PregnancyNETNCT01667978
The Effect of Protease Inhibitors on the Pharmacokinetics of Oral Norethindrone Contraception
A study testing Norethindrone acetate in people with Pregnancy and HIV, run by University of Southern California at 2 sites in United States.
Trial summary
The purpose of this study is to learn if women taking the atazanavir and ritonavir have lower levels of a birth control medication called norethindrone. Norethindrone (also called the mini pill) is an FDA (Food and Drug Administration) approved progestin-only birth control pill used to prevent pregnancy. Read more about this study
- Who is it for?
- Ages 18 to 44 years, women onlyHealthy volunteers can take part
- What is being tested?
- Norethindrone acetate
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 35 participants
- Where
- 2 sitesUnited States
- Study dates
- Jun 2012to Sep 2014
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 44 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Ages: 18-44 years Gender: female Accepts: healthy volunteers and HIV-1 infected women Acceptable medications include: no other medications, NRTI combinations, entry inhibitors, integrase inhibitors, and CCR5 agonists. NRTI combinations may include but are not limited to: zidovudine (ZDV), lamivudine (3TC), emtricitabine (FTC), didanosine (ddl), stavudine (d4T), abacavir (ABC), and tenofovir disoproxil fumarate (TDF). NNRTI: etravirine, and rilpivirine.
Who cannot join
- History of bilateral oophorectomy, ovarian dysfunction or no regular periods. CD4+ cell count <200 cells/mm3 No current or uncontrolled thyroid, liver, or renal disease BMI <40 kg/m^2 Current pregnancy, breastfeeding or pregnancy within 30 days of enrollment. Depomedroxyprogesterone acetate injection (DMPA) within 180 days prior to study entry.
- Other hormonal therapies (e.g. oral contraceptive agents, Provera, vaginal ring, contraceptive patch, monthly contraceptive injection, hormone replacement therapy, anabolic therapies, including nandrolone decanoate or megestrol acetate) within the 21 days prior to study entry.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Los Angeles County Hospital University of Southern California (LAC USC)
Los Angeles, California, 90033-1029
Los Angeles County University of Southern California
Los Angeles, California, 90033-1029
About this study
The purpose of this study is to learn if women taking the atazanavir and ritonavir have lower levels of a birth control medication called norethindrone. Norethindrone (also called the mini pill) is an FDA (Food and Drug Administration) approved progestin-only birth control pill used to prevent pregnancy. Norethindrone is the standard medication used in women who take the progestin only pill to prevent pregnancy. There are other birth control pills which contain different medications. The investigators want to learn if HIV medications (atazanavir and ritonavir) make the blood level of this birth control pill higher or lower. If the levels of norethindrone are too low it may not work to prevent pregnancy. The investigators also hope to learn about changes in the vaginal fluids and cervical fluids when women are taking this birth control pill.
Read the detailed description
BACKGROUND/RATIONALE : It is recognized that there is a dearth of clinically applied, population based, empiric data to guide contraceptive recommendations in HIV + women on ARVs.(1) Protease inhibitors (PI) and non nucleoside reverse transcriptase inhibitors (NNRTI ) induce micro enzyme systems such as CYP 3a4, which in turn alters the bio-availability and pharmacokinetics of other concurrently administered medications.(2) Empiric trials from small samples, often of 10-20 HIV negative subjects, have demonstrated that concurrent administration of combined oral contraceptives (COC) and a PI or a NNRTI have been associated with decreased plasma ethinyl estradiol (EE) levels. These pharmacokinetic findings have raised concern that decreased bio-availability of EE may result in decreased contraceptive efficacy, with possible increased unintended pregnancy. Some of these COC studies have demonstrated that there is no change in the serum levels of norethindrone (NET) on ARVs.(3-16) However, there are no published trials focused on oral NET or oral progestin-only pills (POP) to guide management in HIV+ women.(17)
OBJECTIVES:
Primary objective of this study is:
To detect a ±40% difference in AUC of serum NET in HIV+ women taking ATV/RTV as compared to AUC of NET in HIV+ women taking an ARV regimen that has demonstrated no interaction with NET in the past.
Primary endpoint: Natural log-transformed NET PK parameter AUC from 0 to 72 hours following oral administration, with multiple discrete serum data points for each subject on ATV/RTV. This will be compared to natural log-transformed NET PK AUC from 0 to 72 hours following oral administration, with multiple discrete serum data points for controls HIV+ women taking an ARV regimen that has demonstrated no interaction with NET in the past.
