, and D.  
POPULATION 
Women who are 16 years of age or older, and who are either HIV+ and 
on stable ART, or who are HIV- and in the continuation phase of anti-TB 
therapy on daily INH/RIF.  
STRATIFICATION 
At entry, women with body mass index (BMI) ≥30 kg/m2 will be limited to 
no more than five within Groups B-D and no more than three within 
Group A. 


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Page 4 of 14 
REGIMEN  
Women in Groups A and C will receive 1.5 mg LNG EC once at study 
entry.  
Women in Groups B and D will receive 3.0 mg LNG EC once at study 
entry. 
 
Schema Figure 1: Study Design 
 
 


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Page 5 of 14 
Hypotheses (copied from protocol v2): 
2.1.1 
Primary Hypotheses: 
1)  
Women receiving double-dose levonorgestrel (LNG) emergency contraception (EC) with 
efavirenz (EFV)-based antiretroviral therapy (ART) will achieve similar LNG 
concentrations compared to women receiving standard-dose LNG EC on dolutegravir 
(DTG)-based ART. 
2) 
Women receiving double-dose LNG EC with rifampicin (RIF)-containing tuberculosis (TB) 
therapy will achieve similar LNG concentrations compared to women receiving standard-
dose LNG EC on DTG-based ART. 
2.1.2 
Secondary Hypotheses: 
1) 
Among women receiving EFV-based ART, double-dose LNG EC will achieve significantly 
higher LNG concentrations than standard-dose LNG EC. 
2) 
Women receiving standard-dose LNG EC with EFV-based ART will achieve significantly 
lower LNG concentrations than women receiving standard-dose LNG EC on DTG-based 
ART. 
3) 
Double-dose and standard-dose LNG EC will have similar safety profiles. 
2.2 
Study Objectives 
This Primary SAP addresses the following primary and secondary objectives listed in the study 
protocol. Other study objectives in the protocol will be addressed in subsequent analysis plans.  
Inference framework varies by objective/hypothesis above, and some comparisons rely on 
interpretation of confidence intervals rather than hypothesis testing. Because there is not a single 
framework across the analysis, these details will be provided by outcome below. 
Objectives (copied from protocol v2): 
2.2.1 
Primary Objectives 
1)  
To determine if doubling the dose of the LNG EC effectively overcomes the known drug-
drug interaction (DDI) with EFV-based ART.  
2)  
To determine if doubling the dose of the LNG EC effectively overcomes the expected DDI 
with RIF-containing TB therapy. 
2.2.2 
Secondary Objectives 
1)  
To estimate the difference in LNG pharmacokinetic (PK) exposure with double-dose LNG 
EC compared to standard-dose LNG EC in women receiving EFV-based ART.  
2) 
To estimate the difference in LNG PK exposure with standard-dose LNG EC in women 
receiving EFV-based ART compared to women receiving DTG-based ART.  


