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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 : November 16, 2018
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 Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Prevention
Conditions Malaria
HIV Infections
Interventions Drug: Lopinavir/ritonavir
Drug: Efavirenz
Drug: Zidovudine
Drug: Lamivudine
Enrollment 389
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Without Protease Inhibitor With Protease Inhibitor
Hide Arm/Group Description

ZDV 300mg/3TC 150mg/EFV 600mg

Efavirenz: 600mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg

Lopinavir/ritonavir: LPV 200mg/r 50mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

Period Title: Overall Study
Started 195 194
Delivered 187 190
Completed 173 175
Not Completed 22 19
Reason Not Completed
Death             0             1
Physician Decision             0             2
Withdrawal by Subject             3             3
Lost to Follow-up             19             13
Arm/Group Title Without Protease Inhibitor With Protease Inhibitor Total
Hide Arm/Group Description

ZDV 300mg/3TC 150mg/EFV 600mg

Efavirenz: 600mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg

Lopinavir/ritonavir: LPV 200mg/r 50mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

Total of all reporting groups
Overall Number of Baseline Participants 195 194 389
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 195 participants 194 participants 389 participants
29.5  (5.4) 29.0  (5.4) 29.3  (7.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 195 participants 194 participants 389 participants
Female
195
 100.0%
194
 100.0%
389
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
Gestational Age, wk  
Mean (Standard Deviation)
Unit of measure:  Weeks
Number Analyzed 195 participants 194 participants 389 participants
21.1  (4.1) 21.2  (4.3) 21.1  (5.9)
Previous Preganancies  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 195 participants 194 participants 389 participants
0 16 8 24
1 20 25 45
≥2 159 161 320
Bed Net Ownership  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 195 participants 194 participants 389 participants
None 85 85 170
Untreated 28 33 61
ITN 77 70 147
Yes; unknown treatment status 5 5 10
Unknown 0 1 1
Receiving TMP-SMX prophylaxis at enrollment   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 195 participants 194 participants 389 participants
125 124 249
[1]
Measure Description: Trimethoprim/sulfamethoxazole (TMP-SMX) is an antibiotic used to treat a variety of bacterial infections. It consists of one part trimethoprim to five parts sulfamethoxazole.
Hemoglobin level, g/dL  
Mean (Standard Deviation)
Unit of measure:  g/dL
Number Analyzed 195 participants 194 participants 389 participants
10.9  (1.3) 11.0  (1.2) 10.9  (1.8)
CD4+ T-cell count  
Median (Inter-Quartile Range)
Unit of measure:  Cells/mm3
Number Analyzed 195 participants 194 participants 389 participants
374
(270 to 485)
368
(282 to 506)
370.5
(274 to 494)
HIV RNA load  
Median (Inter-Quartile Range)
Unit of measure:  Log10 copies/mL
Number Analyzed 195 participants 194 participants 389 participants
4.3
(3.5 to 4.8)
4.1
(3.3 to 4.7)
4.1
(3.4 to 4.8)
WHO stage HIV disease   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 195 participants 194 participants 389 participants
1 181 189 370
2 13 5 18
3 1 0 1
4 0 0 0
[1]
Measure Description: Stage 1=Asymptomatic; Stage 2= Moderate unexplained weight loss, Recurrent respiratory infections, Herpes zoster, Angular cheilitis, Recurrent oral ulceration, Papular pruritic eruptions, Seborrheic dermatitis, Fungal nail infections; Stage 3=Unexplained severe weight loss, Unexplained chronic diarrhea for >1 month, Unexplained persistent fever for >1 month, Persistent oral candidiasis, Oral hairy leukoplakia, Pulmonary tuberculosis, Severe presumed bacterial infections, Acute necrotizing ulcerative stomatitis, gingivitis, or periodontitis; Unexplained anemia; Stage 4 =HIV wasting syndrome,etc
1.Primary Outcome
Title Prevalence of Malaria Defined as Positive Placental Blood Smear
Hide Description Number of participants with positive placental blood smear for malaria
Time Frame Delivery
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Placental blood smear
Arm/Group Title With Protease Inhibitor Without Protease Inhibitor
Hide Arm/Group Description:

ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg

Lopinavir/ritonavir: LPV 200mg/r 50mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

ZDV 300mg/3TC 150mg/EFV 600mg

Efavirenz: 600mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

Overall Number of Participants Analyzed 158 158
Measure Type: Number
Unit of Measure: participants
5 6
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection With Protease Inhibitor, Without Protease Inhibitor
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .76
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
.26 to 2.67
Estimation Comments [Not Specified]
2.Primary Outcome
Title Prevalence of Malaria Defined as Positive Placental Blood PCR
Hide Description Number of participants with positive placental blood PCR for malaria
Time Frame Delivery
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Placental blood PCR
Arm/Group Title With Protease Inhibitor Without Protease Inhibitor
Hide Arm/Group Description:

ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg

Lopinavir/ritonavir: LPV 200mg/r 50mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