The secondary objectives of this study are:
To evaluate the effect of ATV/RTV on other PK exposure endpoints and parameters of NET (with natural log transformation). The sample and control groups mentioned above will again be compared. Endpoints include:
minimum plasma concentration (Cmin), maximum plasma concentration (Cmax), time to Cmax (Tmax), and half-life (T1/2).
SAMPLE SIZE: Recruitment of 16 participants in each arm, with the goal of attaining 32 evaluable HIV-1-seropositive female subjects in total.
POPULATION/STUDY ARMS: HIV-1-infected female subjects 18-44 years of age
METHODOLOGY/INTERVENTIONS/FOLLOW-UP: A two-arm, open-label, prospective, steady state trial to characterize the pharmacokinetics (PK) of oral norethindrone (NET) as a progestin only contraceptive pill (POP) in HIV+ women receiving atazanavir and ritonavir therapy (ATV/RTV). The investigators will identify a control group of HIV+ women who are taking ARV regimens that have not significantly altered oral NET levels in prior trials. Subjects will be enrolled in the trial for approximately 4 weeks A 28 day continuous packet of NET 0.35 mg will be provided to all enrolled volunteers for 21 days of continuous administration. Women who participate in this study will demonstrate a means of continuing their ARV regimens for the duration of the study, ARV therapy will not be provided by this study. On day 22 subjects will be admitted for serial pharmacokinetic (PK) specimens collection following the final study dose of NET.
Subjects will be enrolled into one of the 2 arms based on their current ARV regimen.
Study group: Women on stable ARV/RTV (300/100mg daily) with additional ARV regimens that have not significantly altered oral NET levels in prior trials. (n=12).
Control group: Stable on current ARV, no protease inhibitors (PI), ARV regimens that have not significantly altered oral NET levels in previous research.
OUTCOMES: Intensive PK sampling for NET will be performed in those in intervention and control arms after 21 days of NET administration. To determine side effect profile of NET by self-administered daily questionnaire during the 3-4 week study enrollment period
STATISTICS: Area under the concentration-time curve (AUC), peak plasma concentration, and the lowest plasma concentration for NET in HIV+ women receiving this PI therapy will be determined and compared to similar values in HIV positive control subjects who are not taking PI therapy. Statistical consultation will be obtained from the USC Keck School of Medicine Department of Bio statistics and Laboratory of Applied Pharmacokinetics
- Being tested
- Norethindrone acetate
- Keywords
- contraception, mini pill, norethindrone, atazanavir, ritonavir, norvir, reyataz, pregnancy prevent, birth control, HIV, AIDS, antiviral, antiretroviral
- Medical subject headings
- Acquired Immunodeficiency Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Norethindrone acetateDrug
Also called Both control and experimental group with take norethindrone. However the experimental group will be taking a protease inhibitor: atazanavir and ritonavir
| Study group | Role | What they receive |
|---|---|---|
| PI | Experimental | Study group with PI: atazanavir ritonavir Receives: Drug: Norethindrone acetate |
| Control | Placebo comparator | o PI therapy, control group Receives: Drug: Norethindrone acetate |
What is being measured
The primary outcome is the main question the study is designed to answer.
AUC Norethindrone
0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Day 21
Measured: following 21 days of continuous ingestion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Aug 2012 (estimated)
- Study startJun 2012
- Primary completionSep 2013
- Study completionSep 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for PregnancyStudies of the same condition, open and under way.
- More trials run by University of Southern CaliforniaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 35 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Southern California
- Sponsor type
- University, hospital or other
- Collaborators
- Society of Family Planning
- Responsible party
- Principal investigator, Jessica Maria Atrio, University of Southern California
- Investigators
- Jessica M Atrio, MD, Principal investigator, University of Southern California
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01667978
- Sponsor's protocol ID
- HS-12-00005
- Acronym
- NET
- Status last verified
- Aug 2015
- First submitted
- 15 Aug 2012
- Last updated
- 20 Aug 2015
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Atrio J, Stek A, Vora H, Sanchez-Keeland L, Zannat F, Natavio M. The effect of protease inhibitors on the cervical mucus of HIV-positive women taking norethindrone contraception. Eur J Contracept Reprod Health Care. 2015 Apr;20(2):149-53. doi: 10.3109/13625187.2014.957826. Epub 2014 Oct 6.
