Malaria
Conditions
Keywords
dihydroartemisinin-piperaquine, sulfadoxine-pyrimethamine, IPTp, reproductive tract infection, microbiome, drug resistance
Brief summary
This trial tests the hypothesis that intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) + dihydroartemisin-piperaquine (DP) will significantly reduce the risk of adverse birth outcomes compared to IPTp with SP alone or DP alone. This double-blinded randomized controlled phase III trial of 2757 HIV uninfected pregnant women enrolled at 12-20 weeks gestation will be randomized in equal proportions to one of three IPTp treatment arms: 1) SP given every 4 weeks, or 2) DP given every 4 weeks, or 3) SP+DP given every 4 weeks. SP or DP placebos will be used to ensure adequate blinding is achieved in the study and follow-up will end 28 days after giving birth.
Detailed description
Malaria in pregnancy remains a major challenge in Africa, where approximately 50 million women are at risk for P. falciparum infection during pregnancy each year. Among pregnant women living in malaria endemic areas symptomatic disease is uncommon, but infection with malaria parasites is associated with maternal anemia and adverse birth outcomes including abortions, stillbirth, preterm birth, low birth weight (LBW), and infant mortality. The World Health Organization (WHO) recommends the use of long-lasting insecticidal nets (LLINs) and intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) for the prevention of malaria in pregnancy in endemic areas of Africa. However, there is concern for diminishing efficacy of these interventions due to the spread of vector resistance to the pyrethroid insecticides used in LLINs and parasite resistance to SP. Thus, there is an urgent need for new strategies for the prevention of malaria in pregnancy and improving birth outcomes. Artemisinin-based combination therapies (ACTs) are now the standard treatment for malaria in Africa. Dihydroartemisin-piperaquine (DP) is a fixed-dose ACT and an attractive alternative to SP for IPTp. DP is highly efficacious, and the long half-life of piperaquine provides at least 4 weeks of post-treatment prophylaxis. Recent randomized controlled trials showed that, compared to IPTp with SP, IPTp with DP dramatically reduced risks of malaria-specific outcomes but there were minimal differences between the SP and DP groups in risks of adverse birth outcomes. The key question for this study is why IPTp with either SP or DP is associated with similar risks of adverse birth outcomes despite the far superior antimalarial activity of DP. The likely explanation is that SP, a broad-spectrum antibiotic, protects against non-malarial causes of LBW and preterm birth. The central hypothesis is that SP improves birth outcomes independent of its antimalarial activity and that IPTp with a combination of SP+DP will offer antimalarial and non-antimalarial benefits, thus providing superior prevention of adverse birth outcomes compared to either drug used alone. To test this hypothesis, a double-blinded randomized clinical trial will conducted in a rural area of Uganda with very high malaria transmission intensity, where there is already an established infrastructure for clinical research. Specific aims will be (1) to compare the risk of adverse birth outcomes among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP, (2) To compare safety and tolerability of IPTp regimens among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP, and (3) to compare risks of malaria-specific and non-malarial outcomes among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP. This study will be the first to evaluate the efficacy and safety of a novel combination of well-studied drugs for improving birth outcomes and findings may well have important policy implications, with a change in standard practice for millions of pregnant women in Africa.
Interventions
SP (Kamsidar) will be supplied by Kampala Pharmaceutical Industries (KPI), Uganda. SP will be given as a single dose consisting of 3 full strength tablets.
DP (Duo-Cotecxin) will be supplied by Holley-Cotec, Beijing, China. DP will consist of 3 full strength tablets given once a day for 3 consecutive days.
Sponsors
National Institutes of Health (NIH)
Infectious Diseases Research Collaboration, Uganda
Grant Dorsey, M.D, Ph.D.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Placebos will be used to mimic the identical dosing strategy such that every 4 weeks women will receive two drugs on day 1 (SP and placebo or DP and placebo or SP and DP) followed by one drug on days 2 and 3 (DP or placebo). Two placebos will be used, one that mimics the appearance of SP and one that mimics the appearance of DP. A randomization list will be computer generated by a member of the project who will not be directly involved in the conduct of the study. The randomization list will include consecutive treatment numbers with corresponding random treatment assignments. Randomized codes will correspond to the 3 treatment arms using permuted variable sized blocks of 6 and 9.
