Protease Inhibitors to Reduce Malaria Morbidity in HIV-Infected Pregnant Women (PROMOTE-PIs)

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Diana Havlir, University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT00993031
First received: October 8, 2009
Last updated: October 15, 2013
Last verified: October 2013

October 8, 2009
October 15, 2013
December 2009
July 2013   (final data collection date for primary outcome measure)
Prevalence of malaria defined as positive placental blood smear or positive placental blood PCR [ Time Frame: Delivery ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT00993031 on ClinicalTrials.gov Archive Site
  • Placental malaria defined as positive placental histopathology or positive rapid diagnostic test [ Time Frame: Delivery ] [ Designated as safety issue: No ]
  • Maternal malaria defined as the number of treatments for new episodes of malaria per time at risk [ Time Frame: Time from randomization until 24 months after delivery or cessation of breastfeeding ] [ Designated as safety issue: No ]
  • Prevalence of severe maternal anemia defined by hemoglobin < 8g/dl at any point during the trial in each treatment group [ Time Frame: Time from randomization until 24 months postpartum or cessation of breastfeeding ] [ Designated as safety issue: No ]
  • Prevalence of composite clinical outcome defined by LBW, stillbirth(intrauterine fetal demise >20wks GA), late spontaneous abortion(miscarriage 12-20wks GA), preterm delivery(<37wks gestation), neonatal death(death of liveborn infant within first 28days) [ Time Frame: Time from randomization until 24 months postpartum or cessation of breastfeeding ] [ Designated as safety issue: No ]
  • Incidence of pre-eclampsia defined by hypertension > 140/90 on two occasions measured > 6 hours apart with ≥1+ proteinuria on clean catch urine dipstick [ Time Frame: Time of randomization until 4 weeks postpartum ] [ Designated as safety issue: No ]
  • Maternal HIV RNA suppression of <400 copies/mL and of <50 copies/mL [ Time Frame: At delivery and 24 weeks after the start of the treatment regimen ] [ Designated as safety issue: No ]
  • Change in maternal CD4 cell counts and % CD4 [ Time Frame: From ART initiation to delivery and from delivery to the cessation of breastfeeding ] [ Designated as safety issue: No ]
  • Development of one or more new maternal HIV antiretroviral resistance mutations [ Time Frame: Measured at delivery and 24 weeks postpartum. ] [ Designated as safety issue: No ]
  • Incidence of maternal to child transmission of HIV, measured by infant HIV DNA PCR [ Time Frame: From delivery to 24 weeks of life or the cessation of breastfeeding if that occurs prior to 24 weeks of life ] [ Designated as safety issue: No ]
  • ART levels in plasma and hair samples [ Time Frame: Women at 30-34 weeks gestation and 12 weeks postpartum; Infants at delivery, 12 weeks and 24 weeks of life. ] [ Designated as safety issue: No ]
  • Prevalence of Grade 3 or 4 toxicity at any point during the trial in the two treatment groups in women and in infants [ Time Frame: Time from randomization until 24 months postpartum or cessation of breastfeeding ] [ Designated as safety issue: Yes ]
Same as current
Not Provided
Not Provided
 
Protease Inhibitors to Reduce Malaria Morbidity in HIV-Infected Pregnant Women
Protease Inhibitors to Reduce Malaria Morbidity in HIV-Infected Pregnant Women

This study is an open-label, single site, randomized controlled trial comparing protease inhibitor (PI)-based antiretroviral therapy (ART) to non-PI based ART for HIV-infected pregnant and breastfeeding women of all CD4 cell counts at high risk of malaria. The study is designed to test the hypothesis that pregnant women receiving a PI-based ART regimen will have lower risk of placental malaria compared to pregnant women receiving a non-PI based ART regimen. The primary study endpoint of the study is placental malaria. This study also enrolls the infants of these women at the time of delivery.

The study site will be the Tororo district hospital campus situated in Eastern Uganda, an area of high malaria transmission. Using convenience sampling, we will enroll 500 HIV-infected pregnant women and their infants from the Tororo community. Eligible women between 12-28 weeks gestation will be randomized at enrollment to receive either a PI- based or an NNRTI-based ART regimen after stratification by gravidity (G1 versus G2+) and gestational age (<24 weeks versus ≥ 24 weeks at enrollment).

Treatment group A will receive Zidovudine 300mg + Lamivudine 150mg + Lopinavir/ritonavir 200mg/50mg. Treatment group B will receive Zidovudine 300mg + Lamivudine 150mg + Efavirenz 600mg.

At enrollment, all study participants will receive a long lasting ITN and, as available, a basic care package including a safe water vessel, multivitamins and condoms, as per current standard of care for HIV-infected pregnant women in Uganda, if they have not already received these interventions from the referral site. Two ITNs will be provided for each mother-infant pair. Participants will receive all routine and acute medical care at a designated study clinic open 7 days a week from 8 a.m. to 5 p.m. If medical care is needed after hours, participants will be instructed to come to Tororo District Hospital premises (where the study clinic is located) and request that the study physician on-call be contacted. They will be followed up from the time of enrollment during pregnancy and through the cessation of breastfeeding; seen monthly for routine assessments and laboratory evaluations. Following delivery, the infants of enrolled women will be followed until 6 weeks following the cessation of breastfeeding but not beyond 58 weeks of life. Study participants will be followed closely for adverse events potentially due to study drugs and for malaria and HIV treatment outcomes. During the follow-up period, all patients presenting to the clinic with a new episode of fever will undergo standard evaluation (history, physical examination and Giemsa-stained blood smear) for the diagnosis of malaria.

Women will receive the study treatment from the time of study entry and randomization (12-28 weeks gestation) until 1 week following the cessation of breastfeeding (but no longer than 1 year + 1 week postpartum). If a subject experiences a toxicity endpoint, ART will be changed to provide antiviral activity prior to delivery. Exclusive breastfeeding will be encouraged until 24 weeks postpartum which is the standard of care in Uganda. As per updated WHO guidelines, women will be encouraged to introduce food at 6 months of life and continue breastfeeding until 1 year of life. Women will be counseled to wean over the course of 1 month and continue antiretrovirals for at least 1 week following weaning. Furthermore, if an infant is found to be HIV-infected, Uganda MOH and WHO guidelines recommend the continuation of breastfeeding until 2 years of life and daily TS. All women will receive daily oral trimethoprim/sulfamethoxazole (TS) per Ugandan MOH guidelines.

Per Ugandan MOH guidelines, all newborns will receive nevirapine syrup (10mg/ml) starting within 12 hours after birth for 6 weeks, daily oral TS from 6 weeks of life until 6 weeks following the cessation of breastfeeding, and their mothers will be instructed on ITN use for their infants.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
  • Malaria
  • HIV Infections
  • Drug: Lopinavir/ritonavir
    LPV 200mg/r 50mg
    Other Names:
    • Kaletra
    • Aluvia
  • Drug: Efavirenz
    600mg
  • Drug: Zidovudine
    Zidovudine 300 mg
  • Drug: Lamivudine
    Lamivudine 150 mg
  • Experimental: Group A
    ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg
    Interventions:
    • Drug: Lopinavir/ritonavir
    • Drug: Zidovudine
    • Drug: Lamivudine
  • Active Comparator: Group B
    ZDV 300mg/3TC 150mg/EFV 600mg
    Interventions:
    • Drug: Efavirenz
    • Drug: Zidovudine
    • Drug: Lamivudine

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
391
July 2013
July 2013   (final data collection date for primary outcome measure)

Inclusion Criteria:

  1. Age > 16 years (if <18 years old, living independently from parents)
  2. Documentation of HIV status must come from two assays. Assays include DNA PCR, HIV RNA, Western blot, or rapid HIV antibody test
  3. Confirmed pregnancy by positive serum or urine pregnancy test or ultrasound
  4. Estimated gestational age between 12 and 28 weeks (based on first day of last menstrual period with physical exam confirmation and ultrasound confirmation) at time of enrollment
  5. Residency within 30 km of the study site
  6. Willing to provide informed consent

Exclusion Criteria:

  1. Current or prior use of HAART
  2. Exposure to single-dose NVP (alone or with zidovudine or zidovudine/lamivudine or other abbreviated monotherapy or dual therapy for PMTCT) less than 24 months prior to enrollment
  3. Prior dose-limited toxicity to TS within 14 days of study enrollment
  4. Receipt of any contraindicated medications within 14 days of study enrollment (See Appendix III.)
  5. Active tuberculosis or other WHO Stage 4 diseases
  6. Screening laboratory values:

    1. Hemoglobin: <7.5 g/dL (Note: Women found to have a hemoglobin <7.5 at screening may receive iron and folic acid and/or a blood transfusion at the physician's discretion. If a repeat hemoglobin is ≥7.5 g/dL, the woman may be considered for study inclusion.)
    2. Absolute neutrophil count (ANC): <750/mm3
    3. Platelet count: <50,000/mm3
    4. ALT: >225 U/L (>5.0x ULN)
    5. AST: >225 U/L (>5.0x ULN)
    6. Bilirubin (total): > 2.5x ULN
    7. Creatinine: > 1.8x ULN
  7. Known cardiac conduction abnormalities or structural heart defect

NOTE: A woman will be excluded from study participation during the current pregnancy if she goes into labor, experiences ruptured membranes or develops active tuberculosis or a WHO stage 4 condition following study enrollment but prior to study drug initiation.

Female
16 Years and older
No
Contact information is only displayed when the study is recruiting subjects
Uganda
 
NCT00993031
H5741-34342, PO1HD059454, 2009-141, HS-670, 592/ESR/NDA/DID-09/2009, H5741-34342 and 10-02958
Yes
Diana Havlir, University of California, San Francisco
University of California, San Francisco
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Principal Investigator: Diane Havlir, MD University of California, San Francisco
Study Chair: Deborah Cohan, MD, MPH University of California, San Francisco
Principal Investigator: Moses R Kamya, MBChB, MMed, PhD Makerere University
Study Chair: Pius Okong, MMed, PhD Ugandan Ministry of Health
Principal Investigator: Grant Dorsey, MD, PhD University of California, San Francisco
University of California, San Francisco
October 2013

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