A Single-arm, Open-label, Study to Assess the Pharmacokinetics of Darunavir and Ritonavir, Darunavir and Cobicistat, Etravirine, and Rilpivirine in HIV-1 Infected Pregnant Women

Tracking Information
First Submitted Date ICMJE	March 2, 2009
First Posted Date ICMJE	March 4, 2009
Results First Submitted Date	June 30, 2017
Results First Posted Date	September 15, 2017
Last Update Posted Date	February 14, 2018
Actual Study Start Date ICMJE	April 9, 2009
Actual Primary Completion Date	August 11, 2016 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: December 18, 2017)	Predose (Trough) Plasma Concentration (C0h) [ Time Frame: Predose on Weeks 24-28 (Visit 4, 2nd trimester), 34-38 (visit 5, 3rd trimester) and 6-12 weeks postpartum (visit 8) ]C0h is defined as the predose (trough) plasma concentration or concentration just prior to study drug administration.; Minimum Plasma Concentration (Cmin) [ Time Frame: Between Predose and 24 hours postdose at Weeks 24-28 (Visit 4, 2nd trimester), 34-38 (visit 5, 3rd trimester) and 6-12 weeks postpartum (visit 8) ]The Cmin is the minimum observed plasma concentration.; Maximum Plasma Concentration (Cmax) [ Time Frame: Between Predose and 24 hours postdose at Weeks 24-28 (Visit 4, 2nd trimester), 34-38 (visit 5, 3rd trimester) and 6-12 weeks postpartum (visit 8) ]The Cmax is the maximum observed plasma concentration.; Time to Reach the Maximum Plasma Concentration (Tmax) [ Time Frame: Between Predose and 24 hours postdose at Weeks 24-28 (Visit 4, 2nd trimester), 34-38 (visit 5, 3rd trimester) and 6-12 weeks postpartum (visit 8) ]The Tmax is defined as actual sampling time to reach maximum observed plasma concentration.; Area Under the Plasma Concentration-Time Curve From Time of Administration to 12 Hours Post-dose (AUC0-12h) [ Time Frame: Between Predose and 24 hours postdose at Weeks 24-28 (Visit 4, 2nd trimester), 34-38 (visit 5, 3rd trimester) and 6-12 weeks postpartum (visit 8) ]The AUC (0-12) is the area under the plasma concentration-time curve from time zero to 12 hours post dose. The selected arms were based on the dosing frequency (twice daily).; Area Under the Plasma Concentration-Time Curve From Time of Administration to 24 Hours Post-dose (AUC0-24h) [ Time Frame: Between Predose and 24 hours postdose at Weeks 24-28 (Visit 4, 2nd trimester), 34-38 (visit 5, 3rd trimester) and 6-12 weeks postpartum (visit 8) ]The AUC (0-24) is the area under the plasma concentration-time curve from time zero to 24 hours post dose. The selected arms were based on the dosing frequency (once daily).
