Clinical trial NCT00016601: Depo-Medroxyprogesterone Acetate (DMPA, Depo-Provera) Use With Certain Anti-HIV Drugs in HIV-Infected Women
Official title: An Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Between Depo-Medroxyprogesterone Acetate (DMPA, Depo-Provera) and Selected Protease Inhibitor (PI) and Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Therapies Among HIV-Infected Women
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV Infections
Keywords: Delayed-Action Preparations
Drug Interactions
Drug Therapy, Combination
Nevirapine
HIV Protease Inhibitors
Ritonavir
Indinavir
Nelfinavir
Reverse Transcriptase Inhibitors
Anti-HIV Agents
Pharmacokinetics
Medroxyprogesterone 17-Acetate
efavirenz
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2001-08-31
Enrollment: 76
Sex: FEMALE
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to look at the level of depo-medroxyprogesterone acetate (DMPA or Depo-Provera) in the blood to see if is affected by certain anti-HIV drugs (nelfinavir \[NFV\], efavirenz \[EFV\], indinavir \[IDV\] in combination with ritonavir \[RTV\], and nevirapine \[NVP\]). This study will also look at the levels of these anti-HIV drugs to see if they are affected by DMPA.

DMPA is a hormonal birth control method that is given as an injection. It is not known if taking DMPA together with anti-HIV drugs changes the amount of DMPA and/or the amount of anti-HIV drugs in the blood. If higher levels of DMPA occur, side effects may increase. If lower levels of anti-HIV drugs occur, the drugs may become less effective against HIV. This study will look at the levels of anti-HIV drugs and DMPA in the blood when these medications are used together.

Detailed description: DMPA, an injectable depot formulation of medroxyprogesterone (MPA), is a commonly used form of "progestin-only" contraception. Information is limited on the specific P450 isozymes that metabolize MPA; however, it appears that CYP3A4 is 1 pathway of hepatic clearance. Drugs known to be inhibitors of the CYP3A4 pathway (such as protease inhibitors \[PIs\]) may lead to elevated concentrations of MPA. Secondly, MPA given as DMPA injections has been shown to induce the activity of CYP3A4 by 25 percent. It is possible that this action may result in enhanced clearance of the substrates of CYP3A4, including PIs and nonnucleoside reverse transcriptase inhibitors (NNRTIs), which in turn may result in reduced drug exposure and possible ARV failure. This study is designed to address the lack of information on potential interactions between PIs or NNRTIs and DMPA.

Patients are enrolled into 1 of 5 arms based on their current ARV regimen:

Arm A (control group): No current ARVs or receiving nucleoside reverse transcriptase inhibitors (NRTIs) only.

Arm B: NFV (1250 mg bid or 750 mg tid) in combination with NRTIs. Arm C: EFV (600 mg qd) in combination with NRTIs. Arm D: IDV (800 mg bid) and RTV (100 mg bid or 200 mg bid) in combination with NRTIs.

Arm E: NVP (200 mg bid) in combination with NRTIs. Acceptable NRTIs and any fixed combination of these medications include: zidovudine (ZDV), lamivudine, didanosine, stavudine (d4T), zalcitabine, and abacavir; concurrent therapy using ZDV and d4T is not allowed. ARV therapy is not provided by this study. One dose of DMPA is provided to all patients at entry (Day 0) and an optional dose of DMPA will be available at the final visit (Week 12) for those who are interested in continuing with DMPA outside of the protocol and who do not experience adverse events from the first DMPA injection. Patients in Arms B, C, D, and E have intensive pharmacokinetic sampling done at entry and at Week 4 to measure ARV levels. All patients have blood tests at Weeks 2, 4, 6, 8, 10, and 12 to measure levels of DMPA and progesterone. In addition, tests to monitor HIV-1 RNA levels, CD4 and CD8 counts, hematology, blood chemistries, and liver function are performed periodically.