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Page 6 of 14 
3) 
To verify the absence of significant DDI between LNG EC and DTG-based ART. 
4) 
To compare the safety of double-dose LNG EC compared to standard-dose LNG EC.  
5)  
To evaluate the relationship between baseline measures of body weight (body fat 
percentage, total weight, and body mass index [BMI]) and LNG PK exposure. 
2.2.3 
Exploratory Objectives 
1)  
To characterize the relationship between short- and long-term adherence to ART or TB 
therapy and LNG exposure using objective pharmacologic measures. [Note: only short-
term adherence will be assessed in the primary analysis, via measured concentrations of 
targeted ART or TB medications.] 
2.3 
Overview of Sample Size Considerations 
Given that a therapeutic target for minimum exposure required or average exposure expected for 
single dose use of LNG as emergency contraception (EC) is unknown, this study is estimating 
whether adjusted dosing of LNG under a known DDI achieves similar exposure to LNG single 
dose as measured by the geometric mean ratio (GMR) of the AUC of LNG concentrations over 
the 8 hours post dose.  
Assuming 30 women per comparison group, coefficient of variation of AUG(LNG0-8hr)= 0.45 
{and standard deviation on 0.429 of AUC(LNG) as calculated from CV using the formula square 
root of [ln(CV^2+1)] }, and significance level 10% (corresponding to inverting 2 one-sided tests, 
each at 5% significance), then under true GMR=100%, there is 88% statistical power for 
declaring similarity in LNG exposure between groups using No-Effect Bounds of (70%,143%). 
Under similar assumptions, a 90% 2-sided confidence interval (calculated as median LCB and 
UCB from simulations), about a true GMR=100% ranges over (83%, 120%). Final sample sizes 
for accrual goals were inflated by 10% to protect against losses to follow-up. 
The protocol document has further details on sample size justification. 
Note that information above has been copied from the protocol. For analysis and reporting 
purposes, it has been decided to report GMR on the ratio scale (where 1=equivalence rather than 
100%), and so the No-Effect Bounds in the analysis sections below use adjusted scaling to match 
the GMR scale for analysis and reporting. 
2.4 
Overview of Formal Interim Monitoring 
2.4.1 
Timing of reviews 
This study will be formally monitored at least annually by an ACTG network-appointed SMC. The 
first interim review will occur no more than one year after the enrollment of the first participant or 
approximately 3 months after 25 women have completed the study, whichever occurs earlier. An 
additional SMC review may be triggered if the accrual at one year is less than 50% of total 
expected accrual. The protocol provides further details on an interim review triggered by slow 
accrual. An unplanned interim review will be triggered if, at any time, any participant experiences 
an SAE that is attributed to LNG (by adjudication by the core team and DAIDS clinical 


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Page 7 of 14 
representative), or if more than five women need to be replaced in the PK analysis set (see 
protocol section 9.2).  
Note: Eligibility and enrollment issues that cause participant replacement will not be included in 
the above limit of 5 women.  
2.4.2 
Scope of reviews 
There are no plans to initiate PK testing prior to initiation of the primary and/or final analysis, and 
thus there are no planned early looks or interim analysis of the primary efficacy outcome, or 
related outcomes calculated from PK concentrations. Therefore, the scope of interim reviews will 
be study conduct and safety. 
3 
Outcome Measures 
Note: Outcome Measure information in italics inside boxes reflects the clinicaltrials.gov record 
specifications. Even though some secondary outcomes below are evaluated after the PCD, 
because study duration is only one month, we anticipate that all primary and secondary outcomes 
will be reported with the initial clinicaltrials.gov results submission.  
3.1 
Primary Outcome Measures 
Title: LNG PK Parameter Area under the concentration-time curve (AUC0-8h) calculated 
based on intensive LNG PK samples obtained from individual participants 
Description: AUC for each participant will be calculated from LNG concentrations 
measured over 8 hours using the linear up/log down version of the trapezoidal rule (i.e., 
noncompartmental technique) using the software package Phoenix WinNonLin 
(Certara®). This version of the trapezoidal rule uses linear interpolation between 
untransformed data up to Cmax, and between log-transformed data from Cmax through Clast. 
Assay lower limit of quantification for LNG was 0.025 ng/mL; values < LLOQ were 
imputed as 0 (if pre-dose) or as 0.125 (if post-dose) 
Time Frame: Intensive LNG PK samples within 30 minutes pre-dose, and at 0.5, 1, 1.5, 
2, 3, 4, 6, and 8 hours post-dose 
Analysis Population: Participants with PK concentrations over 8 hours post LNG dose 
and who took both assigned dose of LNG study treatment and expected doses of ART or 
TB therapy 
Reporting Groups: A-D 
Associated Study Objective: Primary Objectives 1 and 2, Secondary Objectives 1 
and 2 (see table below for more details) 
 
Summary Statistics per group (those in italics included in clinicaltrials.gov results 
record):  
• 
Original scale (ng*h/mL, mcg*h/mL as reported by testing lab): n, mean, sd, 
CV, median, IQR (Q1, Q3), Range (min, max) 
• 
Natural log scaled: geometric mean, 95% CI on GM 


