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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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Janssen Scientific Affairs, LLC
ClinicalTrials.gov Identifier:
NCT00855335
First received: March 2, 2009
Last updated: August 15, 2017
Last verified: August 2017
  Purpose
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.

Condition Intervention Phase
HIV HIV Infections Pregnancy Drug: Darunavir Drug: Ritonavir Drug: Etravirine Drug: Rilpivirine Drug: Darunavir/Cobicistat (FDC) Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Janssen Scientific Affairs, LLC:

Primary Outcome Measures:
  • 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 prior to study drug administration.

  • Minimum Plasma Concentration (Cmin) [ Time Frame: Predose, 1, 2, 3, 4, 6, 9, 12, 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: Predose, 1, 2, 3, 4, 6, 9, 12, 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: Predose, 1, 2, 3, 4, 6, 9, 12, 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: Predose, 1, 2, 3, 4, 6, 9, 12 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: Predose, 1, 2, 3, 4, 6, 9, 12, 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).


Secondary Outcome Measures:
  • 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 participantss 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.


Enrollment: 77
Actual Study Start Date: April 9, 2009
Study Completion Date: August 11, 2016
Primary Completion Date: August 11, 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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.
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.
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.
Experimental: Group 3: Etravirine
TMC125 (etravirine) Two 200 mg tablets twice daily up to 12 weeks postpartum.
Drug: Etravirine
Two 200 mg tablets twice daily up to 12 weeks postpartum.
Experimental: Group 4: Rilpivirine
TMC278 (rilpivirine) One 25 mg tablet once daily up to 12 weeks postpartum.
Drug: Rilpivirine
One 25 mg tablet once daily up to 12 weeks postpartum.
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.
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.

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).
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00855335

Locations
United States, Florida
Daytona Beach, Florida, United States
Jacksonville, Florida, United States
Miami, Florida, United States
Pensacola, Florida, United States
Port Saint Lucie, Florida, United States
West Palm Beach, Florida, United States
United States, Georgia
Savannah, Georgia, United States
United States, Illinois
Chicago, Illinois, United States
United States, Massachusetts
Springfield, Massachusetts, United States
United States, Michigan
Dearborn, Michigan, United States
United States, New York
Syracuse, New York, United States
The Bronx, New York, United States
United States, North Carolina
Chapel Hill, North Carolina, United States
Greensboro, North Carolina, United States
United States, Pennsylvania
Philadelphia, Pennsylvania, United States
United States, Texas
Bellaire, Texas, United States
Puerto Rico
San Juan Pr, Puerto Rico
Sponsors and Collaborators
Janssen Scientific Affairs, LLC
Investigators
Study Director: Janssen Scientific Affairs, LLC Clinical Trial Janssen Scientific Affairs, LLC
  More Information

Responsible Party: Janssen Scientific Affairs, LLC
ClinicalTrials.gov Identifier: NCT00855335     History of Changes
Other Study ID Numbers: CR015442
TMC114HIV3015 ( Other Identifier: Janssen Scientific Affairs, LLC )
Study First Received: March 2, 2009
Results First Received: June 30, 2017
Last Updated: August 15, 2017

Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Janssen Scientific Affairs, LLC:
HIV-1
HIV
Pregnancy
Postpartum
Human immunodeficiency virus
PREZISTA
INTELENCE
NORVIR
TMC114
TMC125
darunavir
ritonavir
etravirine
rilpivirine
TMC278
Cobicistat
treatment experienced

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Ritonavir
Darunavir
Cobicistat
Rilpivirine
Etravirine
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on September 21, 2017