Pharmacokinetic Interactions Between DMPA and LPV/r Among HIV-Infected Women

This study has been completed.
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT01296152
First received: February 14, 2011
Last updated: November 18, 2015
Last verified: November 2015

February 14, 2011
November 18, 2015
May 2011
October 2012   (final data collection date for primary outcome measure)
  • Medroxyprogesterone Acetate (MPA) Pharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-12weeks) [ Time Frame: Day 0, Weeks 2, 4, 6, 8, 10 and 12 ] [ Designated as safety issue: Yes ]
    This evaluates the effect of lopinavir/ritonavir (LPV/r) on pharmacokinetic parameter AUC of MPA by looking at the MPA AUC from day 0 to week 12. AUC0-12weeks was calculated using single MPA concentrations sampled immediately prior to DMPA administration on day 0, and at 2, 4, 6, 8, 10 and 12 weeks after administration of the single DMPA dose.
  • AUC0-12hour for LPV at Baseline (Day 0) Before DMPA Administration and at Week 4 (Four Weeks After DMPA Administration) [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
    This evaluates the effect of DMPA on LPV PK parameter AUC by comparing PK AUCs of LPV from 0 to 12 hours obtained at study Day 0 (before DMPA was administered) with PK AUCs of LPV from 0 to 12 hours at study Week 4 (4 weeks after DMPA was administered). Blood samples were drawn for LPV concentration levels at time zero (before LPV/r dosing) and at 30 minutes and 1, 2, 3, 4, 5, 6, 8 and 10 hours after LPV/r dosing at day 0 and week 4.
  • Natural log-transformed medroxyprogesterone acetate (MPA) pharmacokinetic parameter area under the concentration-time curve (AUC) obtained from this study and natural log-transformed MPA PK AUC0-12wk from the study control arm in ACTG A5093 [ Time Frame: Day 0 to Week 12 ] [ Designated as safety issue: Yes ]
    This will evaluate the effect of lopinavir/ritonavir (LPV/r) on pharmacokinetic parameter AUC of MPA. This evaluation will be performed using two-sample nonparametric Wilcoxon test by comparing the PK AUCs of MPA from this current study with the PK AUCs of MPA from individual subjects enrolled into the study control arm (MPA administered alone, N=14) in ACTG A5093.
  • Determine the effect of MPA on the PK of lopinavir (LPV) among HIV-infected subjects using the AUC for LPV at baseline (day 0) before MPA administration and at week 4 [ Time Frame: Day 0 to Week 4 ] [ Designated as safety issue: Yes ]
    This will evaluate the effect of DMPA on LPV PK parameter AUC. This evaluation will be performed using the paired-sample nonparametric Wilcoxon test by comparing PK AUCs of LPV obtained on study Day 0 (before DMPA is administered) with PK AUCs of LPV on study Week 4 (4 weeks after DMPA is administered).
Complete list of historical versions of study NCT01296152 on ClinicalTrials.gov Archive Site
  • Percentage of Participants With Progesterone Levels Less Than the Lower Limit of Quantification (LLQ). [ Time Frame: 0, 2, 4, 6, 8, 10, and 12 weeks ] [ Designated as safety issue: Yes ]
    This evaluates the suppression of ovulation due to the potential PK interaction between DMPA and LPV/r. The LLQ of progesterone is 0.5ng/mL. The threshold for suppression of ovulation is 5ng/mL.
  • MPA PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on MPA Levels. [ Time Frame: 0, 2, 4, 6, 8, 10, and 12 weeks ] [ Designated as safety issue: Yes ]
    This evaluates the effect of LPV/r on the secondary MPA PK parameter Cmin based on MPA levels measured at weeks 0, 2, 4, 6, 8, 10, and 12.
  • MPA PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on MPA Levels. [ Time Frame: 0, 2, 4, 6, 8, 10, and 12 weeks ] [ Designated as safety issue: Yes ]
    This evaluates the effect of LPV/r on the secondary MPA PK parameter Cmax based on MPA levels measured at weeks 0, 2, 4, 6, 8, 10, and 12.
  • MPA PK Parameter Time to Cmax (Tmax) Determined Based on MPA Levels. [ Time Frame: 0, 2, 4, 6, 8, 10, and 12 weeks ] [ Designated as safety issue: Yes ]
    This evaluates the effect of LPV/r on the secondary MPA PK parameter Tmax based on MPA levels measured at weeks 0, 2, 4, 6, 8, 10, and 12.
  • MPA PK Parameter Clearance (CL/F) Determined Based on MPA Levels. [ Time Frame: 0, 2, 4, 6, 8, 10, and 12 weeks ] [ Designated as safety issue: Yes ]
    This evaluates the effect of LPV/r on the secondary MPA PK parameter CL/F based on MPA levels measured at weeks 0, 2, 4, 6, 8, 10, and 12.
  • MPA PK Parameter Half-Life (T1/2) Determined Based on MPA Levels. [ Time Frame: 0, 2, 4, 6, 8, 10, and 12 weeks ] [ Designated as safety issue: Yes ]
    This evaluates the effect of LPV/r on the secondary MPA PK parameter T1/2 based on MPA levels measured at weeks 0, 2, 4, 6, 8, 10, and 12.
  • LPV PK Parameter Cmin. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
    This evaluates the effect of MPA on the secondary LPV PK parameter Cmin obtained from both sampling periods, before DMPA injection at study day 0 and four weeks after DMPA injection at study week 4.
  • LPV PK Parameter Cmax. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
    This evaluates the effect of MPA on the secondary LPV PK parameter Cmax obtained from both sampling periods, before DMPA injection at study day 0 and four weeks after DMPA injection at study week 4.
  • LPV PK Parameter Tmax. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
    This evaluates the effect of MPA on the secondary LPV PK parameter Tmax obtained from both sampling periods, before DMPA injection at study day 0 and four weeks after DMPA injection at study week 4.
  • LPV PK Parameter CL/F. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
    This evaluates the effect of MPA on the secondary LPV PK parameter CL/F obtained from both sampling periods, before DMPA injection at study day 0 and four weeks after DMPA injection at study week 4.
  • LPV PK Parameter T1/2. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
    This evaluates the effect of MPA on the secondary LPV PK parameter T1/2 obtained from both sampling periods, before DMPA injection at study day 0 and four weeks after DMPA injection at study week 4.
  • Ritonavir (RTV) PK Parameter AUC0-12h. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
    This evaluates the effect of MPA on the PK parameter AUC0-12h of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4. Blood samples were drawn for RTV concentration levels at time zero (before LPV/r dosing) and at 30 minutes and 1, 2, 3, 4, 5, 6, 8 and 10 hours after LPV/r dosing at day 0 and week 4.
  • RTV PK Parameter Cmin. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
    This evaluates the effect of MPA on the PK parameter Cmin of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4.
  • RTV PK Parameter Cmax. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
    This evaluates the effect of MPA on the PK parameter Cmax of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4.
  • RTV PK Parameter Tmax. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
    This evaluates the effect of MPA on the PK parameter Tmax of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4.
  • RTV PK Parameter CL/F. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
    This evaluates the effect of MPA on the PK parameter CL/F of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4.
  • RTV PK Parameter T1/2. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
    This evaluates the effect of MPA on the PK parameter T1/2 of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4.
  • Percentage of Participants With Menstrual Irregularities of Grade 1 and Higher Deemed Possibly, Probably or Definitely Related to Study Treatment. [ Time Frame: From day 0 to week 12 ] [ Designated as safety issue: Yes ]
    This evaluates toxicity and safety of concomitant medication of DMPA and LPV/r, focusing specifically on the adverse event (AE) menstrual irregularities with abnormal vaginal bleeding. The AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see references in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening, Grade 5=Death. Relationship to study treatment was determined by the study's co-chairs.
  • Percentage of Participants With HIV-1 RNA Levels <400 Copies/mL. [ Time Frame: Day 0, Weeks 2, 4, 8, and 12 ] [ Designated as safety issue: Yes ]
    This evaluates the short-term impact of MPA on virologic suppression in participants taking LPV/r who have received a dose of DMPA by measuring percentage of participants with HIV-1 RNA levels <400 copies/mL at day 0 (prior to DMPA injection) and at weeks 2, 4, 8 and 12 (after DMPA injection). An FDA-approved HIV-1 RNA assay with a lower limit of detection of 75 copies/mL or less was required and the same HIV-1 RNA assay was required to be performed for each participant across all study visits. The Roche COBAS AmpliPrep/TaqMan HIV-1 and Abbott RealTime HIV-1 tests were used.
  • Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay. [ Time Frame: Day 0, Weeks 4 and 12 ] [ Designated as safety issue: No ]
    This evaluates the effect of MPA on CMI to HIV and VZV at baseline before DMPA (day 0) and after DMPA (weeks 4 and 12) . Cytokines are interferon-gamma (IFN-gamma) and interleukin 2 (IL-2), and Stimuli are HIV and VZV. Summary of adjusted ELISPOT assay results is in spot forming cells (SFC)/10^6 peripheral blood mononuclear cells (PBMC) by study weeks 0, 4 and 12. The outcome measures of IFN-gamma and IL-2 measured for HIV and VZV are presented here together to provide all results pertaining to the same objective in a single data table.
  • CMI to HIV and the Common Opportunistic Agent VZV Using the Lymphocyte Proliferation Assay (LPA). [ Time Frame: Day 0, Weeks 4 and 12 ] [ Designated as safety issue: No ]
    This evaluates the effect of MPA on CMI to HIV and VZV. This outcome was measured at Baseline Before DMPA (Day 0) and After DMPA (Weeks 4 and 12) using the Lymphocyte Proliferation Assay (LPA). The data table shows a summary of LPA assay results by study week with stimuli HIV and VZV. Proliferation results are reported as a stimulation index (SI) which represents the ratio of the stimulated counts per minute to unstimulated control counts per minute.
  • Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. [ Time Frame: Day 0, Weeks 4 and 12 ] [ Designated as safety issue: No ]
    This evaluates the effect of MPA on Tregs at baseline (Day 0), week 4 and week 12 using flow cytometry in freshly thawed PBMCs. A summary of CD4+ and cluster of differentiation 8 (CD8+) anchored T-cell subsets by study week, in percent that express the marker of interest, is presented here together to provide all results pertaining to this objective in a single data table.
  • Progesterone levels obtained at study weeks 0, 2, 4, 6, 8, 10, and 12 from both this current study and the study control arm in ACTG A5093 [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
    This evaluates the suppression of ovulation due to the potential PK interaction between DMPA and LPV/r.
  • Natural log-transformed MPA PK parameters Cmin, Cmax. Tmax, T1/2, and Cl/F determined based on MPA levels obtained at study weeks 0, 2, 4, 6, 8, 10, and 12 from this current study and those from the study control arm in ACTG A5093 [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
    This evaluates the effect of LPV/r on the secondary MPA PK parameters.
  • Natural log-transformed LPV PK parameters Cmin, Cmax, Tmax, T1/2, and Cl/F obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4 [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
    This evaluates the effect of MPA on the secondary LPV PK parameters.
  • Natural log-transformed RTV PK parameters AUC0-12h, Cmin, Cmax, Tmax, and Cl/F obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4 [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
    This evaluates the effect of MPA on the PK parameters of RTV.
  • Laboratory toxicities and signs and symptoms with toxicity grades recorded while on study. HIV-1 RNA copies at study entry and study week 12 [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
    This evaluates toxicity and safety of concomitant medication of DMPA and LPV/r and also evaluates the short-term virologic suppression.
  • CMI to HIV and two common opportunistic agents C. albicans (candida) and varicella-zoster virus (VZV) measured at baseline before DMPA and after DMPA at week 4 and at week 12 using flow cytometry [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    This evaluates the effect of MPA on cell-mediated immunity to HIV and the common opportunistic agents.
  • Tregs at baseline, week 4, and week 12 using flow cytometry in freshly thawed and in antigen-stimulated PBMCs measured at baseline before DMPA and after DMPA at week 4 and week 12 using flow cytometry [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    This evaluates the effect of MPA on Tregs.
Not Provided
Not Provided
 
Pharmacokinetic Interactions Between DMPA and LPV/r Among HIV-Infected Women
An Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Between Depo-Medroxyprogesterone Acetate (DMPA) and Lopinavir/Ritonavir (LPV/r) and of the Effects of DMPA on Cellular Immunity and Regulation in HIV-Infected Women
This study was done to look at the level of Depo-Provera, an injectable birth control, in the blood to see whether it is affected by the anti-HIV drug Kaletra (lopinavir/ritonavir [LPV/r]). It is not known whether taking Depo-Provera together with Kaletra changes the amount of Kaletra in blood. Therefore, this study also looked at the levels of HIV and Kaletra before and after receiving a shot of Depo-Provera. This study evaluated the safety of Depo-Provera and Kaletra when they are used together. In addition to what is stated above, this study also explored any effect of Depo-Provera on the immune system.

The primary study objective was addressed by calculating the Area Under the Concentration-Time Curve (AUC) from week 0 (prior to DMPA injection) to week 12 (twelve weeks after DMPA injection) in our study participants.

DMPA was supplied and administered as part of the protocol, however Kaletra was not. It was required that participants already be on a Kaletra based regimen prior to entering the study, as described in the eligibility criteria.

Arm A of AIDS Clinical Trial Group (ACTG) A5093, which consisted of 14 participants who were administered DMPA without Kaletra, was used as reference data.

Interventional
Phase 2
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
HIV-1 Infection
Drug: depo-medroxyprogesterone acetate
At study entry/ Day 0, participants will receive Depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
Other Names:
  • DMPA
  • Depo-Provera
Experimental: Depo-medroxyprogesterone acetate (DMPA)
At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
Intervention: Drug: depo-medroxyprogesterone acetate

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
25
October 2012
October 2012   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • HIV-1 infection
  • Documentation of plasma HIV-1 RNA </= 400 copies/mL within 30 days prior to study entry.
  • Last menstrual period </= 35 days prior to study entry.
  • If last menstrual period >35 days prior to study entry, serum follicle-stimulating hormone (FSH) must be </= 40 Milli-International units per Milliliter (MIU/mL)
  • Stable anti-retroviral (ARV) regimen consisting of BID LPV/r plus 2 or more nucleoside reverse transcriptase inhibitors (NRTIs) for at least 30 days if postpartum or for at least the previous 14 days if on a previously stable antiretroviral regimen without modifications prior to study entry
  • Cluster of Differentiation 4 (CD4+) cell count ≥200 cells/mm^3 within 30 days prior to study entry
  • Certain laboratory values within 30 days prior to study entry
  • Premenopausal females with normal ovarian function
  • Negative serum or urine-Human Chorionic Gonadotropin (HCG) pregnancy test within 72 hours prior to study entry
  • All subjects 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.Subjects of reproductive potential, who are participating in sexual activity that could lead to pregnancy, must agree to use an additional reliable method of contraception while in the study.
  • Ability and willingness to give written informed consent
  • Documentation of Pap smear within one year prior to study entry.
  • Documentation of hepatitis B (surface antigen) and hepatitis B (core antibody) and hepatitis C (antibody) status prior to study entry.
  • Documentation of varicella-zoster virus (VZV) status by history of varicella or herpes zoster, or history of varicella or herpes zoster vaccination or documentation of anti-VZV antibodies.
  • Willingness to abstain from alcohol 24 hours prior to and during the 10-hour pharmacokinetic (PK) specimen draws.
  • Willingness to abstain from any grapefruit product or supplement for 24 hours prior to entry and for the duration of the study.

Exclusion Criteria:

  • Received DMPA within 180 days prior to study entry.
  • Received other hormonal therapies within the 30 days prior to study entry.
  • Concurrent dual nucleoside therapy of zidovudine (ZDV) and stavudine (d4T) within 30 days prior to study entry.
  • Use of any prohibited medications within 30 days prior to study entry. Prohibited Medications were:

    • amiodarone (Cordarone)
    • astemizole (Hismanal)
    • bepridil (Vascor)
    • carbamazepine (Tegretol)
    • cisapride (Propulsid)
    • clarithromycin (Biaxin)
    • cyclosporine (Sandimmune, Neoral)
    • dihydroergotamine (Migranal and others)
    • ergotamine (Ergostat, Gotamine, and others)
    • erythromycin (E-mycin, erythromycin ethylsuccinate (EES) and others)
    • flecainide (Tambocor)
    • glucocorticoids
    • Hypericum perforatum (St. John's wort)
    • itraconazole (Sporanox)
    • ketoconazole (Nizoral)
    • lovastatin (Mevacor)
    • midazolam (Versed)
    • nefazadone (Serzone)
    • phenobarbital (Luminal)
    • phenytoin (Dilantin)
    • pimozide (Orap)
    • pioglitazone (Actos)
    • propafenone (Rythmol)
    • propofol (Diprivan)
    • quinidine (Quinidex)
    • rifabutin (Mycobutin)
    • rifampin (Rifadin, Rifamate, Rifater, Rimactane)
    • rosiglitazone (Avandia)
    • simvastatin (Zocor)
    • tacrolimus (Prograf)
    • terfenadine
    • ticlopidine (Ticlid), and
    • triazolam (Halcion)
  • Breastfeeding.
  • Less than 30 days postpartum at study entry.
  • Bilateral oophorectomy.
  • Hypersensitivity to DMPA, MPA, or any of the other ingredients in DMPA.
  • More than a 50% change in tobacco smoking within the 30 days prior to study entry or plans to significantly change tobacco use during the study.
  • Invasive cancer of the reproductive tract; known or suspected malignancy of the breast, or known increased risk for breast cancer; undiagnosed vaginal bleeding; liver tumors; or serious ocular disorders at any time prior to study entry.
  • Uncontrolled hypothyroidism or hyperthyroidism within 30 days of study entry.
  • Acute infections or other opportunistic diseases requiring medication within 14 days prior to study entry.
  • Receipt of any immunizations within 2 weeks prior to enrollment.
  • Use of any immunosuppressant medication including systemic corticosteroids within 30 days prior to study entry.
  • Chronic immunosuppressive conditions other than HIV.
  • Initiated, discontinued, or changed doses of drugs that are cytochrome P450 3A4 (CYP3A4) substrates within 30 days of study entry.
  • History of deep venous thrombosis or pulmonary emboli.
Female
13 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States,   Puerto Rico
 
NCT01296152
ACTG A5283, 1U01AI068636
Yes
Not Provided
Not Provided
AIDS Clinical Trials Group
AIDS Clinical Trials Group
National Institute of Allergy and Infectious Diseases (NIAID)
Study Chair: Susan E Cohn, M.D., M.P.H. Northwestern University CRS
Study Chair: Amneris E Luque, M.D. University of Rochester ACTG CRS
AIDS Clinical Trials Group
November 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP