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

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ClinicalTrials.gov Identifier: NCT00993031
Recruitment Status : Completed
First Posted : October 9, 2009
Results First Posted : December 2, 2017
Last Update Posted : December 2, 2017
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Diana Havlir, University of California, San Francisco

Study Description
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Brief Summary:
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 or disease Intervention/treatment Phase
Malaria HIV Infections Drug: Lopinavir/ritonavir Drug: Efavirenz Drug: Zidovudine Drug: Lamivudine Phase 3

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.


Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 389 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Protease Inhibitors to Reduce Malaria Morbidity in HIV-Infected Pregnant Women
Actual Study Start Date : December 15, 2009
Actual Primary Completion Date : July 2013
Actual Study Completion Date : July 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS Malaria
U.S. FDA Resources

Arms and Interventions
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Arm Intervention/treatment
Experimental: Group A
ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg
 Drug: Lopinavir/ritonavir
LPV 200mg/r 50mg
Other Names:
  • Kaletra
  • Aluvia
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


Outcome Measures
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Primary Outcome Measures :
  1. Prevalence of Malaria Defined as Positive Placental Blood Smear [ Time Frame: Delivery ]
    Number of participants with positive placental blood smear for malaria

  2. Prevalence of Malaria Defined as Positive Placental Blood PCR [ Time Frame: Delivery ]
    Number of participants with positive placental blood PCR for malaria


Secondary Outcome Measures :
  1. Placental Malaria Defined as Positive Placental RDT [ Time Frame: Delivery ]
    Number of participants with positive placental RDT for malaria. Malaria rapid diagnostic tests (RDTs) assist in the diagnosis of malaria by detecting evidence of malaria parasites (antigens) in human blood. RDTs permit a reliable detection of malaria infections particularly in remote areas with limited access to good quality microscopy services.

  2. Maternal Malaria Defined as the Number of Treatments for New Episodes of Malaria Per Time at Risk During Pregnancy [ Time Frame: Number of treatments given for clinical malaria based on postive blood smear from time from randomization until 24 months after delivery or cessation of breastfeeding ]
  3. 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 ]
    number of evaluated participants with severe maternal anemia defined by hemoglobin < 8g/dl at any point during the trial in each treatment group

  4. 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 ]
    Percent of evaluated participants with 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 live-born infant within first 28 days)

  5. 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 ]
  6. 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 ]
  7. Change in Maternal CD4 Cell Counts and % CD4 [ Time Frame: From ART initiation to delivery and from delivery to the cessation of breastfeeding ]
  8. Development of One or More New Maternal HIV Antiretroviral Resistance Mutations [ Time Frame: Measured at delivery and 24 weeks postpartum. ]
  9. 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 ]
  10. 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. ]
  11. 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 ]
  12. Placental Malaria Defined Placental Histopathologic Analysis [ Time Frame: Delivery ]
    Number of participants with positive placental histopathology slide for malaria

  13. Maternal Malaria Defined as the Number of Treatments for New Episodes of Malaria Per Time at Risk After Pregnancy [ Time Frame: Number of treatments given for clinical malaria based on postive blood smear from time from delivery until 24 months after delivery or cessation of breastfeeding ]

Eligibility Criteria
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Ages Eligible for Study:   16 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.

Contacts and Locations
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00993031


Locations
Uganda
Tororo District Hospital
Tororo, Uganda
Sponsors and Collaborators
University of California, San Francisco
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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
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Publications of Results:

Other Publications:

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
P01HD059454 ( U.S. NIH Grant/Contract )
2009-141 ( Other Identifier: Makerere Univ Fac of Med Research and Ethics Committee )
HS-670 ( Other Identifier: Uganda National Council for Science and Tech )
592/ESR/NDA/DID-09/2009 ( Other Identifier: Uganda National Drug Authority )
H5741-34342 and 10-02958 ( Other Identifier: UCSF Committee on Human Research )
First Posted: October 9, 2009    Key Record Dates
Results First Posted: December 2, 2017
Last Update Posted: December 2, 2017
Last Verified: October 2017

Keywords provided by Diana Havlir, University of California, San Francisco:
HIV
Placental Malaria
Pregnancy
Uganda
 Protease inhibitors
Trimethoprim-sulfamethoxazole
Treatment experienced

Additional relevant MeSH terms:
HIV Infections
Malaria
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Protozoan Infections
Parasitic Diseases
Ritonavir
Lopinavir
HIV Protease Inhibitors
 Lamivudine
Zidovudine
Efavirenz
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Antimetabolites