Protease Inhibitors to Reduce Malaria Morbidity in HIV-Infected Pregnant Women (PROMOTE-PIs)
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Malaria HIV Infections |
Drug: Lopinavir/ritonavir Drug: Efavirenz Drug: Zidovudine Drug: Lamivudine |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Prevention |
| Official Title: | Protease Inhibitors to Reduce Malaria Morbidity in HIV-Infected Pregnant Women |
- Prevalence of malaria defined as positive placental blood smear or positive placental blood PCR [ Time Frame: Delivery ] [ Designated as safety issue: No ]
- 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 ]
| Estimated Enrollment: | 500 |
| Study Start Date: | December 2009 |
| Estimated Study Completion Date: | July 2013 |
| Estimated Primary Completion Date: | July 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Group A
ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg
|
Drug: Lopinavir/ritonavir
LPV 200mg/r 50mg
Other Names:
Drug: Zidovudine
Zidovudine 300 mg
Drug: Lamivudine
Lamivudine 150 mg
|
|
Active Comparator: Group B
ZDV 300mg/3TC 150mg/EFV 600mg
|
Drug: Efavirenz
600mg
Drug: Zidovudine
Zidovudine 300 mg
Drug: Lamivudine
Lamivudine 150 mg
|
Detailed Description:
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.
Eligibility| Ages Eligible for Study: | 16 Years and older |
| Genders Eligible for Study: | Female |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Age > 16 years (if <18 years old, living independently from parents)
- Documentation of HIV status must come from two assays. Assays include DNA PCR, HIV RNA, Western blot, or rapid HIV antibody test
- Confirmed pregnancy by positive serum or urine pregnancy test or ultrasound
- 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
- Residency within 30 km of the study site
- Willing to provide informed consent
Exclusion Criteria:
- Current or prior use of HAART
- 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
- Prior dose-limited toxicity to TS within 14 days of study enrollment
- Receipt of any contraindicated medications within 14 days of study enrollment (See Appendix III.)
- Active tuberculosis or other WHO Stage 4 diseases
Screening laboratory values:
- 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.)
- Absolute neutrophil count (ANC): <750/mm3
- Platelet count: <50,000/mm3
- ALT: >225 U/L (>5.0x ULN)
- AST: >225 U/L (>5.0x ULN)
- Bilirubin (total): > 2.5x ULN
- Creatinine: > 1.8x ULN
- 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.
Contacts and Locations| Contact: Diane V Havlir, MD | 01-415-476-4082 ext 400 | dhavlir@php.ucsf.edu |
| Contact: Deborah Cohan, MD, MPH | 01-415-206-3658 | cohand@obgyn.ucsf.edu |
| Uganda | |
| Tororo District Hospital | Recruiting |
| Tororo, Uganda | |
| Contact: Julia Mwesigwa, MBChB julimwesigwa@yahoo.com | |
| 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 |
More Information
No publications provided by University of California, San Francisco
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Diana Havlir, Professor, University of California, San Francisco |
| ClinicalTrials.gov Identifier: | NCT00993031 History of Changes |
| Other Study ID Numbers: | H5741-34342, PO1HD059454, 2009-141, HS-670, 592/ESR/NDA/DID-09/2009, H5741-34342 and 10-02958 |
| Study First Received: | October 8, 2009 |
| Last Updated: | June 26, 2012 |
| Health Authority: | United States: Food and Drug Administration Uganda: National Drug Authority Uganda: National Council for Science and Technology |
Keywords provided by University of California, San Francisco:
|
HIV Placental Malaria Pregnancy Uganda |
Protease inhibitors Trimethoprim-sulfamethoxazole Treatment experienced |
Additional relevant MeSH terms:
|
HIV Infections Acquired Immunodeficiency Syndrome Malaria Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Immunologic Deficiency Syndromes Immune System Diseases Slow Virus Diseases Protozoan Infections Parasitic Diseases Protease Inhibitors |
Ritonavir Lopinavir Trimethoprim-Sulfamethoxazole Combination Efavirenz Zidovudine Lamivudine Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Anti-Infective Agents, Urinary Anti-Infective Agents Therapeutic Uses Renal Agents Antimalarials Antiprotozoal Agents |
ClinicalTrials.gov processed this record on March 10, 2013