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Descriptive analysis will include the following: 
a) LNG concentration-time plots will be provided to inform the derivation of the 
primary AUC outcome and other PK parameters (secondary outcomes) 
Statistical Analysis Summary:  
DTG is not expected to alter LNG PKs. Because DTG is not expected to have DDIs with LNG, 
Group C (DTG) acts as a control arm for certain comparisons stated in the table below. 
Note 1: GMR presented on ratio scale where equivalence is 1 (and not 100%).  
Note 2: The Exact reference groups require additional specification of the key other med (ARV/TB 
med). Group codes are given for redundancy.  
Statistical 
Analysis 
Comparison 
Group selection 
Type of 
Statistical 
Test 
Estimation 
Parameter 
Confidence 
Interval 
Comments 
1 – 
primary 
objective 
#1 
LNG 3.0 mg 
(among those on 
EFV) versus 
LNG 1.5 mg 
(among those on 
DTG); 
Or Group B 
versus Group C 
None 
(non-
inferiority 
framework 
uses CI 
rather 
than 
hypothesis 
testing) 
Geometric 
Mean ratio 
(GMR) of 
AUC(LNG0-
8hr) between 
comparison 
groups 
2-sided, 
90% interval 
CI on GMR 
compared to 
reference No-
Effect Bounds 
(0.7, 1.43) to 
assess similarity 
between groups 
2 – 
primary 
objective 
#2 
LNG 3.0 mg 
(among those on 
RIF) versus LNG 
1.5 (among 
those on DTG); 
Or Group D 
versus Group C 
None 
(non-
inferiority 
framework 
uses CI 
rather 
than 
hypothesis 
testing) 
Geometric 
Mean ratio 
(GMR) of 
AUC(LNG0-
8hr) between 
comparison 
groups 
2-sided, 
90% interval 
CI on GMR 
compared to 
reference No-
Effect Bounds 
(0.7,1.43) to 
assess similarity 
between groups 
3 – 
secondary 
objective 
#1 
Among those on 
EFV, LNG 3.0 
mg versus LNG 
1.5 mg ; 
Or Group B 
versus Group A 
Exact 
Wilcoxon 
Rank Sum 
test for 
superiority 
hypothesis 
testing 
framework 
Geometric 
Mean ratio 
(GMR) of 
AUC(LNG0-
8hr) between 
comparison 
groups 
2-sided, 
90% interval 
Secondary: 
Evaluation if CI 
for GMR fully 
above 1  
4 – 
secondary 
objective 
#2 
LNG 1.5 mg 
(among those on 
EFV) versus 
LNG 3.0 (among 
those on DTG);  
Or Group A 
versus Group C 
Exact 
Wilcoxon 
Rank Sum 
test for 
superiority 
hypothesis 
testing 
framework 
Geometric 
Mean ratio 
(GMR) of 
AUC(LNG0-
8hr) between 
comparison 
groups 
2-sided, 
90% interval 
Secondary: 
Evaluation if CI 
for GMR fully 
below 1 


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3.2 
Secondary Outcome Measures 
3.2.1 
Safety 
 
Title: Percentage of participants with occurrence of any serious or targeted adverse 
event (AE) potentially or definitely related to one-time Levonorgestrel administration. 
Description: Adverse events were graded according to the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), 
corrected Version 2.1, July 2017. Relationship of adverse events to study treatment was 
determined by the study core team and DAIDS clinical representative. 
Time Frame: From study entry to day 28 
Analysis Population: Participants who received assigned dose of Levonorgestrel 
Reporting Groups: A-D 
Associated Study Objective: Secondary Objective #4  
Details: Occurrence of the safety outcomes (i.e., number of participants meeting a safety 
outcome) as defined above will be enumerated and summarized by individual study 
group. Safety outcomes may be summarized separately by severity grade or type 
(category or MedDRA grouping) of adverse event. From the protocol definition of the 
safety outcome, the targeted list of reportable AEs includes the following: grade 3 or 
higher AEs, grade 2 or higher nausea, diarrhea, menorrhagia or metrorrhagia, and 
ectopic pregnancies. 
Inference: Comparison of the relative number (%) of participants with safety outcome 
who took single-dose LNG versus the relative number of participants with this outcome 
who took double-dose LNG, will be performed using the safety analysis comparison set 
as defined below. The statistical hypothesis test for this comparison will be a Fisher’s 
exact test, using a superiority-testing framework. This comparison may also be repeated 
for the two following pairwise comparisons:  
(1) single-dose LNG versus double-dose LNG among HIV+ women taking EFV-based 
ART 
(2) single-dose LNG among HIV+ women taking DTG-based ART versus double-dose 
LNG among women living with TB taking RIF-containing TB therapy. 
Since this study was not powered to compare occurrence of AEs between LNG double-
dose versus single-dose, inference related to comparisons above will focus on describing 
the magnitude and range of plausible values of observed differences between groups, 
and will not conclude similarity based on the absence of significant differences by 
Fisher’s exact test. 


