Evaluate Azithromycin Plus Chloroquine And Sulfadoxine Plus Pyrimethamine Combinations For Intermittent Preventive Treatment Of Falciparum Malaria Infection In Pregnant Women In Africa

Study Overview
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Brief Summary
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The primary objective is to establish superiority of AZCQ over SP in protective efficacy for IPTp as measured by the proportion of subjects with sub-optimal pregnancy outcome.

Detailed Description
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After interim analysis of efficacy data by an External Data Monitoring Committee, this study was terminated. Investigators were notified on 22 Aug 2013. There were no safety concerns that led to this termination.

Official Title
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A Phase 3, Open Label, Randomized, Comparative Study To Evaluate Azithromycin Plus Chloroquine And Sulfadoxine Plus Pyrimethamine Combinations For Intermittent Preventive Treatment Of Falciparum Malaria Infection In Pregnant Women In Africa

Conditions
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Intermittent Preventive Treatment In Pregnancy (IPTp)

Intervention / Treatment
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* Drug: Azithromycin plus chloroquine
* Drug: sulfadoxine-pyrimethamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pregnant women (all gravidae) with ≥14 and ≤26 weeks of gestational age (by ultrasound). Evidence of a personally signed and dated informed consent/assent document. Assent will be obtained from subjects <18 years of age. Subjects who are willing to and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Subjects who are available for follow up at delivery and on 28 days post delivery. Exclusion Criteria: Age <16 years old or >35 years old. Multiple gestations as per the ultrasound at screening. Clinical symptoms of malaria. Hemoglobin < 8 g/dL (at enrollment). Any condition requiring hospitalization at enrollment. History of convulsions, hypertension, diabetes or any other chronic illness that may adversely affect fetal growth and viability. Inability to tolerate oral treatment in tablet form. Known allergy to the study drugs (azithromycin, chloroquine, and sulfadoxine-pyrimethamine) or to any macrolides or sulphonamides. Requirement to use medication during the study that might interfere with the evaluation of the study drug eg, trimethoprim-sulfamethoxazole use in subjects positive for HIV infection. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation. Evidence of current obstetric complications that may adversely impact the pregnancy and/or fetal outcomes, including presence of congenital anomalies, placenta previa or abruption. Known severe Sickle Cell (SS) disease or Sickle Hemoglobin C (SC) anemia. Known family history of prolonged QT Syndrome, serious ventricular arrhythmia, or sudden cardiac death.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZCQ<br>Azithromycin/chloroquine | Drug: Azithromycin plus chloroquine<br>* combination tablet of 250mg azithromycin/155 chloroquine, Once daily PO for three days per treatment. There are total 3 treatments at 4-8 weeks intervals. The first treatment course will be administered during the second trimester (14-26 weeks of gestation as confirmed by ultrasound). The last treatment course should be given to subjects prior to or during 36 weeks of gestation.<br>|
| Active Comparator: SP<br>sulfadoxine-pyrimethamine (Fansidar) | Drug: sulfadoxine-pyrimethamine<br>* Fansidar tablet (500 mg sulfadoxine /25 mg pyrimethamine), once daily, PO, single dose per treatment. There are total 3 treatments at 4-8 weeks intervals. The first treatment course will be administered during the second trimester (14-26 weeks of gestation as confirmed by ultrasound). The last treatment course should be given to subjects prior to or during 36 weeks of gestation.<br>* Other names: Fansidar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Participants With Sub-optimal Pregnancy Outcome in Intent-to-Treat (IIT) Population | Adverse pregnancy outcomes were defined as live-borne neonate (singleton) with low birth weight (LBW) (<2,500 g), premature births (<37 weeks as confirmed by the Ballard score), abortion (≤28 weeks), still birth (>28 weeks), lost to follow-up prior to termination of pregnancy or delivery, or missing birth weight of the neonates. | Approximately 40 weeks of gestational age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Sub-optimal Pregnancy Outcome in Efficacy Analyzable Per Protocol (PP) Population | Adverse pregnancy outcomes were defined as live-borne neonate (singleton) with LBW (<2,500g), premature births (<37 weeks as confirmed by the Ballard score), abortion (≤28 weeks), still birth (>28 weeks), lost to follow-up prior to termination of pregnancy or delivery, or missing birth weight of the neonates. | Approximately 40 weeks of gestational age | 