PubMed 25285572DuBois BN, Atrio J, Stanczyk FZ, Cherala G. Increased exposure of norethindrone in HIV+ women treated with ritonavir-boosted atazanavir therapy. Contraception. 2015 Jan;91(1):71-5. doi: 10.1016/j.contraception.2014.08.009. Epub 2014 Aug 30.
PubMed 25245190
Study at a glance
From the registry record, last updated by the sponsor on 20 Aug 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Protease Inhibitors on the Pharmacokinetics of Oral Norethindrone Contraception
- ClinicalTrials.gov ID
- NCT01667978
- Acronym / sponsor ID
- NET / HS-12-00005
- Keywords
- contraception, mini pill, norethindrone, atazanavir, ritonavir, norvir, reyataz, pregnancy prevent
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 35 participants (actual)
- Lead sponsor
- University of Southern CaliforniaUniversity, hospital or other
- Collaborators
- Society of Family Planning
- Study start
- Jun 2012
- Primary completion
- Sep 2013 (actual)
- Study completion
- Sep 2014 (actual)
- First posted
- 17 Aug 2012 (estimated)
- Results
- Posted 20 Aug 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to learn if women taking the atazanavir and ritonavir have lower levels of a birth control medication called norethindrone. Norethindrone (also called the mini pill) is an FDA (Food and Drug Administration) approved progestin-only birth control pill used to prevent pregnancy. Norethindrone is the standard medication used in women who take the progestin only pill to prevent pregnancy. There are other birth control pills which contain different medications. The investigators want to learn if HIV medications (atazanavir and ritonavir) make the blood level of this birth control pill higher or lower. If the levels of norethindrone are too low it may not work to prevent pregnancy. The investigators also hope to learn about changes in the vaginal fluids and cervical fluids when women are taking this birth control pill.
Detailed description
BACKGROUND/RATIONALE : It is recognized that there is a dearth of clinically applied, population based, empiric data to guide contraceptive recommendations in HIV + women on ARVs.(1) Protease inhibitors (PI) and non nucleoside reverse transcriptase inhibitors (NNRTI ) induce micro enzyme systems such as CYP 3a4, which in turn alters the bio-availability and pharmacokinetics of other concurrently administered medications.(2) Empiric trials from small samples, often of 10-20 HIV negative subjects, have demonstrated that concurrent administration of combined oral contraceptives (COC) and a PI or a NNRTI have been associated with decreased plasma ethinyl estradiol (EE) levels. These pharmacokinetic findings have raised concern that decreased bio-availability of EE may result in decreased contraceptive efficacy, with possible increased unintended pregnancy. Some of these COC studies have demonstrated that there is no change in the serum levels of norethindrone (NET) on ARVs.(3-16) However, there are no published trials focused on oral NET or oral progestin-only pills (POP) to guide management in HIV+ women.(17)
OBJECTIVES:
Primary objective of this study is:
To detect a ±40% difference in AUC of serum NET in HIV+ women taking ATV/RTV as compared to AUC of NET in HIV+ women taking an ARV regimen that has demonstrated no interaction with NET in the past.
Primary endpoint: Natural log-transformed NET PK parameter AUC from 0 to 72 hours following oral administration, with multiple discrete serum data points for each subject on ATV/RTV. This will be compared to natural log-transformed NET PK AUC from 0 to 72 hours following oral administration, with multiple discrete serum data points for controls HIV+ women taking an ARV regimen that has demonstrated no interaction with NET in the past.
The secondary objectives of this study are:
To evaluate the effect of ATV/RTV on other PK exposure endpoints and parameters of NET (with natural log transformation). The sample and control groups mentioned above will again be compared. Endpoints include:
minimum plasma concentration (Cmin), maximum plasma concentration (Cmax), time to Cmax (Tmax), and half-life (T1/2).
SAMPLE SIZE: Recruitment of 16 participants in each arm, with the goal of attaining 32 evaluable HIV-1-seropositive female subjects in total.
POPULATION/STUDY ARMS: HIV-1-infected female subjects 18-44 years of age
METHODOLOGY/INTERVENTIONS/FOLLOW-UP: A two-arm, open-label, prospective, steady state trial to characterize the pharmacokinetics (PK) of oral norethindrone (NET) as a progestin only contraceptive pill (POP) in HIV+ women receiving atazanavir and ritonavir therapy (ATV/RTV). The investigators will identify a control group of HIV+ women who are taking ARV regimens that have not significantly altered oral NET levels in prior trials. Subjects will be enrolled in the trial for approximately 4 weeks A 28 day continuous packet of NET 0.35 mg will be provided to all enrolled volunteers for 21 days of continuous administration. Women who participate in this study will demonstrate a means of continuing their ARV regimens for the duration of the study, ARV therapy will not be provided by this study. On day 22 subjects will be admitted for serial pharmacokinetic (PK) specimens collection following the final study dose of NET.
Subjects will be enrolled into one of the 2 arms based on their current ARV regimen.
Study group: Women on stable ARV/RTV (300/100mg daily) with additional ARV regimens that have not significantly altered oral NET levels in prior trials. (n=12).
Control group: Stable on current ARV, no protease inhibitors (PI), ARV regimens that have not significantly altered oral NET levels in previous research.
OUTCOMES: Intensive PK sampling for NET will be performed in those in intervention and control arms after 21 days of NET administration. To determine side effect profile of NET by self-administered daily questionnaire during the 3-4 week study enrollment period
STATISTICS: Area under the concentration-time curve (AUC), peak plasma concentration, and the lowest plasma concentration for NET in HIV+ women receiving this PI therapy will be determined and compared to similar values in HIV positive control subjects who are not taking PI therapy. Statistical consultation will be obtained from the USC Keck School of Medicine Department of Bio statistics and Laboratory of Applied Pharmacokinetics
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| PI | Experimental | Drug: Norethindrone acetateStudy group with PI: atazanavir ritonavir |
| Control | Placebo comparator | Drug: Norethindrone acetateo PI therapy, control group |
Who may qualify
- Ages
- 18 to 44 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- Ages: 18-44 years Gender: female Accepts: healthy volunteers and HIV-1 infected women Acceptable medications include: no other medications, NRTI combinations, entry inhibitors, integrase inhibitors, and CCR5 agonists. NRTI combinations may include but are not limited to: zidovudine (ZDV), lamivudine (3TC), emtricitabine (FTC), didanosine (ddl), stavudine (d4T), abacavir (ABC), and tenofovir disoproxil fumarate (TDF). NNRTI: etravirine, and rilpivirine.
Key exclusion criteria (2 listed)
- History of bilateral oophorectomy, ovarian dysfunction or no regular periods. CD4+ cell count <200 cells/mm3 No current or uncontrolled thyroid, liver, or renal disease BMI <40 kg/m^2 Current pregnancy, breastfeeding or pregnancy within 30 days of enrollment. Depomedroxyprogesterone acetate injection (DMPA) within 180 days prior to study entry.
- Other hormonal therapies (e.g. oral contraceptive agents, Provera, vaginal ring, contraceptive patch, monthly contraceptive injection, hormone replacement therapy, anabolic therapies, including nandrolone decanoate or megestrol acetate) within the 21 days prior to study entry.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Norethindrone acetateAlso: Both control and experimental group with take norethindrone. However the experimental group will be taking a protease inhibitor: atazanavir and ritonavir | Drug | Control, PI |
Primary outcome
AUC Norethindrone
Time frame: following 21 days of continuous ingestion
0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Day 21
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Aug 2015.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 25285572Atrio J, Stek A, Vora H, Sanchez-Keeland L, Zannat F, Natavio M. The effect of protease inhibitors on the cervical mucus of HIV-positive women taking norethindrone contraception. Eur J Contracept Reprod Health Care. 2015 Apr;20(2):149-53. doi: 10.3109/13625187.2014.957826. Epub 2014 Oct 6.
- Derived from this study: PubMed 25245190DuBois BN, Atrio J, Stanczyk FZ, Cherala G. Increased exposure of norethindrone in HIV+ women treated with ritonavir-boosted atazanavir therapy. Contraception. 2015 Jan;91(1):71-5. doi: 10.1016/j.contraception.2014.08.009. Epub 2014 Aug 30.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jessica M Atrio, MD principal investigator
University of Southern California
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Norethindrone acetate in people with Pregnancy and HIV, run by University of Southern California at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Aug 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Aug 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
AUC Norethindrone (time frame: following 21 days of continuous ingestion). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01667978, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Aug 2015.