Intervention model description
Double blinded randomized controlled trial
Eligibility
Sex/Gender
FEMALE
Age
16 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Viable singleton pregnancy confirmed by ultrasound 2. Estimated gestational age between 12-20 weeks 3. Confirmed to be HIV- uninfected by rapid test 4. 16 years of age or older 5. Residency within Busia District of Uganda 6. Provision of informed consent 7. Agreement to come to the study clinic for any febrile episode or other illness and avoid medications given outside the study protocol 8. Willing to deliver in the hospital
Exclusion criteria
1. History of serious adverse event to SP or DP 2. Active medical problem requiring inpatient evaluation at the time of screening 3. Intention of moving outside of Busia District Uganda 4. Chronic medical condition requiring frequent medical attention 5. Prior chemopreventive therapy or any other antimalarial therapy during this pregnancy 6. Early or active labor (documented by cervical change with uterine contractions) 7. Multiple pregnancies (i.e. twins/triplets)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Risk of Having a Composite Adverse Birth Outcome | Time from first dose of study drugs up to 28 days postpartum, an average of 6 months | Composite adverse birth outcome defined as the occurrence of any of the following: * Spontaneous abortion: Fetal loss at \< 28 weeks gestational age * Stillbirth: Infant born deceased at \> 28 weeks gestational age * Low Birth Weight (LBW): Live birth with birth weight \< 2500 gm * Preterm birth: Live birth at \< 37 weeks gestational age * Small-for-gestational age (SGA): Live birth with weight-for-gestational age \< 10th percentile of reference population * Neonatal death: Live birth with neonatal death within the first 28 days of life |
| Incidence of Serious Adverse Events (SAE) Per Time at Risk | Time from first dose of study drugs up to 28 days postpartum, an average of 6 months | SAEs as defined by the July 2017 NIH DAIDS Toxicity Tables |
| Incidence of Any Grade 3 or 4 or Serious Adverse Events Per Time at Risk | Time from first dose of study drugs up to 28 days postpartum, an average of 6 months | Grade 3 and 4 AEs or SAEs as defined by the July 2017 NIH DAIDS Toxicity Tables |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Anemia Adverse Event Per Time at Risk | Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months | Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables |
| Incidence of Grade 3-4 AEs Possibly Related to Study Drugs | Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months | Grade 3-4 AEs possibly or definitely related to study drug defined by the July 2017 NIH DAIDS Toxicity Tables |
| Risk of Placental Malaria | At the time of delivery | Detection of malaria parasites or pigment by histopathology |
| Incidence of Malaria During Pregnancy | Day study drugs first given until delivery, an average of 6 months | Episodes of symptomatic malaria (incidence per person year at risk following initiation of study drugs) |
| Microscopic Parasitemia During Pregnancy | Day study drugs first given until delivery, an average of 6 months | Proportion of routine samples with asexual parasites detected by microscopy |
| Prevalence of Anemia During Pregnancy | Day study drugs are first given until delivery | Proportion of routine hemoglobin measurements \< 11 g/dL |
| Stillbirth | Time of delivery | Stillbirth defined as infant born deceased at \> 28 weeks gestational age |
| Low Birth Rate | Time of delivery | Low birth weight defined as live birth with birth weight \< 2500 gm |
| Preterm Delivery | Time of delivery | Preterm delivery defined as live birth at \< 37 weeks gestational age |
| Microscopic or Sub-microscopic Parasitemia During Pregnancy | Day study drugs first given until delivery, an average of 6 months | Proportion of routine samples with asexual parasites detected by microscopy or qPCR |