Original Primary Outcome Measures ICMJE; (submitted: March 2, 2009)	To assess the influence of pregnancy on the pharmacokinetics of darunavir/ritonavir (darunavir/r) and/or etravirine during the second and third trimesters of gestation, as well as postpartum [ Time Frame: During the second and third trimesters of gestation, as well as postpartum ]
Change History	Complete list of historical versions of study NCT00855335 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: December 18, 2017)	Number of Participants With Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Plasma Viral Load (<) 50 Copies/Milliliter (mL) [ Time Frame: Up to postpartum (6-12 weeks) ]Number of participants were assessed with a viral load (VL) lesser than (<) 50 HIV-1 RNA copies/ mL over time.; Mean Change From Baseline in Log10 Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Viral Load Value [ Time Frame: Baseline, 4 weeks after baseline, 2nd and 3rd trimesters of pregnancy and postpartum (2-5 weeks and 6-12 weeks) ]Mean change from baseline in log 10 HIV-1 RNA VL was assessed up to postpartum (6-12 weeks).; Mean Change From Baseline in CD4+ Cell Count [ Time Frame: Baseline, 4 weeks after baseline, 2nd and 3rd trimesters of pregnancy and postpartum (2-5 weeks and 6-12 weeks) ]Mean Change From Baseline in CD4+ Cell Count were assessed for immunology testing.; Number of Participants With Resistance at Virological Failure [ Time Frame: Up to follow-up phase (16 weeks after postpartum) ]Resistance analysis was determined using genotypic and phenotypic analysis at the time of virological failure. For participants with a baseline viral load greater than (>) 200 copies/mL, virologic failure was defined as follows: HIV ribonucleic acid (RNA) levels that did not fall by at least 0.5 log 4 weeks after Baseline; viral load >1000 copies/mL (at 2 successive visits) by gestational weeks 34-38; or viral load >200 copies/mL (at 2 successive visits) after reaching a viral load less than or equal to (<=) 200 copies/mL. For participants with a baseline viral load <=200 copies/mL, virologic failure was defined as viral load of >200 copies/mL (at 2 successive visits) at any point during the study.; Plasma Concentration of Drug in the Cord Plasma and Maternal Plasma Samples Collected at the Time of Delivery [ Time Frame: On day of delivery - Intrapartum (Visit 6) ]The drug concentrations were evaluated in the cord plasma and maternal plasma samples collected at the time of delivery.; Number of Infants With Human Immunodeficiency Virus (HIV) Positive Test Result [ Time Frame: Birth to age 16 weeks ]The infants were evaluated for HIV positive tests using HIV polymerase chain reaction test (PCR).; Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to follow up period (16 weeks after postpartum) ]An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Original Secondary Outcome Measures ICMJE; (submitted: March 2, 2009)	Changes in anti-viral activity and safety and tolerability of darunavir/r and/or etravirine-based antiretroviral regimens during gestation and postpartum; compare darunavir/r and/or etravirine concentrations between serum and cord blood; pregnancy outcom [ Time Frame: During gestation and postpartum. ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	A Single-arm, Open-label, Study to Assess the Pharmacokinetics of Darunavir and Ritonavir, Darunavir and Cobicistat, Etravirine, and Rilpivirine in HIV-1 Infected Pregnant Women
Official Title ICMJE	A Single Arm, Open Label Study to Assess the Pharmacokinetics of Darunavir and Ritonavir, Darunavir and Cobicistat, Etravirine, and Rilpivirine in HIV-1 Infected Pregnant Women
Brief Summary	The purpose of this study is to study how changes in the body during pregnancy influence the blood levels of TMC114 (darunavir) and ritonavir taken together, darunavir and cobicistat taken as a fixed-dose combination, TMC125 (etravirine) taken alone or with darunavir and ritonavir or rilpivirine in patients with human immunodeficiency virus-1 (HIV-1). This study will examine how these drugs are absorbed in the body, how they are distributed within the body and how they are removed from the body over time. Any pregnant woman who is currently receiving darunavir with ritonavir, darunavir with cobicistat, etravirine or rilpivirine for HIV-1, and who meets the eligibility criteria for the study, will be allowed to enroll. Patients must be willing to remain on study medication during the course of their pregnancy, and 12 weeks postpartum. The information collected may help answer questions about how to best prescribe these three drugs for pregnant women.