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At interim review: Safety (all AE) data will be summarized by cohort and by observed 
LNG dose group. The only planned formal statistical hypothesis test will be for the safety 
outcome compared by LNG dose groups (single-dose LNG versus double-dose LNG) 
using the safety analysis comparison set listed below. 
3.2.2 
Secondary LNG PK Parameters  
 
Title: LNG PK Parameters calculated based on intensive LNG PK samples obtained from 
individual participants 
Descriptions:  
Note: Unless otherwise indicated, standard noncompartmental techniques were used to 
determine the PK parameter using the software package Phoenix WinNonLin (Certara®). 
Cmax: Cmax for each participant was the maximum observed concentration.  
Cmin: Cmin for each participant was the minimum observed concentration after the 
observed dose among post-dose concentrations. Assay lower limit of quantification for 
LNG was 0.025 ng/mL; values < LLOQ were imputed as 0.0125. 
CL/F: Apparent oral clearance (CL/F) was calculated from the observed LNG 
concentration from LNG PK samples at pre-dose through 48 hours post-dose. Assay 
lower limit of quantification for LNG was 0.025 ng/mL; values < LLOQ were imputed as 0 
(if pre-dose) or as 0.0125 (if post-dose). 
Vd: Volume of distribution (Vd) was calculated for each participant from observed LNG 
concentration from LNG PK samples at pre-dose through 48 hours post-dose.  
T1/2: T1/2 for each participant was calculated from the observed LNG concentration from 
LNG PK samples at pre-dose through 48 hours post-dose. Assay lower limit of 
quantification for LNG was 0.025 ng/mL; values < LLOQ were imputed as 0 (if pre-dose) 
or as 0.0125 (if post-dose). 
Tmin: Tmin for each participant was time to the minimum observed LNG concentration 
after the observed dose.  
Other AUC: AUC for each participant was from LNG concentrations calculated over 24 or 
48 hours and modeled to AUCinfinity using the linear up/log down version of trapezoidal 
rule (i.e., noncompartmental technique). This version of the trapezoidal rule uses linear 
interpolation between untransformed data up to Cmax, and between log-transformed data 
from Cmax through Clast. Assay lower limit of quantification for LNG was 0.025 ng/mL; 
values < LLOQ were imputed as 0 (if pre-dose) or as 0.0125 (if post-dose). 
Time Frame: Intensive LNG PK samples within 30 minutes pre-dose, and 0.5, 1, 1.5, 2, 
3, 4, 6, and 8, 24 and 48 hours post-dose [adjusting to appropriate time frame above] 
Analysis Population: Participants with PK concentrations over 24 or 48 hours and who 
took both assigned doses of LNG study treatment and expected doses of ART or TB 
therapy. 
Reporting Groups: A-D 
 
 


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Associated study objectives: Primary Objectives 1 and 2, Secondary Objectives 1 
and 2  
Descriptive Summary Statistics per group:  
• 
Original scale: n, mean, sd, CV, median, Q1, Q3, min, max  
• 
Natural log scaled: geometric mean, 95% CI on GM  
Statistical Analysis Summary: Tables parallel to the Summary table for the primary 
outcome will be produced for subset of secondary PK parameters, which are 
based on LNG concentrations. The same reference interval will be used as a 
comparison for these additional PK parameters. PK parameters not formulated 
from LNG concentrations (e.g. Tmax, Terminal half-life) will only have descriptive 
summary statistics. 
 
3.3 
Other Outcome Measures 
1) ART or RIF exposure in plasma: Targeted concentrations of ART/TB medications 
(Note: according to single sample testing, no PK parameters will be modeled): 
• 
EFV : concentration from sample drawn 12-20 hours post previous dose EFV 
• 
DTG: concentration from sample drawn 20-28 hours post previous dose DTG 
• 
RIF: concentration from sample drawn 1-16 hours post previous dose RIF 
 
The actual time/concentration profile will be plotted for each target drug (and indicating 
study group for EFV). Summary statistics for the distribution of targeted drug 
concentrations will be provided.  
 
For each drug/metabolite, concentrations will be categorized into 2 groups based on 
adequate exposure versus inadequate exposure as follows: 
 
EFV: threshold of 650 ng/mL (reference: lower 95% prediction bound on EFV 
concentration 20 hours post-dose from population PK modeling as published in Csajka 
et.al. Clinical Pharmacology and Therapeutics, 73:1, 2003) 
DTG: threshold of 398 ng/mL (based on lower 95% bound of Ctrough of 50mg dose) 
RIF (and associated metabolite desacetyl RIF): LLOQ of the assay (i.e. 75 ng/mL for RIF, 
37.5 ng/mL for desacetyl RIF)  
 
Those with documented inadequate exposure to the perpetrator drug, using the 
thresholds above, will be flagged for exclusion from a secondary, per-protocol analysis of 
LNG. Note: For RIF, both RIF and desacetyl RIF metabolyte need to be LLOQ in order to 
be excluded in the per-protocol analysis. See below for details. 
 
Note: References for DTG thresholds below: 
1. Min, S., Sloan, L., DeJesus, E., Hawkins, T., McCurdy, L., Song, I., ... & Lalezari, J. (2011). 
Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day 
monotherapy in HIV-1-infected adults. Aids, 25(14), 1737-174 


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2. Song, I., Chen, S., Lou, Y., Borland, J., Fujiwara, T., Piscitelli, S., & Min, S. (2009, July). 
Pharmacokinetic and pharmacodynamic relationship of S/GSK1349572, a next generation 
integrase inhibitor in HIV-1 infected patients. In International AIDS Society Conference. 
 
4 
Statistical Principles 
4.1 
General Considerations 
4.1.1 
Analysis sets 
Full analysis set:  
Participants who take LNG study treatment will be included in descriptive analyses of baseline, 
study conduct and descriptive summaries of AEs and other safety data (see below for separate 
analysis set for safety outcome measures). 
 
Primary PK analysis set (primary outcome/objective):  
Participants must meet all the following: 
• 
Took assigned dose of LNG study medication 
• 
Reported taking scheduled doses of other Rx (ART or TB Rx) over the 72 hours prior to 
PK sampling and over the 8-hour PK sampling period, as applicable 
• 
Have a AUC(0-8hr) PK parameter estimated  
 
Note: Baseline tables may be repeated for the PK analysis set if this analysis set differs from the 
Full analysis set. 
 
Per-protocol PK analysis set: 
Excluding participants whose perpetrator drug (i.e. EFV, DTG, or RIF) measured concentration 
was below the pre-specified threshold defined above in section 3.3 above. 
 
Safety analysis set for comparisons of safety outcome measures between single-dose and 
double-dose LNG: 
Participants who receive a dose of LNG that does not match their assigned dose will be excluded 
from comparisons of single versus double-dose LNG.  
4.1.2 
Other general considerations 
• 
Because comparisons are not between groups assigned by randomization (except A and 
B below), there will be exploration of imbalances at baseline between pairs of relevant 
comparison groups not based upon randomization.  
 
Pairwise comparisons include groups:  
o 
B vs C (related to comparison in primary objective #1) 
o 
D vs C (related to comparison in primary objective #2)  
o 
B vs A (related to comparison in secondary objective #1; randomized) 
o 
A vs C (related to comparison in secondary objective #2)  
 
The baseline characteristics examined will be limited to the following: age (in years), BMI 
(CDC categories), body fat percentage (categories or continuous), country, race/ethnicity; 


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and among the HIV study groups: CD4 cell count, detectable plasma HIV-1 RNA, NRTI 
backbone containing tenofovir. Statistical tests used will be Fisher’s exact test (or 
extension) for dichotomous (other categorical) characteristics, and exact Wilcoxon Rank 
Sum test for continuous characteristics. Due to the modest sample size, any adjusted 
analyses may need to adjust one covariate at a time.  
 
Note: other baseline characteristics (e.g. OB/GYN characteristics) may be summarized 
overall and within study group. 
 
