Clinical trial NCT01296152: Pharmacokinetic Interactions Between DMPA and LPV/r Among HIV-Infected Women
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-1 Infection
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2011-02-15
Enrollment: 25
Sex: FEMALE
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Medroxyprogesterone Acetate (MPA) Pharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-12weeks)
timeFrame: Day 0, Weeks 2, 4, 6, 8, 10 and 12
measure: AUC0-12hour for LPV at Baseline (Day 0) Before DMPA Administration and at Week 4 (Four Weeks After DMPA Administration)
timeFrame: Day 0 and Week 4
Secondary outcomes:
measure: Percentage of Participants With Progesterone Levels Less Than the Lower Limit of Quantification (LLQ).
timeFrame: 0, 2, 4, 6, 8, 10, and 12 weeks
measure: MPA PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on MPA Levels.
timeFrame: 0, 2, 4, 6, 8, 10, and 12 weeks
measure: MPA PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on MPA Levels.
timeFrame: 0, 2, 4, 6, 8, 10, and 12 weeks
measure: MPA PK Parameter Time to Cmax (Tmax) Determined Based on MPA Levels.
timeFrame: 0, 2, 4, 6, 8, 10, and 12 weeks
measure: MPA PK Parameter Clearance (CL/F) Determined Based on MPA Levels.
timeFrame: 0, 2, 4, 6, 8, 10, and 12 weeks
measure: MPA PK Parameter Half-Life (T1/2) Determined Based on MPA Levels.
timeFrame: 0, 2, 4, 6, 8, 10, and 12 weeks
measure: LPV PK Parameter Cmin.
timeFrame: Day 0 and Week 4
measure: LPV PK Parameter Cmax.
timeFrame: Day 0 and Week 4
measure: LPV PK Parameter Tmax.
timeFrame: Day 0 and Week 4
measure: LPV PK Parameter CL/F.
timeFrame: Day 0 and Week 4
measure: LPV PK Parameter T1/2.
timeFrame: Day 0 and Week 4
measure: Ritonavir (RTV) PK Parameter AUC0-12h.
timeFrame: Day 0 and Week 4
measure: RTV PK Parameter Cmin.
timeFrame: Day 0 and Week 4
measure: RTV PK Parameter Cmax.
timeFrame: Day 0 and Week 4
measure: RTV PK Parameter Tmax.
timeFrame: Day 0 and Week 4
measure: RTV PK Parameter CL/F.
timeFrame: Day 0 and Week 4
measure: RTV PK Parameter T1/2.
timeFrame: Day 0 and Week 4
measure: Percentage of Participants With Menstrual Irregularities of Grade 1 and Higher Deemed Possibly, Probably or Definitely Related to Study Treatment.
timeFrame: From day 0 to week 12
measure: Percentage of Participants With HIV-1 RNA Levels <400 Copies/mL.
timeFrame: Day 0, Weeks 2, 4, 8, and 12
measure: Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay.
timeFrame: Day 0, Weeks 4 and 12
measure: CMI to HIV and the Common Opportunistic Agent VZV Using the Lymphocyte Proliferation Assay (LPA).
timeFrame: Day 0, Weeks 4 and 12
measure: Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs.
timeFrame: Day 0, Weeks 4 and 12
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California LA (5048)
state: California
city: Washington
country: United States
facility: Children's National Medical Center Washington DC NICHD CRS (5015)
state: District of Columbia
city: Washington
country: United States
facility: Washington Hospital Center NICHD CRS (5023)
state: District of Columbia
city: Ft. Lauderdale
country: United States
facility: South Florida Childrens Diagnostic & Treatment Cen (5055)
state: Florida
city: Chicago
country: United States
facility: Northwestern University CRS (2701)
state: Illinois
city: Chicago
country: United States
facility: Rush University Cook County Hospital Chicago NICHD CRS (5083)
state: Illinois
city: New Orleans
country: United States
facility: Tulane University New Orleans NICHD CRS (5095)
state: Louisiana
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS (1101)
state: New York
city: Stony Brook
country: United States
facility: SUNY Stony Brook NICHD CRS (5040)
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs (3201)
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS
state: Ohio
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS (2401)
state: Ohio
city: Seattle
country: United States
facility: University of Washington AIDS CRS (1401)
state: Washington
city: San Juan
country: Puerto Rico
facility: San Juan Hospital PR NICHD CRS (5031)
Study officials:
affiliation: Northwestern University CRS
name: Susan E Cohn, M.D., M.P.H.
role: STUDY_CHAIR
affiliation: University of Rochester ACTG CRS
name: Amneris E Luque, M.D.
role: STUDY_CHAIR
References:
citation: The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009)
citation: Luque AE, Cohn SE, Park JG, Cramer Y, Weinberg A, Livingston E, Klingman KL, Aweeka F, Watts DH. Depot medroxyprogesterone acetate in combination with a twice-daily lopinavir-ritonavir-based regimen in HIV-infected women showed effective contraception and a lack of clinically significant interactions, with good safety and tolerability: results of the ACTG 5283 study. Antimicrob Agents Chemother. 2015 Apr;59(4):2094-101. doi: 10.1128/AAC.04701-14. Epub 2015 Jan 26.