ZDV 300mg/3TC 150mg/EFV 600mg

Efavirenz: 600mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

Overall Number of Participants Analyzed 157 155
Measure Type: Number
Unit of Measure: participants
6 7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection With Protease Inhibitor, Without Protease Inhibitor
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .76
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value .85
Confidence Interval (2-Sided) 95%
.29 to 2.46
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Placental Malaria Defined as Positive Placental RDT
Hide Description 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.
Time Frame Delivery
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Some participants did not have a placental specimen taken at delivery in the hospital (e.g. deliveries that occurred at home, missed by staff error, etc)
Arm/Group Title With Protease Inhibitor Without Protease Inhibitor
Hide Arm/Group Description:

ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg

Lopinavir/ritonavir: LPV 200mg/r 50mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

ZDV 300mg/3TC 150mg/EFV 600mg

Efavirenz: 600mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

Overall Number of Participants Analyzed 157 155
Measure Type: Number
Unit of Measure: participants
6 7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection With Protease Inhibitor, Without Protease Inhibitor
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .45
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value .75
Confidence Interval (2-Sided) 95%
.36 to 1.59
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Maternal Malaria Defined as the Number of Treatments for New Episodes of Malaria Per Time at Risk During Pregnancy
Hide Description [Not Specified]
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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title With Protease Inhibitor Without Protease Inhibitor
Hide Arm/Group Description:

ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg

Lopinavir/ritonavir: LPV 200mg/r 50mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

ZDV 300mg/3TC 150mg/EFV 600mg

Efavirenz: 600mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

Overall Number of Participants Analyzed 194 195
Measure Type: Number
Unit of Measure: treatments
17 17
5.Secondary Outcome
Title 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)
Hide Description 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)
Time Frame Time from randomization until 24 months postpartum or cessation of breastfeeding
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title With Protease Inhibitor Without Protease Inhibitor
Hide Arm/Group Description:

ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg

Lopinavir/ritonavir: LPV 200mg/r 50mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

ZDV 300mg/3TC 150mg/EFV 600mg

Efavirenz: 600mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

Overall Number of Participants Analyzed 186 180
Measure Type: Number
Unit of Measure: % of evaluated participants with outcome
33.9 27.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection With Protease Inhibitor, Without Protease Inhibitor
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .21
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.22
Confidence Interval (2-Sided) 95%
.89 to 1.66
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Placental Malaria Defined Placental Histopathologic Analysis
Hide Description Number of participants with positive placental histopathology slide for malaria
Time Frame Delivery
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title With Protease Inhibitor Without Protease Inhibitor
Hide Arm/Group Description:

ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg

Lopinavir/ritonavir: LPV 200mg/r 50mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

ZDV 300mg/3TC 150mg/EFV 600mg

Efavirenz: 600mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

Overall Number of Participants Analyzed 162 165
Measure Type: Number
Unit of Measure: participants
62 47
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection With Protease Inhibitor, Without Protease Inhibitor
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .06
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.34
Confidence Interval (2-Sided) 95%
.98 to 1.83
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Maternal Malaria Defined as the Number of Treatments for New Episodes of Malaria Per Time at Risk After Pregnancy
Hide Description [Not Specified]
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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Group A Group B
Hide Arm/Group Description:

ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg

Lopinavir/ritonavir: LPV 200mg/r 50mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

ZDV 300mg/3TC 150mg/EFV 600mg

Efavirenz: 600mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

Overall Number of Participants Analyzed 190 187
Measure Type: Number
Unit of Measure: treatments
21 13
Time Frame Gestational age between 12 and 28 weeks at time of enrollment up to at least 1 year of follow up after delivery or until study termination.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Group A Group B
Hide Arm/Group Description

ZDV 300mg/3TC 150mg/LPV 200mg/r 50mg

Lopinavir/ritonavir: LPV 200mg/r 50mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

ZDV 300mg/3TC 150mg/EFV 600mg

Efavirenz: 600mg

Zidovudine: Zidovudine 300 mg

Lamivudine: Lamivudine 150 mg

All-Cause Mortality
Group A Group B
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Group A Group B
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   28/194 (14.43%)      32/195 (16.41%)    
Blood and lymphatic system disorders     
Deep venous Thrombosis   0/194 (0.00%)  0 2/195 (1.03%)  2
Gastrointestinal disorders     
Enteritis   0/194 (0.00%)  0 1/195 (0.51%)  1
General disorders     
Death, natural causes   2/194 (1.03%)  2 0/195 (0.00%)  0
Hepatobiliary disorders     
Severe anemia   7/194 (3.61%)  7 5/195 (2.56%)  5
Neutropenia   9/194 (4.64%)  9 5/195 (2.56%)  5
Thrombocytopenia   2/194 (1.03%)  2 3/195 (1.54%)  3
Pyelonephritis   3/194 (1.55%)  3 1/195 (0.51%)  2
Infections and infestations     
Complicated malaria   0/194 (0.00%)  0 1/195 (0.51%)  1
Pregnancy, puerperium and perinatal conditions     
Abruptio-placenta   1/194 (0.52%)  1 0/195 (0.00%)  0
Antepartum hemorrhage   2/194 (1.03%)  2 0/195 (0.00%)  0
Abdominal pain   0/194 (0.00%)  0 1/195 (0.51%)  1
Intra-uterine fetal death   6/194 (3.09%)  6 5/195 (2.56%)  5
Premature rupture of membranes   0/194 (0.00%)  0 2/195 (1.03%)  2
Preterm contractions   0/194 (0.00%)  0 3/195 (1.54%)  3
Spontaneous abortion   0/194 (0.00%)  0 2/195 (1.03%)  2
Renal and urinary disorders     
Urinary tract infection   1/194 (0.52%)  1 0/195 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Pneumonia   0/194 (0.00%)  0 2/195 (1.03%)  2
Tuberculosis   0/194 (0.00%)  0 2/195 (1.03%)  2
Respiratory distress   0/194 (0.00%)  0 1/195 (0.51%)  1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Group A Group B
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   140/194 (72.16%)      137/195 (70.26%)    
Blood and lymphatic system disorders     
Hemorrhage   1/194 (0.52%)  1 1/195 (0.51%)  1
Neutropenia   58/194 (29.90%)  100 62/195 (31.79%)  130
Pallor   4/194 (2.06%)  5 1/195 (0.51%)  5
Reduced WBC count   2/194 (1.03%)  2 3/195 (1.54%)  3
Serum glucose, low   1/194 (0.52%)  1 1/195 (0.51%)  1
Thrombocytopenia   18/194 (9.28%)  23 11/195 (5.64%)  24
Gastrointestinal disorders     
Diarrhea   8/194 (4.12%)  8 6/195 (3.08%)  10
Vomiting   4/194 (2.06%)  4 4/195 (2.05%)  4
General disorders     
Abdominal pain   63/194 (32.47%)  84 46/195 (23.59%)  64
Chills   8/194 (4.12%)  8 5/195 (2.56%)  5
Dizziness/Lightheadedness   2/194 (1.03%)  2 4/195 (2.05%)  4
Dysphagia/odynophagia   1/194 (0.52%)  1 2/195 (1.03%)  2
Fatigue/malaise   33/194 (17.01%)  39 26/195 (13.33%)  37
Headache   15/194 (7.73%)  19 11/195 (5.64%)  13
Nausea   5/194 (2.58%)  5 3/195 (1.54%)  3
Oral sores   0/194 (0.00%)  0 1/195 (0.51%)  7
Pain, general *  15/194 (7.73%)  17 16/195 (8.21%)  21
Temperature, elevated   10/194 (5.15%)  11 7/195 (3.59%)  8
Hepatobiliary disorders     
Anemia   18/194 (9.28%)  34 24/195 (12.31%)  33
Deep vein thrombosis   0/194 (0.00%)  0 2/195 (1.03%)  2
Pancreatitis   1/194 (0.52%)  1 0/195 (0.00%)  0
Metabolism and nutrition disorders     
Anorexia   5/194 (2.58%)  5 8/195 (4.10%)  14
Unintentional weight loss   2/194 (1.03%)  2 1/195 (0.51%)  1
Musculoskeletal and connective tissue disorders     
Myalgia   0/194 (0.00%)  0 2/195 (1.03%)  2
Nervous system disorders     
Seizure   0/194 (0.00%)  0 1/195 (0.51%)  2
Pregnancy, puerperium and perinatal conditions     
Pre-term premature rupture of membranes   1/194 (0.52%)  1 2/195 (1.03%)  2
Psychiatric disorders     
Altered mental status   0/194 (0.00%)  0 1/195 (0.51%)  1
Neurosensory alteration   2/194 (1.03%)  2 2/195 (1.03%)  6
Renal and urinary disorders     
Dysuria   2/194 (1.03%)  2 0/195 (0.00%)  0
Elevated ALT   3/194 (1.55%)  4 6/195 (3.08%)  7
Elevated AST   4/194 (2.06%)  4 0/195 (0.00%)  0
Elevated bilirubin   0/194 (0.00%)  0 1/195 (0.51%)  1
Pyelonephritis   1/194 (0.52%)  1 3/195 (1.54%)  3
Urine Protein   41/194 (21.13%)  47 25/195 (12.82%)  33
Respiratory, thoracic and mediastinal disorders     
Cough   23/194 (11.86%)  33 19/195 (9.74%)  36
Dyspnea/respiratory distress   4/194 (2.06%)  7 5/195 (2.56%)  16
Wheezing   2/194 (1.03%)  10 0/195 (0.00%)  0
Skin and subcutaneous tissue disorders     
Pruritis   5/194 (2.58%)  7 4/195 (2.05%)  5
Rash (non-infectious)   4/194 (2.06%)  4 2/195 (1.03%)  2
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
A semi-immune population of adults at relatively low risk for malaria; a high rate of TMP-SMX prophylaxis ; A lower than expected incidence of malaria, resulting in the possibility that the study was underpowered
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Diane V Havlir, MD
Organization: University of California, San Francisco
Phone: 01-415-476-4082 ext 400
Publications of Results:
Responsible Party: Diana Havlir, 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 Submitted: October 8, 2009
First Posted: October 9, 2009
Results First Submitted: January 5, 2015
Results First Posted: December 2, 2017
Last Update Posted: November 16, 2018