Detailed Description	There are many biological changes that occur during pregnancy, some of which may affect the way HIV medications are absorbed, distributed and removed within the body. Some medications have been used for HIV treatment during pregnancy, but little is known about how pregnancy affects the class of drugs being used in this study. To participate in this study, patients must be receiving 600mg of TMC114 (darunavir) taken with 100mg ritonavir twice daily or 800mg of TMC114 (darunavir) with 100mg of ritonavir once daily or 800 mg of darunavir taken with 150mg of cobicistat taken once daily or 200mg of TMC125 (etravirine) (with or without darunavir/ ritonavir) taken twice daily or 25mg of TMC278 (rilpivirine) taken once daily plus additional antiretroviral drugs needed to construct an active antiretroviral regimen. Darunavir and ritonavir, darunavir and cobicistat, etravirine, or rilpivirine will be supplied to study participants. Darunavir and ritonavir are human immunodeficiency virus (HIV) protease inhibitors (PIs); cobicistat is a pharmacoenhancer which boosts the levels of darunavir but has no anti-HIV activity; etravirine and rilpivirine are non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV. Twelve-hour or twenty four-hour blood sampling will be done for each patient at each of three study visits: Visit 4 (2nd trimester), Visit 5 (3rd trimester), and Visit 8 (6-12 weeks postpartum). Eight blood draws will be taken during each visit: One prior to intake of study medication, and one for each of seven post-dose sampling time-points (hours 1, 2, 3, 4, 6, 9 and 12). The study is designed primarily to examine the pharmacokinetics of darunavir/ritonavir (darunavir/r), darunavir/ cobicistat, etravirine or rilpivirine during the second and third trimesters of gestation, as well as postpartum. Pharmacokinetics measures how the body absorbs, distributes and excretes medication. The study will also examine any changes in anti-viral activity during pregnancy, and the postpartum period. It will note any safety and tolerability of the medications used by the mother, and will measure the level of darunavir/ritonavir, darunavir/ cobicistat, etravirine or rilpivirine in the newborn's cord blood at the time of delivery; outcomes for both mother and child will be assessed as well. During the treatment period, patients will be seen at regular visits in the clinic, where the investigator will assess the patient's medical condition, any Adverse Events and study drug compliance. Laboratory evaluations for efficacy and safety will be done at regular visits as well as blood pressure monitoring. Up to forty-eight (48) HIV positive pregnant women will participate in this study. Study enrollment will be closed once 12 evaluable patients taking darunavir/ritonavir once daily, 12 evaluable patients taking darunavir/cobicistat once daily, 12 evaluable patients taking darunavir/ritonavir twice daily, 12 evaluable patients taking etravirine taking twice daily and 12 evaluable patients taking rilpivirine once daily have been enrolled. The study will be conducted at approximately 14 research centers in the United States and 1 in Puerto Rico. In order to participate, patients must be pregnant for 13-24 weeks. The primary purpose (or outcome) of the study is to assess the influence of pregnancy on the pharmacokinetics of darunavir/ritonavir, darunavir/ cobicistat, etravirine or rilpivirine during the second and third trimesters of gestation, as well as postpartum. Darunavir: One 600 mg or two 300 mg tablets taken twice daily by mouth (two or four tablets a day total). Ritonavir: 100mg tablet taken twice daily by mouth (two tablets a day total), together with darunavir. Darunavir: Two 400 mg tablets taken once daily by mouth (two tablets a day total). Ritonavir: 100mg tablet taken once daily by mouth (one tablet a day total), together with darunavir. Darunavir/ cobicistat: a fixed dose combination containing 800mg of darunavir and 150mg of cobicistat. Etravirine: Two 100 mg tablets taken twice daily by mouth (four tablets a day total). Rilpivirine: One 25mg tablet taken once daily by mouth (one tablet a day total). Study medication will be given from the baseline visit (second pregnancy trimester) until Visit 8 (up to 12 weeks after delivery).
Study Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	HIV; HIV Infections; Pregnancy
Intervention ICMJE	Drug: Darunavir TMC114 (darunavir) two 300 mg or one 600 mg tablet twice daily up to 12 weeks postpartum in Group 1. TMC114 (darunavir) 800mg tablet once daily up to 12 weeks postpartum in Group 2.; Drug: Ritonavir 100 mg tablet twice daily up to 12 weeks postpartum.; Drug: Etravirine Two 200 mg tablets twice daily up to 12 weeks postpartum.; Drug: Rilpivirine One 25 mg tablet once daily up to 12 weeks postpartum.; Drug: Darunavir/Cobicistat (FDC) Fixed dose combination (FDC) tablet of TMC114 (darunavir) 800 mg and cobicistat 150 mg once daily up to 12 weeks postpartum.
Study Arms	Experimental: Group 1: Darunavir 600 /Ritonavir 100 TMC114 (darunavir) Two 300 milligram (mg) or one 600 mg tablet twice daily up to 12 weeks postpartum / ritonavir one 100 mg tablet twice daily with darunavir up to 12 weeks postpartum. Interventions: Drug: Darunavir Drug: Ritonavir; Experimental: Group 2: Darunavir 800/Ritonavir 100 TMC114 (darunavir) 800mg tablet once daily up to 12 weeks postpartum/ ritonavir one 100 mg tablet once daily with darunavir up to 12 weeks postpartum. Interventions: Drug: Darunavir Drug: Ritonavir; Experimental: Group 3: Etravirine TMC125 (etravirine) Two 200 mg tablets twice daily up to 12 weeks postpartum. Intervention: Drug: Etravirine; Experimental: Group 4: Rilpivirine TMC278 (rilpivirine) One 25 mg tablet once daily up to 12 weeks postpartum. Intervention: Drug: Rilpivirine; Experimental: Group 5: Darunavir 800/Cobicistat 150 Fixed dose combination (FDC) tablet of TMC114 (darunavir) 800 mg and cobicistat 150 mg once daily up to 12 weeks postpartum. Intervention: Drug: Darunavir/Cobicistat (FDC)
Publications *	Osiyemi O, Yasin S, Zorrilla C, Bicer C, Hillewaert V, Brown K, Crauwels HM. Pharmacokinetics, Antiviral Activity, and Safety of Rilpivirine in Pregnant Women with HIV-1 Infection: Results of a Phase 3b, Multicenter, Open-Label Study. Infect Dis Ther. 2018 Mar;7(1):147-159. doi: 10.1007/s40121-017-0184-8. Epub 2018 Jan 15.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: February 14, 2017)	77
Original Estimated Enrollment ICMJE; (submitted: March 2, 2009)	24
Actual Study Completion Date	August 11, 2016
Actual Primary Completion Date	August 11, 2016 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Pregnant females (18-26 weeks of gestation); documented HIV-1 infection; Receiving darunavir/ritonavir, darunavir/cobicistat, etravirine, or rilpivirine at the time of study entry; Willing to remain on darunavir/ritonavir, darunavir/cobicistat, etravirine, or rilpivirine as well as a background regimen, for the duration of the study, including 12 weeks postpartum; Able to comply with the protocol requirements and to provide written informed consent. Exclusion Criteria: Patients with any currently active acquired immune deficiency syndrome (AIDS) defining illness and AIDS-related opportunistic infection; Patients using cytokine inhibitors (e.g., thalidomide), anabolic hormones, cytokines (e.g., IL-2, INF), efavirenz, hydroxyurea, oral hypoglycemics, systemic chemotherapy or known teratogenic agent; Use of an investigational agent within 90 days; Any known fetal anomaly; Any current obstetric complication, including multiple gestations and pre-term labor; Hepatitis B and/or C virus infection; Grade 2 or higher anemia; Thyroid disease; Uncontrolled Diabetes Mellitus Types I and II, or gestational diabetes, as determined by the investigator
Sex/Gender	Sexes Eligible for Study: Female
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Puerto Rico, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00855335
Other Study ID Numbers ICMJE	CR015442; TMC114HIV3015 ( Other Identifier: Janssen Scientific Affairs, LLC )
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement	Not Provided
Responsible Party	Janssen Scientific Affairs, LLC
Study Sponsor ICMJE	Janssen Scientific Affairs, LLC
Collaborators ICMJE	Not Provided
Investigators ICMJE	Study Director: Janssen Scientific Affairs, LLC Clinical Trial Janssen Scientific Affairs, LLC
PRS Account	Janssen Scientific Affairs, LLC
Verification Date	February 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP