A5283: 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 CSRC

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A5283 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 WomenCSRC Presentation 2/11/10

• A5283 Team (Core Team)
• Susan E. Cohn Amneris E. Luque Co-Chairs
• Elizabeth Livingston Vice-Chair
• Fran Aweeka Robert DiCenzo Pharmacologists
• Jeong-Gun Park Biostatistician
• Adriana Weinberg Immunologist
• D. Heather Watts NICHD Karin Klingman DAIDS
• Deborah A. Scott Clinical Trials Specialist
• Sponsored by NIAID

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Background

• Depo-medroxyprogesterone (DMPA) is an injectable
  depot formulation of MPA, a synthetic progestin,
  providing effective contraception for 3 months
  after IM injection, and used by millions of women
  around the world.
• Little is known about DMPA use with ritonavir
  boosted PIs which are also metabolized through
  the cytochrome P450 system (CYP 3A4)

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Rationale

• The use of injectable progestins such as DMPA, is
  high in many areas of the world with high HIV
  prevalence, underscoring the need to understand
  potential drug-drug interactions with ARV
  medications.
• Preliminary information indicates that DMPA may
  suppress cell mediated immunity, however this
  effect has not been evaluated in a controlled
  fashion.

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Study Design
Week 4
Week 12

• Study Group
• 15 HIV infected
• 13 years
• On stable ART
• LPV/r NRTIs 3 mos
• VL ? 400 copies/ml
• CD4 cell count 200/µL
• Neg Pregnancy test

DAY 0
LPV PK RIT PK DMPA PK PBMC CD4 VL
DMPA PK PBMC CD4 VL
LPV PK RIT PK DMPA PK PBMC CD4 VL
Progesterone levels, DMPA PK Adherence
assessment q 2wk
DMPA
DMPA
Historical Controls ACTG 5093 14 on DMPA no
ARV or NRTI only

• Primary Objectives
• Evaluate the effect of BID LPV/r on the PK of
  DMPA using the DMPA AUC from baseline (day 0) to
  week 12.
• Determine the effect of DMPA on the PK of LPV
  using AUC for LPV prior to DMPA (day 0) and at
  week 4

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Secondary Objectives

• Determine if potential PK interactions between
  LPV/r and DMPA affect suppression of ovulation,
  measured by of subjects with progesterone level
  gt 5 ng/mL
• Evaluate the effect of LPV/r on other PK
  parameters of DMPA such as Cmin, Cmax, Tmax,
  Half-life (T1/2), and Clearance (CI/F)
• Evaluate the effect of DMPA on other PK
  parameters of LPV such as Cmin, Cmax, Tmax,
  T1/2, and Clearance (Cl/F)

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Secondary Objectives (cont.)

• Evaluate the effect of DMPA on PK parameters of
  RTV such as AUC, Cmin, Cmax, T1/2, Tmax, and
  Clearance (Cl/F).
• Evaluate the toxicity and safety of concomitant
  LPV/r administered twice daily and DMPA,
  including the short term impact of DMPA on
  virologic suppression at week 12.

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Secondary Objectives (cont.)

• Evaluate the effect of DMPA on cell-mediated
  immunity (CMI) to HIV and on common opportunistic
  agents at baseline, week 4 (peak MPA levels) and
  week 12 (maximum MPA cumulative exposure)
• Evaluate the effect of DMPA on regulatory T cells
  (Tregs) at baseline, week 4, and week 12

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Evaluation Screening Entry/ Day 0 Post-Entry Evaluations (Weeks) Post-Entry Evaluations (Weeks) Post-Entry Evaluations (Weeks) Post-Entry Evaluations (Weeks) Post-Entry Evaluations (Weeks) Post-Entry Evaluations (Weeks) Discontinuation Evaluations
Evaluation Screening Entry/ Day 0 2 4 6 8 10 12 Discontinuation Evaluations
Documentation of HIV X
Medical History/Medication History X
Complete Physical Examination X X
Targeted Physical Examination X X X X X X X
Concomitant medications X X X X X X X X X
Signs and symptoms assessment X X X X X X X X X
Baseline adherence assessment X
ARV adherence assessment X X X X X X X
Hematology X X X
Liver function tests X X X
Chemistry X X X
Urinalysis X X
Pregnancy Testing X X X whenever pregnancy is suspected whenever pregnancy is suspected whenever pregnancy is suspected whenever pregnancy is suspected X
CD4 X X X
HIV-1 RNA X X X X X X
Serum FSH/LH X X X X X X X X
Stored Plasma/PBMC X X X X
LPV and RTV PK sample collection X X
Serum progesterone level X X X X X X X
Plasma for DMPA PK specimen sample collection X X X X X X X
DMPA injection X X
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Projected accrual and study duration

• 15 women will be enrolled to have adequate power
  for both primary objectives, assuming patients
  who do not completed PK evaluations will be
  replaced
• We will open this protocol to all domestic ACTG
  and IMPAACT sites
• We anticipate screening and enrolling 15-19 women
  with 1 subject accrued per month, or about 18
  months to fully accrue this study
• We added 2 subjects to the 13 evaluable subjects
  needed assuming a 10 drop out/loss to f/up and
  the possibility of lost or unusable PK samples
  after the study has been completed
• We do not anticipate any recruitment difficulties
  given the feedback from site surveys and the
  small sample size

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Safety issues

• Safety and tolerability of DMPA will be monitored
  by means of adverse event reports (AER) and
  toxicity reports presenting laboratory and
  clinical data.
• The study team will discuss these reports on
  regularly scheduled conference calls or by e-mail
  and make any decisions needed to protect subjects
  from undue risk.
• Weight, mood changes, changes in menses will be
  monitored.
• Women who become pregnant will be monitored for
  safety and outcomes.

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Analysis plan Use of Historical Controls

• DMPA PK parameter AUCs from baseline (week 0,
  pre-dose) to week 12 (AUC0-12wk) will be compared
  between DMPA administered alone (the PK AUC
  obtained from ACTG A5093 controls) and DMPA
  co-administered with LPV/r, using the
  nonparametric Wilcoxon rank-sum test.
• LPV/r PK parameters AUC from baseline (hour 0,
  predose) to hour 12 (AUC0-12h) will be compared
  between LPV/r alone period (study day 0) and
  LPV/r co-administration period (study week 4),
  using the nonparametric Wilcoxon signed-rank test
  .

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Analysis plans Immunologic objectives

• Paired analysis will assess changes in VZV, HIV
  and candida-specific memory, effector, and Tregs
  and in natural Tregs in response to DMPA from
  baseline to week 12.
• Changes in cell-mediated immunity (CMI) will be
  analyzed using the nonparametric Wilcoxon
  signed-rank test, and summarized by the median
  change (and 25th, 75th percentiles) as well as
  the median (25th,75th percentiles) at baseline,
  week 4. and week 12.