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HIV InfectionPhase 1NCT00326716

Pharmacokinetics of Atazanavir/Ritonavir in HIV-1 Infected Pregnant Women

A Phase 1 study testing Atazanavir + Ritonavir + Combivir in people with HIV Infection, run by Bristol-Myers Squibb at 6 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

To determine what dosing regimen of atazanavir (ATV) / ritonavir (RTV) produces adequate drug exposure during pregnancy compared to drug exposure in historical data in human immunodeficiency virus (HIV) infected participants. Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
HIV Infection
What is being tested?
Atazanavir + Ritonavir + Combivir
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
69 participants
Where
6 sitesin 3 countries
Study dates
Jun 2006to Aug 2009
Phase
Phase 1
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 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • HIV-infected pregnant women
  • > 18 years of age
  • Between week 12 and 32 gestation
  • CD4 > 200 cells/mm³
  • Treatment-naive with HIV RNA > 400 c/mL, on HAART with HIV RNA <50 c/mL, or previously treated with ATV (< 3 weeks) with HIV RNA>400 c/mL

Who cannot join

None listed.

Trial locations and contacts

6 sites in 3 countries.

6 sites in 3 countries

South Africa3 sites

  • Local Institution

    Soweto, Gauteng, 2001

  • Local Institution

    Sunnyside, Gauteng, 0002

  • Local Institution

    Westdene, Gauteng, 2092

Other trials in South Africa

United States2 sites

  • Women's Hospital Of Texas

    Houston, Texas, 77054

  • Triple O Medical Services, P.A.

    West Palm Beach, Florida, 33401

Other trials in United States

Puerto Rico1 site

  • Local Institution

    San Juan, 00936

Other trials in Puerto Rico

About this study

Official title: A Study of the Pharmacokinetics of Atazanavir (ATV)/Ritonavir(RTV) Administered as Part of Highly Active Antiretroviral Therapy (HAART) in HIV-1 Infected Pregnant Women

To determine what dosing regimen of atazanavir (ATV) / ritonavir (RTV) produces adequate drug exposure during pregnancy compared to drug exposure in historical data in human immunodeficiency virus (HIV) infected participants.

Conditions
HIV Infection
Being tested
Atazanavir + Ritonavir + Combivir
Keywords
HIV-1 infected pregnant women, either treatment naive or on ATV/RTV combined with ZDV/3TC
Medical subject headings
HIV Infections

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Atazanavir + Ritonavir + CombivirDrug

    Also called Reyataz, BMS-232632

    Capsules, tablets, Oral, initially ATV 300 mg + RTV 100 mg + ZDV/3TC 300/150 mg, dose escalated to ATV 400 mg + RTV 100 mg + ZDV/3TC 300/150 mg, ATV and RTV once daily, lamivudine (ZDV) / zidovudine (3TC) twice daily (BID), up to 36 weeks

Study groups in NCT00326716
Study groupRoleWhat they receive
TreatmentExperimentalNot described
Receives: Drug: Atazanavir + Ritonavir + Combivir

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Infant Gestational Age at Delivery

    Measured: At the time of delivery

  2. Infant Gender

    Measured: At the time of delivery

  3. Infant Race

    Measured: At the time of delivery

  4. Mean ATV Maximum Plasma Concentration (Cmax) in One Dosing Interval

    Cmax = maximum observed plasma concentration of atazanavir at specified time points.

    Measured: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum

  5. Mean RTV Maximum Plasma Concentration (Cmax) in One Dosing Interval

    Cmax = maximum observed plasma concentration of ritonavir at specified time points.

    Measured: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum

  6. Mean ATV Area Under the Concentration Curve (AUC TAU)

    AUC = area under the concentration curve (AUC [TAU]) of atazanavir in one dosing interval from time zero to 24 hours.

    Measured: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum

  7. Mean RTV Area Under the Concentration Curve (AUC TAU)

    AUC = area under the concentration curve (AUC [TAU]) of ritonavir in one dosing interval.