| Small-for-gestational Age | Time of delivery | Small-for-gestational age defined as live birth with weight-for-gestational age \< 10th percentile of reference population |
| Incidence of Stillbirth Adverse Event Per Time at Risk | Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months | Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables |
| Incidence of Congenital Anomaly Adverse Event Per Time at Risk | Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months | Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables |
| Incidence of Neutropenia Adverse Event Per Time at Risk | Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months | Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables |
| Incidence of Proteinuria Adverse Event Per Time at Risk | Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months | Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables |
| Incidence of Thrombocytopenia Adverse Event Per Time at Risk | Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months | Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables |
| Incidence of Postpartum Hemorrhage Adverse Event Per Time at Risk | Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months | Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables |
| Incidence of Pre-eclampsia Adverse Event Per Time at Risk | Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months | Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables |
| Incidence of Preterm Birth <28 Gestational Age Adverse Event Per Time at Risk | Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months | Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables |
| Incidence of Elevated Temperature Adverse Event Per Time at Risk | Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months | Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables |
| Prevalence of Severe Anemia During Pregnancy | Day study drugs are first given until delivery, an average of 6 months | Proportion of routine hemoglobin measurements \< 8 g/dL |
| Neonatal Death | Time of delivery | Neonatal death defined as live birth with neonatal death within the first 28 days of life |
| Number of Participants With Spontaneous Abortion | Time of delivery | Spontaneous abortion defined as fetal loss at \< 28 weeks gestational age |
Countries
Uganda
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| SP + DP placebo every 4 weeks Sulfadoxine-pyrimethamine (SP): SP (Kamsidar) will be supplied by Kampala Pharmaceutical Industries (KPI), Uganda. SP will be given as a single dose consisting of 3 full strength tablets. | 918 |
| DP + SP placebo every 4 weeks Dihydroartemisinin-piperaquine (DP): DP (Duo-Cotecxin) will be supplied by Holley-Cotec, Beijing, China. DP will consist of 3 full strength tablets given once a day for 3 consecutive days. | 920 |
| SP + DP given every 4 weeks Sulfadoxine-pyrimethamine (SP): SP (Kamsidar) will be supplied by Kampala Pharmaceutical Industries (KPI), Uganda. SP will be given as a single dose consisting of 3 full strength tablets.
Dihydroartemisinin-piperaquine (DP): DP (Duo-Cotecxin) will be supplied by Holley-Cotec, Beijing, China. DP will consist of 3 full strength tablets given once a day for 3 consecutive days. | 919 |
| Total | 2,757 |
Baseline characteristics
| Characteristic | SP + DP placebo every 4 weeks | DP + SP placebo every 4 weeks | SP + DP given every 4 weeks | Total |
|---|---|---|---|---|
| Age, Continuous | 24.5 years STANDARD_DEVIATION 6.2 | 24.7 years STANDARD_DEVIATION 6.3 | 24.2 years STANDARD_DEVIATION 6 | 24.5 years STANDARD_DEVIATION 6.2 |
| Bednet ownership Long-lasting insecticide-treated net | 452 Participants | 446 Participants | 462 Participants | 1360 Participants |
| Bednet ownership None | 423 Participants | 434 Participants | 415 Participants | 1272 Participants |
| Bednet ownership Untreated net | 43 Participants | 40 Participants | 42 Participants | 125 Participants |
| Detection of malaria parasites by microscopy or qPCR | 634 Participants | 637 Participants | 657 Participants | 1928 Participants |
| Gestational age | 15.8 weeks STANDARD_DEVIATION 2.6 | 15.7 weeks STANDARD_DEVIATION 2.5 | 16.0 weeks STANDARD_DEVIATION 2.6 | 15.8 weeks STANDARD_DEVIATION 2.6 |
| Gestational age categories 12-16 weeks | 522 Participants | 530 Participants | 481 Participants | 1533 Participants |
| Gestational age categories >16 weeks | 396 Participants | 390 Participants | 438 Participants | 1224 Participants |
| Gravidity Multigravidae | 688 Participants | 686 Participants | 657 Participants | 2031 Participants |
| Gravidity Primigravidae | 230 Participants | 234 Participants | 262 Participants | 726 Participants |
| Height in cm | 159 cm STANDARD_DEVIATION 6 | 159 cm STANDARD_DEVIATION 7 | 159 cm STANDARD_DEVIATION 6 | 159 cm STANDARD_DEVIATION 6 |
| Highest level of education Higher | 19 Participants | 20 Participants | 19 Participants | 58 Participants |
| Highest level of education None | 44 Participants | 31 Participants | 36 Participants | 111 Participants |
| Highest level of education Primary school | 592 Participants | 593 Participants | 600 Participants | 1785 Participants |
| Highest level of education Secondary school | 263 Participants | 276 Participants | 264 Participants | 803 Participants |
| Household wealth index Highest tertile | 307 Participants | 296 Participants | 307 Participants | 910 Participants |
| Household wealth index Lowest tertile | 308 Participants | 294 Participants | 295 Participants | 897 Participants |
| Household wealth index Middle tertile | 293 Participants | 319 Participants | 309 Participants | 921 Participants |
| Maternal MUAC | 26 cm STANDARD_DEVIATION 4 | 26 cm STANDARD_DEVIATION 3 | 26 cm STANDARD_DEVIATION 3 | 26 cm STANDARD_DEVIATION 3 |
| Mean hemoglobin | 11.6 g/dL STANDARD_DEVIATION 1.3 | 11.7 g/dL STANDARD_DEVIATION 1.3 | 11.5 g/dL STANDARD_DEVIATION 1.4 | 11.6 g/dL STANDARD_DEVIATION 1.4 |
| Prevalence of dhfr/dhps quintuple mutant markers of antifolate resistance dhfr/dhps quintuple mutant | 72 participants | 64 participants | 62 participants | 198 participants |
| Prevalence of dhfr/dhps quintuple mutant markers of antifolate resistance dhfr l164L | 14 participants | 19 participants | 8 participants | 41 participants |
| Prevalence of dhfr/dhps quintuple mutant markers of antifolate resistance dhps A581G | 1 participants | 2 participants | 1 participants | 4 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 918 Participants | 920 Participants | 919 Participants | 2757 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Uganda | 918 participants | 920 participants | 919 participants | 2757 participants |
| Sex: Female, Male Female | 918 Participants | 920 Participants | 919 Participants | 2757 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Weight in kg | 57.3 kg STANDARD_DEVIATION 9.4 | 57.6 kg STANDARD_DEVIATION 9.8 | 57.1 kg STANDARD_DEVIATION 8.9 | 57.4 kg STANDARD_DEVIATION 9.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 896 | 2 / 902 | 0 / 908 |
| other Total, other adverse events | 896 / 896 | 902 / 902 | 908 / 908 |
| serious Total, serious adverse events | 25 / 896 | 26 / 902 | 27 / 908 |
Outcome results
Primary
Incidence of Any Grade 3 or 4 or Serious Adverse Events Per Time at Risk
Grade 3 and 4 AEs or SAEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Time from first dose of study drugs up to 28 days postpartum, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Incidence of Any Grade 3 or 4 or Serious Adverse Events Per Time at Risk | 0.23 Events per person-year |
| DP + SP placebo every 4 weeks | Incidence of Any Grade 3 or 4 or Serious Adverse Events Per Time at Risk | 0.19 Events per person-year |
| SP + DP given every 4 weeks | Incidence of Any Grade 3 or 4 or Serious Adverse Events Per Time at Risk | 0.21 Events per person-year |
Primary
Incidence of Serious Adverse Events (SAE) Per Time at Risk
SAEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Time from first dose of study drugs up to 28 days postpartum, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Incidence of Serious Adverse Events (SAE) Per Time at Risk | 0.06 Events per person-years |
| DP + SP placebo every 4 weeks | Incidence of Serious Adverse Events (SAE) Per Time at Risk | 0.06 Events per person-years |
| SP + DP given every 4 weeks | Incidence of Serious Adverse Events (SAE) Per Time at Risk | 0.06 Events per person-years |
Primary
Risk of Having a Composite Adverse Birth Outcome
Composite adverse birth outcome defined as the occurrence of any of the following: * Spontaneous abortion: Fetal loss at \< 28 weeks gestational age * Stillbirth: Infant born deceased at \> 28 weeks gestational age * Low Birth Weight (LBW): Live birth with birth weight \< 2500 gm * Preterm birth: Live birth at \< 37 weeks gestational age * Small-for-gestational age (SGA): Live birth with weight-for-gestational age \< 10th percentile of reference population * Neonatal death: Live birth with neonatal death within the first 28 days of life
Time frame: Time from first dose of study drugs up to 28 days postpartum, an average of 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SP + DP placebo every 4 weeks | Risk of Having a Composite Adverse Birth Outcome | 222 Participants |
| DP + SP placebo every 4 weeks | Risk of Having a Composite Adverse Birth Outcome | 261 Participants |
| SP + DP given every 4 weeks | Risk of Having a Composite Adverse Birth Outcome | 255 Participants |
Secondary
Incidence of Anemia Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Incidence of Anemia Adverse Event Per Time at Risk | 53 Events per person-years |
| DP + SP placebo every 4 weeks | Incidence of Anemia Adverse Event Per Time at Risk | 28 Events per person-years |
| SP + DP given every 4 weeks | Incidence of Anemia Adverse Event Per Time at Risk | 44 Events per person-years |
Secondary
Incidence of Congenital Anomaly Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Incidence of Congenital Anomaly Adverse Event Per Time at Risk | 4 Events per person-year |
| DP + SP placebo every 4 weeks | Incidence of Congenital Anomaly Adverse Event Per Time at Risk | 13 Events per person-year |
| SP + DP given every 4 weeks | Incidence of Congenital Anomaly Adverse Event Per Time at Risk | 10 Events per person-year |
Secondary
Incidence of Elevated Temperature Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Incidence of Elevated Temperature Adverse Event Per Time at Risk | 2 Events per person-year |
| DP + SP placebo every 4 weeks | Incidence of Elevated Temperature Adverse Event Per Time at Risk | 1 Events per person-year |
| SP + DP given every 4 weeks | Incidence of Elevated Temperature Adverse Event Per Time at Risk | 0 Events per person-year |
Secondary
Incidence of Grade 3-4 AEs Possibly Related to Study Drugs
Grade 3-4 AEs possibly or definitely related to study drug defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Incidence of Grade 3-4 AEs Possibly Related to Study Drugs | 50 Events per person-years |
| DP + SP placebo every 4 weeks | Incidence of Grade 3-4 AEs Possibly Related to Study Drugs | 29 Events per person-years |
| SP + DP given every 4 weeks | Incidence of Grade 3-4 AEs Possibly Related to Study Drugs | 41 Events per person-years |
Secondary
Incidence of Malaria During Pregnancy
Episodes of symptomatic malaria (incidence per person year at risk following initiation of study drugs)
Time frame: Day study drugs first given until delivery, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Incidence of Malaria During Pregnancy | 1.15 Events per person-years |
| DP + SP placebo every 4 weeks | Incidence of Malaria During Pregnancy | 0.02 Events per person-years |
| SP + DP given every 4 weeks | Incidence of Malaria During Pregnancy | 0.04 Events per person-years |
Secondary
Incidence of Neutropenia Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Incidence of Neutropenia Adverse Event Per Time at Risk | 5 Events per person-year |
| DP + SP placebo every 4 weeks | Incidence of Neutropenia Adverse Event Per Time at Risk | 10 Events per person-year |
| SP + DP given every 4 weeks | Incidence of Neutropenia Adverse Event Per Time at Risk | 7 Events per person-year |
Secondary
Incidence of Postpartum Hemorrhage Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Incidence of Postpartum Hemorrhage Adverse Event Per Time at Risk | 2 Events per person-years |
| DP + SP placebo every 4 weeks | Incidence of Postpartum Hemorrhage Adverse Event Per Time at Risk | 3 Events per person-years |
| SP + DP given every 4 weeks | Incidence of Postpartum Hemorrhage Adverse Event Per Time at Risk | 2 Events per person-years |
Secondary
Incidence of Pre-eclampsia Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Incidence of Pre-eclampsia Adverse Event Per Time at Risk | 3 Events per person-years |
| DP + SP placebo every 4 weeks | Incidence of Pre-eclampsia Adverse Event Per Time at Risk | 0 Events per person-years |
| SP + DP given every 4 weeks | Incidence of Pre-eclampsia Adverse Event Per Time at Risk | 2 Events per person-years |
Secondary
Incidence of Preterm Birth <28 Gestational Age Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Incidence of Preterm Birth <28 Gestational Age Adverse Event Per Time at Risk | 0 Events per person-years |
| DP + SP placebo every 4 weeks | Incidence of Preterm Birth <28 Gestational Age Adverse Event Per Time at Risk | 0 Events per person-years |
| SP + DP given every 4 weeks | Incidence of Preterm Birth <28 Gestational Age Adverse Event Per Time at Risk | 3 Events per person-years |
Secondary
Incidence of Proteinuria Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Incidence of Proteinuria Adverse Event Per Time at Risk | 3 Events per person-years |
| DP + SP placebo every 4 weeks | Incidence of Proteinuria Adverse Event Per Time at Risk | 4 Events per person-years |
| SP + DP given every 4 weeks | Incidence of Proteinuria Adverse Event Per Time at Risk | 8 Events per person-years |
Secondary
Incidence of Stillbirth Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Incidence of Stillbirth Adverse Event Per Time at Risk | 15 Events per person-year |
| DP + SP placebo every 4 weeks | Incidence of Stillbirth Adverse Event Per Time at Risk | 16 Events per person-year |
| SP + DP given every 4 weeks | Incidence of Stillbirth Adverse Event Per Time at Risk | 7 Events per person-year |
Secondary
Incidence of Thrombocytopenia Adverse Event Per Time at Risk
Grade 3-4 AEs as defined by the July 2017 NIH DAIDS Toxicity Tables
Time frame: Day study drugs are first given until when study participants reach 28 days postpartum or early study termination, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Incidence of Thrombocytopenia Adverse Event Per Time at Risk | 7 Events per person-years |
| DP + SP placebo every 4 weeks | Incidence of Thrombocytopenia Adverse Event Per Time at Risk | 1 Events per person-years |
| SP + DP given every 4 weeks | Incidence of Thrombocytopenia Adverse Event Per Time at Risk | 2 Events per person-years |
Secondary
Low Birth Rate
Low birth weight defined as live birth with birth weight \< 2500 gm
Time frame: Time of delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SP + DP placebo every 4 weeks | Low Birth Rate | 47 Participants |
| DP + SP placebo every 4 weeks | Low Birth Rate | 59 Participants |
| SP + DP given every 4 weeks | Low Birth Rate | 71 Participants |
Secondary
Microscopic or Sub-microscopic Parasitemia During Pregnancy
Proportion of routine samples with asexual parasites detected by microscopy or qPCR
Time frame: Day study drugs first given until delivery, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Microscopic or Sub-microscopic Parasitemia During Pregnancy | 2099 routine visits with parasitemia |
| DP + SP placebo every 4 weeks | Microscopic or Sub-microscopic Parasitemia During Pregnancy | 551 routine visits with parasitemia |
| SP + DP given every 4 weeks | Microscopic or Sub-microscopic Parasitemia During Pregnancy | 60 routine visits with parasitemia |
Secondary
Microscopic Parasitemia During Pregnancy
Proportion of routine samples with asexual parasites detected by microscopy
Time frame: Day study drugs first given until delivery, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Microscopic Parasitemia During Pregnancy | 771 Routine visits with parasitemia |
| DP + SP placebo every 4 weeks | Microscopic Parasitemia During Pregnancy | 25 Routine visits with parasitemia |
| SP + DP given every 4 weeks | Microscopic Parasitemia During Pregnancy | 60 Routine visits with parasitemia |
Secondary
Neonatal Death
Neonatal death defined as live birth with neonatal death within the first 28 days of life
Time frame: Time of delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SP + DP placebo every 4 weeks | Neonatal Death | 4 Participants |
| DP + SP placebo every 4 weeks | Neonatal Death | 5 Participants |
| SP + DP given every 4 weeks | Neonatal Death | 12 Participants |
Secondary
Number of Participants With Spontaneous Abortion
Spontaneous abortion defined as fetal loss at \< 28 weeks gestational age
Time frame: Time of delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SP + DP placebo every 4 weeks | Number of Participants With Spontaneous Abortion | 12 Participants |
| DP + SP placebo every 4 weeks | Number of Participants With Spontaneous Abortion | 16 Participants |
| SP + DP given every 4 weeks | Number of Participants With Spontaneous Abortion | 13 Participants |
Secondary
Preterm Delivery
Preterm delivery defined as live birth at \< 37 weeks gestational age
Time frame: Time of delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SP + DP placebo every 4 weeks | Preterm Delivery | 48 Participants |
| DP + SP placebo every 4 weeks | Preterm Delivery | 25 Participants |
| SP + DP given every 4 weeks | Preterm Delivery | 44 Participants |
Secondary
Prevalence of Anemia During Pregnancy
Proportion of routine hemoglobin measurements \< 11 g/dL
Time frame: Day study drugs are first given until delivery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Prevalence of Anemia During Pregnancy | 965 Routine visits with anemia |
| DP + SP placebo every 4 weeks | Prevalence of Anemia During Pregnancy | 827 Routine visits with anemia |
| SP + DP given every 4 weeks | Prevalence of Anemia During Pregnancy | 880 Routine visits with anemia |
Secondary
Prevalence of Severe Anemia During Pregnancy
Proportion of routine hemoglobin measurements \< 8 g/dL
Time frame: Day study drugs are first given until delivery, an average of 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SP + DP placebo every 4 weeks | Prevalence of Severe Anemia During Pregnancy | 29 Routine visits with severe anemia |
| DP + SP placebo every 4 weeks | Prevalence of Severe Anemia During Pregnancy | 9 Routine visits with severe anemia |
| SP + DP given every 4 weeks | Prevalence of Severe Anemia During Pregnancy | 12 Routine visits with severe anemia |
Secondary
Risk of Placental Malaria
Detection of malaria parasites or pigment by histopathology
Time frame: At the time of delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SP + DP placebo every 4 weeks | Risk of Placental Malaria | 472 Participants |
| DP + SP placebo every 4 weeks | Risk of Placental Malaria | 324 Participants |
| SP + DP given every 4 weeks | Risk of Placental Malaria | 393 Participants |
Secondary
Small-for-gestational Age
Small-for-gestational age defined as live birth with weight-for-gestational age \< 10th percentile of reference population
Time frame: Time of delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SP + DP placebo every 4 weeks | Small-for-gestational Age | 152 Participants |
| DP + SP placebo every 4 weeks | Small-for-gestational Age | 206 Participants |
| SP + DP given every 4 weeks | Small-for-gestational Age | 194 Participants |
Secondary
Stillbirth
Stillbirth defined as infant born deceased at \> 28 weeks gestational age
Time frame: Time of delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SP + DP placebo every 4 weeks | Stillbirth | 15 Participants |
| DP + SP placebo every 4 weeks | Stillbirth | 16 Participants |
| SP + DP given every 4 weeks | Stillbirth | 7 Participants |