Eligibility criteria: Inclusion Criteria

Patients may be eligible for this study if they:

* Are HIV-positive.
* Have plasma HIV-1 RNA (level of HIV in the blood) below 10,000 copies/ml within 30 days before study entry.
* Had their last menstrual period (LMP) less than 35 days before study entry.
* Have serum follicle-stimulating hormone below 40 MIU/ml if their LMP occurred more than 35 days before study entry.
* Have been on the same anti-HIV drugs for at least 30 days before study entry, if taking anti-HIV drugs. If not taking anti-HIV drugs, patients must have been told about anti-HIV drugs within the 3 months before study entry and have chosen not to take them now or in the future.
* Intend to continue on their anti-HIV drugs, if taking them, for at least 3 months after study entry.
* Have a CD4 cell count above 200 cells/mm3 if taking anti-HIV drugs, or a CD4 cell count above 350 cells/mm3 if not taking anti-HIV drugs, within 30 days before study entry.
* Have not had menopause (change of life) and have a normal reproductive system.
* Have not had any infections or AIDS-related diseases requiring drugs within 14 days before study entry.
* Are 13 years of age or older.
* Are female.
* Have a negative pregnancy test within 30 days before study entry.
* Agree to avoid becoming pregnant for the entire study. If sexually active, agree to use at least 1 barrier method of birth control (male or female condom with or without spermicide \[a cream or gel that kills sperm\] or diaphragm or cervical cap with spermicide) while receiving DMPA in this study.
* Have consent of a parent or guardian if under 18 years of age.
* Weigh at least 40 kg (88 lbs) and are within a certain range of their ideal body weight.

Exclusion Criteria

Patients will not be eligible for this study if they:

* Have taken anti-HIV drugs within 30 days before study entry but have chosen not to take them.
* Are taking only 1 NRTI.
* Are taking anti-HIV drugs other than those listed in the treatment groups, including tenofovir, amprenavir, and lopinavir/ritonavir, or have taken tenofovir, amprenavir, or lopinavir/ritonavir within 30 days before study entry.
* Have taken ZDV and d4T together within 30 days before study entry.
* Are not able to take the anti-HIV drugs properly while on the study, in the opinion of the investigator.
* Are allergic to DMPA, MPA, or any of the other ingredients in DMPA.
* Have received DMPA within 180 days before study entry.
* Have received other hormones (Provera, oral contraceptives, hormonal replacement therapy, or anabolic drugs \[e.g., nandrolone decanoate, megestrol acetate\]) within 30 days before study entry.
* Are taking any of the following: amiodarone, astemizole, bepridil, buspirone, carbamazepine, cimetidine, cisapride, clarithromycin, cyclosporine, dihydroergotamine, diltiazem, ergotamine, erythromycin, flecainide, glucocorticoids, grapefruit juice, St. John's wort, itraconazole, ketoconazole, lovastatin, midazolam, nefazodone, phenobarbital, phenytoin, pimozide, pioglitazone, propafenone, propofol, quinidine, rifabutin, rifampin, rosiglitazone, simvastatin, tacrolimus, terfenadine, ticlopidine, triazolam, or verapamil.
* Have taken any of the following drugs within 30 days before study entry: amiodarone, astemizole, bepridil, buspirone, carbamazepine, cisapride, clarithromycin, cyclosporine, dihydroergotamine, ergotamine, erythromycin, flecainide, glucocorticoids, St. John's wort, itraconazole, ketoconazole, lovastatin, midazolam, nefazodone, phenobarbital, phenytoin, pimozide, pioglitazone, propafenone, propofol, quinidine, rifabutin, rifampin, rosiglitazone, simvastatin, tacrolimus, terfenadine, ticlopidine, or triazolam.
* Have started, stopped, or changed doses, within 30 days before study entry, of certain drugs including: benzodiazepines, except midazolam and triazolam; bupropion; calcium channel blockers, except diltiazem and verapamil; fluconazole; lipid-lowering drugs except pravastatin (i.e., atorvastatin, cerivastatin, and fluvastatin, but not lovastatin and simvastatin); isoniazid; mexiletine; zaleplon; and zolpidem. The patient can, however, remain on stable doses of these drugs during the study.
* Are receiving methadone maintenance treatment for less than 60 days before study entry.
* Are breast-feeding.
* Have had a baby within 30 days before study entry.
* Have had their uterus or both ovaries removed.
* Abuse drugs or alcohol.
* Cannot stop drinking alcohol 1 day before and during the testing at entry and at Week 4.
* Have had a change in smoking habits within 6 weeks before study entry. Patients may have either stopped or started smoking more than 6 weeks before study entry.
* Have cancer of the reproductive system, vaginal bleeding of unknown cause, thyroid problems, liver tumors, or serious eye problems at any time before study entry.
* Are taking investigational drugs without approval of the protocol chair.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Univ of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: Univ of Southern California / LA County USC Med Ctr
state: California
city: Los Angeles
country: United States
facility: Los Angeles County - USC Med Ctr
state: California
city: Denver
country: United States
facility: Children's Hosp of Denver
state: Colorado
city: Jacksonville
country: United States
facility: Univ of Florida Health Science Ctr / Pediatrics
state: Florida
city: Miami
country: United States
facility: Univ of Miami (Pediatric)
state: Florida
city: Chicago
country: United States
facility: Mt Sinai Hosp Med Ctr / Dept of Pediatrics
state: Illinois
city: Chicago
country: United States
facility: Univ of Illinois College of Medicine / Pediatrics
state: Illinois
city: Chicago
country: United States
facility: Chicago Childrens Memorial Hosp (Pediatric)
state: Illinois
city: Chicago
country: United States
facility: The Univ of Chicago Childrens Hosp
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ Hosp
state: Indiana
city: Indianapolis
country: United States
facility: Methodist Hosp of Indiana / Life Care Clinic
state: Indiana
city: Indianapolis
country: United States
facility: Wishard Hosp
state: Indiana
city: New Orleans
country: United States
facility: Tulane Univ / Charity Hosp of New Orleans
state: Louisiana
city: Baltimore
country: United States
facility: Univ of Maryland, Institute of Human Virology
state: Maryland
city: Boston
country: United States
facility: Boston Med Ctr (Pediatric)
state: Massachusetts
city: Detroit
country: United States
facility: Children's Hosp of Michigan
state: Michigan
city: New York
country: United States
facility: Beth Israel Med Ctr
state: New York
city: New York
country: United States
facility: Columbia Presbyterian Med Ctr
state: New York
city: Rochester
country: United States
facility: Community Health Network, Inc
state: New York
city: Rochester
country: United States
facility: St Mary's Hosp (Univ of Rochester/Infectious Diseases)
state: New York
city: Rochester
country: United States
facility: Univ of Rochester Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Health Sciences Ctr at Syracuse / Pediatrics
state: New York
city: Chapel Hill
country: United States
facility: Univ of North Carolina
state: North Carolina
city: Cincinnati
country: United States
facility: Univ of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve Univ
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Med Ctr
state: Ohio
city: Philadelphia
country: United States
facility: Univ of Pennsylvania
state: Pennsylvania
city: Galveston
country: United States
facility: Univ of Texas Galveston
state: Texas
city: Seattle
country: United States
facility: Univ of Washington
state: Washington
city: Seattle
country: United States
facility: Children's Hospital & Medical Center / Seattle ACTU
state: Washington
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp
Study officials:
name: Susan Cohn
role: STUDY_CHAIR
References:
citation: Watts DH, Park JG, Cohn SE, Yu S, Hitti J, Stek A, Clax PA, Muderspach L, Lertora JJ. Safety and tolerability of depot medroxyprogesterone acetate among HIV-infected women on antiretroviral therapy: ACTG A5093. Contraception. 2008 Feb;77(2):84-90. doi: 10.1016/j.contraception.2007.10.002. Epub 2007 Dec 21.