• 
There will not be any adjustments for multiple testing of safety outcomes due to interim 
reviews. There will not be significance level adjustment affecting confidence interval 
calculation for the primary outcome GMRs, as each of the primary pairwise comparisons 
expressed as a GMR is addressing a separate study objective. 
4.2 
Analysis Approaches 
4.2.1 
Calculating Geometric Means, GMRs and associated confidence intervals 
The natural (base e) log of concentration based PK parameters will be calculated, and confidence 
intervals computed based on normality assumptions of the log-transformed data. The respective 
geometric means and CIs will be calculated by taking the antilog of (exponentiating) both the 
estimated means and confidence interval bounds. Differences between parallel comparison 
groups will be calculated as the difference of the log-transformed PK parameters (equivalent to 
the log of the ratio).  
Variance of the difference will assume equal group variances (and thus used pooled variance). 
Sensitivity analyses will check this assumption by repeating CI estimation using Satterthwaite 
version of standard error, which does not assume equal variance between groups. 
The final GMR and respective CI presented will be the exponentiated point estimate of both the 
difference, and the confidence bounds on the confidence interval calculated using normality 
assumptions.  
Further details provided in the Analysis Implementation Plan. 
4.2.2 
Primary PK analysis 
In addition to the primary PK analyses described above (calculation of GMR and 
associated 90% CI on LNG PK parameters), the following supplementary analyses will be 
conducted to test the robustness of results from this primary analysis (based on the 
primary PK analysis set): 
1) Parallel analysis of the per-protocol PK set which excludes participants whose 
measured perpetrator drug concentration was below the pre-defined threshold. 
 
2) Estimation of GMR between non-randomized groups, adjusted for prognostic factors, 
which may be imbalanced between groups. (Note: adjustment will be performed via 
normal linear regression modeling on log-transformed PK parameters). (Adjusted 


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GMRs may also be given for the randomized group comparison so that results 
presented are parallel and this may be interpreted as adjustment for chance 
imbalance within a small sample size despite randomization.) 
Secondary Objective #3: The outcome to address this objective is AUC0-24hr, and the external 
comparison groups are the LNG groups as published in Pariditpan Contraception, 2017 
(Pharmacokinetics of levonorgestrel and ulipristal acetate emergency contraception in women 
with normal and obese body mass index), and as results available via clinicaltrials.gov 
NCT:02689804. Within subgroups defined by normal BMI and obese BMI, the GMR and 
associated 90% CI for AUC0-24hrs for LNG will be estimated between A5375 Group C (DTG) 
and this external historical control group. (This analysis will use Satterthwaite calculation of 
standard error.) 
Secondary Objective #5: The outcomes to address this objective including the primary outcome 
(LNG AUC0-8 hours), as well as the following: Cmax, and AUC48, C48 (or AUC24 and C24, if too 
many participants are missing PK parameters at 48 hour). The independent variables include the 
baseline measurements of body weight including body fat percentage, total weight in kg, and BMI 
in kg/m2. To evaluate the association between these baseline independent variables and the 
outcome of log-transformed LNG PK parameters, generalized linear regression models will be fit, 
with additional explanatory variable of LNG dose and perpetrator drug. Geographic region and 
age will be included for in these models to provide calculation of adjusted GMRs where possible. 
5 
Report Contents 
1. CONSORT Diagram 
a. Screening and screen failures 
b. Enrollment and eligibility violations 
c. Randomization and Assignment to study groups 
d. Analysis sets and analysis exclusions 
2. Baseline characteristics 
a. Baseline Characteristics for Full Analysis set 
b. Baseline Characteristics for Primary PK Analysis set  
3. Targeted medications  
a. Women living with HIV: background ARV regimens 
b. Women with TB: TB medications 
4. Contraceptive use 
a. Recent contraceptive medications and methods 
5. Targeted Historical Medical Diagnoses 
6. LNG Treatment dose received  
7. Adverse events 
8. Tolerability of LNG – targeted symptoms before and after LNG receipt 
9. Analysis of primary outcome measures 
10. Analysis of secondary outcome measures 
11. Correlation of baseline body measurements with LNG exposure as measured by AUC0-
8hr