| Percentage of Neonates With LBW (<2500 g) in ITT Population | LBW was defined as live birth weight <2500 g (up to and including 2499 g). | Approximately 40 weeks of gestational age | 
| Percentage of Neonates With LBW (<2500 g) in Efficacy Analyzable PP Population | LBW was defined as live birth weight <2500 g (up to and including 2499 g). | Approximately 40 weeks of gestational age | 
| Percentage of Participants With Severe Maternal Anemia (Hemoglobin [Hb] <8 g/dL) at 36-38 Weeks of Gestation | Severe maternal anemia was defined as Hb <8 g/dL. | At 36-38 weeks of gestation. | 
| Percentage of Participants With Maternal Anemia (Hb <11 g/dL) at 36-38 Weeks of Gestation | Anemia was defined as Hb <11 g/dL. | At 36-38 weeks of gestation. | 
| Percentage of Participants With Placental Parasitemia at Delivery | Participants with placental parasitemia at delivery were diagnosed using Placental blood smear at birth from participants who deliver at hospital. | Approximately 40 weeks of gestational age | 
| Percentage of Participants With Placental Malaria at Delivery Based on Histology | Participants positive for placental malaria at delivery were evaluated based on placental histology. | Approximately 40 weeks of gestational age | 
| Sexually Transmitted Infection (STI) Episodes Per Participant | Number of episodes of sexually transmitted infection episodes per participant were noted. The STI's including Treponema pallidum, Neisseria gonorrhoeae, Chlamydia trachomatis, from first dose to delivery (diagnosis was based on clinical presentation and lab results). | Approximately 40 weeks of gestational age . | 
| Percentage of Participants With Sub-optimal Pregnancy Outcome Including Neonatal Death and Congenital Malformation | Sub-optimal pregnancy outcome including neonatal deaths and congenital malformations, defined as any of the following: live-borne neonate (singleton) with low birth-weight (or LBW for short, defined as live birth weight <2,500g), premature birth (<37 weeks), abortion (≤28 weeks), still birth (>28 weeks), neonatal death, congenital malformation, lost to follow-up prior to termination of pregnancy or delivery, or missing birth weight of the neonates. | Approximately 40 weeks of gestational age. | 
| Change From Baseline to 36-38 Weeks of Gestation in Hb Concentration. | Change from Baseline to 36-38 weeks of gestation in Hb concentration was noted. | Baseline, at 36-38 weeks of gestation. | 
| Percentage of Neonates With Congenital Abnormalities at Birth | Neonates with congenital abnormalities at birth were noted. | Approximately 40 weeks of gestational age. | 
| Percentage of Perinatal or Neonatal Deaths | Percentage of perinatal or neonatal deaths were noted. | Day 28 after delivery. | 
| Birth Weight of Live Borne Neonate | Birth weight of live borne neonates were calculated in grams. | Approximately 40 weeks of gestational age. | 
| Number of Episodes of Symptomatic Malaria Per Participant From First Intermittent Preventive Treatment of Falciparum Dose to Delivery | This outcome measure determined if an episode of malaria started within the time period of first dose to delivery. Clinical episode of malaria was determined if the participant presented with clinical symptoms of malaria (fever >37.5°C, oral) and diagnosed (either by rapid diagnostic tests or microscopy) with malaria. | Approximately 40 weeks of gestational age | 
| Percentage of Participants Requiring Additional Treatment for Symptomatic Malaria From First Dose to Delivery | This outcome measure evaluated the participants requiring additional treatments for malaria during the study period following the first dose (diagnosed based on clinical presentation and/or lab test results). | Approximately 40 weeks of gestational age | 
| Percentage of Participants With Peripheral Parasitemia at 36-38 Weeks of Gestation | This outcome measure evaluated the percentage of participants positive for peripheral parasitemia at 36-38 weeks of gestation. A participant was positive for parasitemia if the number of asexual parasites per μL was >0. | At 36-38 weeks of gestation | 
| Percentage of Participants With Peripheral Parasitemia at Delivery | This outcome measure evaluated the percentage of participants positive for peripheral parasitemia at delivery. A participant was positive for parasitemia if the number of asexual parasites per μL was >0. | Approximately 40 weeks of gestational age | 
| Percentage of Participants With Cord Blood Parasitemia at Delivery | This outcome measure evaluated the percentage of participants positive for cord blood parasitemia at delivery. A participant was positive for parasitemia if the number of asexual parasites per μL was >0. | Approximately 40 weeks of gestational age | 
| Percentage of Participants With Sexually Transmitted Infections From First Dose to 36-38 Weeks of Gestation | Sexual transmitted disease included Treponema pallidum, Neisseria gonorrhoeae, and Chlamydia trachomatis infections. This was diagnosed based on clinical presentation prior to Week 36-38 and/or lab test results between Week 36-38. | Upto 36-38 weeks of gestation | 
| Percentage of Participants With Chlamydia Trachomatis Infection at 36-38 Weeks of Gestation | Participants positive for Chlamydia trachomatis infection was diagnosed based on laboratory result at 36-38 weeks of gestation. A vaginal swab was collected and PCR assay was used for analysis. | At 36-38 weeks of gestation | 
| Percentage of Participants With Neisseria Gonorrhoeae Infection at 36-38 Weeks of Gestation | Participants positive for Neisseria gonorrhoeae infection was diagnosed based on laboratory result at 36-38 weeks of gestation. A vaginal swab was collected and PCR assay was used for analysis. | At 36-38 weeks of gestation | 
| Percentage of Participants With Treponema Pallidum Infection at 36-38 Weeks of Gestation | Participants positive for Treponema pallidum infection was diagnosed based on laboratory result at 36-38 weeks of gestation. Treponema Pallidum particle Agglutination Assay was used. | At 36-38 weeks of gestation | 
| Percentage of Participants With Trichomonas Vaginalis Infection at 36-38 Weeks of Gestation | Participants positive for Trichomonas vaginalis infection was diagnosed based on laboratory result at 36-38 weeks of gestation. A vaginal swab was collected for the laboratory test. | At 36-38 weeks of gestation | 
| Percentage of Participants With Bacterial Vaginosis Infection at 36-38 Weeks of Gestation. | Bacterial vaginosis was diagnosed based on laboratory result at 36-38 weeks of gestation. A vaginal swab was collected for the Gram staining. | At 36-38 weeks of gestation | 
| Percentage of Neonates With Ophthalmia Neonatorum at Birth Period | Ophthalmia neonatorum was diagnosed at birth. The laboratory diagnosis was performed among neonates with purulent discharge. | Approximately 40 weeks of gestational age | 
| Percentage of Participants With Bacterial Infections Including Pneumonia and Other Lower Respiratory Tract Infections From First Dose to Delivery | Participants positive for bacterial infections including other lower respiratory tract infections were measured anytime from first dose administration to delivery. | Up to approximately 40 weeks of gestational age | 
| Percentage of Participants With Pre-eclampsia From Week 20 to Delivery | Pre-eclampsia was diagnosed as systolic blood pressure of at least 140 mmHg and/or diastolic blood pressure of at least 90 mmHg on two separate readings taken at least 4 hours apart and proteinuria at least 300 mg protein in a 24 hour urine collection. | From Week 20 to approximately 40 weeks of gestational age | 
| Nasopharyngeal Swabs Positive for Macrolide Resistant Streptococcus Pneumoniae | This outcome measure evaluated the Streptococcus pneumoniae sensitivity against macrolide antibiotics. | Visits 6 and 7 | 
| Nasopharyngeal Swabs Positive for Penicillin Resistant Streptococcus Pneumoniae | This outcome measure evaluated the Streptococcus pneumoniae sensitivity against penicillin antibiotics. | Visits 6 and 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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P. falciparum malaria, IPTp