    Measured: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum

  8. Mean ATV Trough Plasma Concentration (Cmin) 24 Hours Following the Daily Dose

    Cmin = plasma concentration 24 hours post dose of atazanavir at specified time points.

    Measured: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum at 24 hours following the daily dose.

  9. Mean RTV Trough Plasma Concentration (Cmin) 24 Hours Following the Daily Dose

    Cmin = plasma concentration 24 hours post dose of ritonavir at specified time points.

    Measured: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum at 24 hours following the daily dose.

  10. Mean ATV Terminal Elimination Half Life (T 1/2)

    T 1/2 = terminal elimination half life of atazanavir at specified time points.

    Measured: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum

  11. Mean RTV Terminal Elimination Half Life (T 1/2)

    T 1/2 = terminal elimination half life of ritonavir at specified time points.

    Measured: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum

  12. Mean ATV Time of Maximum Observed Plasma Concentration (Tmax)

    Tmax = time to reach maximum observed plasma concentration of atazanavir at specified time points.

    Measured: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum

  13. Mean RTV Time of Maximum Observed Plasma Concentration (Tmax)

    Tmax = time to reach the maximum observed plasma concentration of ritonavir at specified time points.

    Measured: Pregnancy Weeks 12 to 28, Weeks 28 to 36, and 4-6 Weeks Postpartum

Secondary outcomes (14)

  1. Maternal HIV Ribonucleic Acid (RNA) Level on Day of Delivery

    The maternal HIV RNA level is assessed by the Roche Amplicor® Ultrasensitive Assay Version 1.5.

    Measured: Day of Delivery ± 2 Days

  2. Median Change From Baseline to Day of Delivery in Maternal HIV RNA Level

    The maternal HIV RNA level was determined at baseline and the day of delivery ± 2 days using VR-OC. The maternal HIV RNA level is assessed by the Roche Amplicor® Ultrasensitive Assay Version 1.5.

    Measured: Baseline, Day of Delivery ± 2 Days

  3. Mean HIV RNA Level at Baseline

    Measured: Baseline

  4. Median Change From Baseline to Day of Delivery in Maternal Cluster of Differentiation 4 (CD4) Cell Count

    The median CD4 cell count change from baseline was calculated for all treated mothers at the time of delivery ± 2 days. Maternal CD4 cell counts were assessed by the Roche Amplicor® Ultrasensitive Assay Version 1.5.

    Measured: Baseline, Day of Delivery ± 2 Days

  5. Mean CD4 Cell Count at Baseline

    Measured: Baseline

  6. Infant HIV Status

    The neonatal HIV-1 status are assessed by the Roche Amplicor HIV-1 DNA Assay Version 1.5 (Roche Molecular Systems).

    Measured: Birth Through 6 Months on Study

  7. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

    AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE =any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event.

    Measured: During study period and 30 days post-study.

  8. Number of Participants With Grade 2 to Grade 4 AEs and SAEs

    AEs and SAEs considered possibly, probably, or certainly related to study treatment, were graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death). Hyperbilirubinemia (Grade 1=1.1 to 1.5 upper limit of normal [ULN] [mild], Grade 2=1.6 to 2.5 ULN [moderate], Grade 3=2.6 to 5.0 ULN [severe], Grade 4= > 5.0 ULN [potentially life threatening]).

    Measured: During Study Period and 30 Days Post-Study.

  9. SAEs in Enrolled Mothers

    SAEs were evaluated for all treated and untreated participants. An SAE was defined as an untoward medical occurrence that results in death, is life-threatening (defined as an event in which the participant was at risk of death at the time of the event); might have caused death if it were more severe, required inpatient hospitalization or prolongation of existing hospitalization, in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, an important medical event that required intervention to prevent serious outcomes.

    Measured: During Study Period and 30 Days Post-Study.

  10. SAEs in Enrolled Infants

    SAEs were evaluated for all treated and untreated participants. An SAE was defined as an untoward medical occurrence that results in death, is life-threatening (defined as an event in which the participant was at risk of death at the time of the event); might have caused death if it were more severe, required inpatient hospitalization or prolongation of existing hospitalization, in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, an important medical event that required intervention to prevent serious outcomes.

    Measured: Birth Through Week 16 of Life

  11. Mean Atazanavir Maternal Plasma Concentration and Neonatal Cord Blood Concentration

    Mean atazanavir maternal plasma concentration and neonatal cord blood concentration as measured at the time of delivery.

    Measured: At Time of Delivery

  12. Median Infant Total Bilirubin Level

    Median infant total bilirubin level as measured at specified time points.

    Measured: Birth (Day 1), Day 3, Day 5, and Day 7 of Life

  13. Mean Atazanavir Plasma Protein Binding

    Atazanavir Plasma Protein Binding Percentage measured at specified time points.

    Measured: Pregnancy Weeks 28 to Delivery at 3 Hours Postdose and 24 Hours Postdose, and Time of Delivery

  14. Multicenter AIDS Cohort Study (MACS) Participant Adherence to Regimen and Drug Components for ATV 300 mg / RTV 100 mg Test Dose

    The MACS was administered to evaluate participant adherence to each drug and the adherence to the regimen. The MACS adherence questionnaire asks patients how many medication doses they missed during the previous day, 2 days, 3 days and 4 days. Drug-specific questions included adherence with dose and frequency. Adherence was defined as taking all doses and numbers of pills as prescribed for each medication. This strict adherence cut-off was based on the guidelines stating that anything less than excellent adherence may result in a virus breakthrough and development of resistance.

    Measured: Study Week 2, Pregnancy Weeks 20 to Weeks 28, Pregnancy Weeks 28 to Delivery, Week 2 Postpartum, Week 4 Postpartum

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 May 2006 (estimated)
  2. Study startJun 2006
  3. Primary completionJan 2009
  4. Study completionAug 2009

Resources

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 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
69 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00326716
Sponsor's protocol ID
AI424-182
Status last verified
Nov 2011
First submitted
15 May 2006
Last updated
16 Nov 2011
Data monitoring committee
No

Publications

  • Xu XS, Rose A, Demers R, Eley T, Ryan J, Stouffer B, Cojocaru L, Arnold M. Quantitative determination of free/bound atazanavir via high-throughput equilibrium dialysis and LC-MS/MS, and the application in ex vivo samples. Bioanalysis. 2014;6(23):3169-82. doi: 10.4155/bio.14.251.

    PubMed 25529885

  • Eley T, Huang SP, Conradie F, Zorrilla CD, Josipovic D, Botes M, Osiyemi O, Hardy H, Bertz R, McGrath D. Clinical and pharmacogenetic factors affecting neonatal bilirubinemia following atazanavir treatment of mothers during pregnancy. AIDS Res Hum Retroviruses. 2013 Oct;29(10):1287-92. doi: 10.1089/AID.2013.0002. Epub 2013 Jul 19.

    PubMed 23782005

  • Conradie F, Zorrilla C, Josipovic D, Botes M, Osiyemi O, Vandeloise E, Eley T, Child M, Bertz R, Hu W, Wirtz V, McGrath D. Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women. HIV Med. 2011 Oct;12(9):570-9. doi: 10.1111/j.1468-1293.2011.00927.x. Epub 2011 May 16.

    PubMed 21569187

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Atazanavir + Ritonavir + Combivir in people with HIV Infection, run by Bristol-Myers Squibb at 6 sites in 3 countries.

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 5 inclusion and 0 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 16 Nov 2011. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in South Africa, United States, Puerto Rico. 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. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 7 Apr 2011). 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?

Infant Gestational Age at Delivery (time frame: At the time of delivery). The study lists 13 primary outcomes in all. 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 NCT00326716, which also lists 3 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 16 Nov 2011.

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