S. Japonicum and Pregnancy Outcomes

Study Overview
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Brief Summary
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The purpose of the study is to understand whether the drug praziquantel (PZQ) is safe for the mother and developing baby when the mother has schistosomiasis (a type of worm) infection, and whether the drug may improve the mother's and baby's health. The usual practice is to wait until after a mother has finished breast feeding before giving the medicine. Approximately 375 infected pregnant women, ages 18 and over, in endemic villages in Leyte, The Philippines will participate. Study volunteers 12-16 weeks pregnant will be given PZQ or an inactive pill (placebo) and stay in the hospital overnight. Small blood samples will be collected before and after the medication is taken. Three stool and urine samples will be taken during a total of 7 study visits. An ultrasound image (picture or outline of the unborn baby) will be performed. When the baby is born, a small blood sample will be taken. Mother and baby will be followed for up to 8 months before the baby is born and 1 month after.

Detailed Description
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This double-blind, placebo-controlled study will investigate praziquantel (PZQ) for the treatment of Schistosomiasis japonicum in pregnant women living in endemic villages of Leyte, The Philippines. The study will enroll 375 pregnant women, ages 18 and over, infected with S. japonicum. The primary study objective is to quantify the efficacy of PZQ treatment for S. japonicum at 12-16 weeks gestation on newborn birth weight among live births. This will be assessed by measuring birth weight within 96 hours of delivery to 10 grams. The secondary objectives are to: 1) assess treatment efficacy with respect to maternal and newborn nutritional status and maternal parasitologic response to treatment; 2) collect preliminary safety and toxicity data on use of PZQ among pregnant women and their newborns; 3) identify extra-placental mechanisms mediating the hypothesized beneficial effect of PZQ on birth outcomes; and 4) identify extra-placental mechanisms mediating the hypothesized beneficial effect of PZQ on birth outcomes. Participants will be involved in study related procedures for 9 months (8 months pre-natally and 1 month post-natally) for mother and infant. This study is linked to DMID protocol 08-0049.

Official Title
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S. Japonicum and Pregnancy Outcomes: A Randomized, Double Blind, Placebo Controlled Trial (RCT)

Conditions
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Schistosomiasis

Intervention / Treatment
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* Drug: Praziquantel
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For screening: Female, age 18 or over. Present to a study midwife with suspected pregnancy. Live in a study village. For the main study: Infected with S. japonicum. Pregnancy as determined by urine pregnancy test. Age 18 or older. Participant is otherwise healthy as determined by history, physical exam, ultrasound and laboratory assessment. Pregnancy between 12-16 weeks gestation. Ability to provide informed consent to participate. Exclusion Criteria: Presence of significant disease/illness that is either acute or chronic. This will be defined by history, physical examination, ultrasound and laboratory assessment. In particular: History of seizures or other neurologic disorder, chronic medical problem determined by history or physical examination, e.g. active hepatitis, tuberculosis, heart disease. Grade 3 or higher laboratory abnormality of blood urea nitrogen (BUN), Creatinine, bilirubin, white blood cell count, or platelet count will warrant exclusion. Grade 2 or higher abnormality of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) will warrant exclusion. For hemoglobin, women with severe anemia defined as hemoglobin less than 7.0 g/dl will be excluded. Women with myoma on ultrasound that are sub-mucosal or women with myoma that is in any location and greater than 5 cm in size. Women with congenital anomalies of the reproductive tract that would be expected to cause decreased fetal weight or greatly increase the risk of prematurity such as duplicate uterus, uterine septum. For less clear cases, the researchers will define significant illness as one that significantly alters a woman's ability to perform activities of daily living, causes symptoms at least two days per week, or necessitates regular use of medication. In the case of acute medical conditions such as urinary tract infection, pneumonia, febrile illness, enrollment may be postponed until the illness is successfully treated (not currently on any medication for the illness) or the illness self resolves if this occurs before 16 weeks gestation. Presence of cysts in the eye suggestive of neurocysticercosis. Regular use of a medication for a chronic medical condition. History of severe allergic reaction (anaphylaxis, facial swelling, or difficulty breathing) or seizure with praziquantel administration. Fetus has congenital anomaly determined by 12-16 week ultrasound or is determined to be nonviable (e.g. blighted ovum). Twin or higher order pregnancy. Woman has been enrolled into this study for a previous pregnancy. Inability to comprehend study procedures and provide informed consent due to limited cognitive abilities or other, or refuses to provide informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Placebo at 12-16 weeks gestation. | Other: Placebo<br>* Made with the same color coded gelatin capsules with the inert compound dextrose.<br>|
| Experimental: Praziquantel<br>Praziquantel at 12-16 weeks gestation. | Drug: Praziquantel<br>* 60 mg/kg administered orally given in split dose (30/mg/kg each) separated by 3 hours; over-encapsulated in gelatin capsules. Two capsule sizes will be made which will be differentiated by color; these will contain 300 mg or 150 mg to allow for best dosing by weight.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Newborn Birth Weight | Birth weight was collected for live infants at the time of delivery by a trained midwife, or within 24 hours of delivery for participants who chose to deliver at home with a helot, a birth attendant without formal training. | Within 24 hours of delivery. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Whose Pregnancy Resulted in a Live Birth | Each participant was followed until delivery to record if the outcome of the pregnancy was a live birth. Live births were defined as the complete expulsion or extraction from its mother of a product of conception, irrespective of the duration of the pregnancy, which, after such separation, breathes or shows any other evidence of life such as heartbeat, umbilical cord pulsation, or definite movement of voluntary muscles, whether the umbilical cord had been cut or the placenta was attached. | At delivery | 
| Mean Change in Maternal Hemoglobin From 14 to 32 Weeks Gestation | Hemoglobin concentration in a venous blood sample collected at 14 and 32 weeks gestation was measured using a multi-analyte analyzer. Each participant's change in hemoglobin concentration between the two timepoints was determined, and the mean and standard deviation for each group calculated. | 14 weeks and 32 weeks gestation | 
| Median Change in Maternal Transferrin Receptor:Ferritin Ratio From 14 to 32 Weeks Gestation | To assess total body iron, one needs to assess the storage compartment, which will contain sequestered iron, and the functional compartment, which represents bioavailable iron. Body iron status is defined by the two laboratory measurements that reflect these compartments, ferritin and serum transferrin receptor. The serum transferrin receptor:ferritin ratio has been shown in quantitative phlebotomy studies to provide an accurate assessment of total body iron over the entire range of status. At 14 and 32 weeks gestation, a blood sample was collected for assessment of total body iron by determination of the transferrin receptor:ferritin ratio. Each participant's change in ratio was calculated, and the median and interquartile range were determined for each group. | 14 weeks and 32 weeks gestation | 
| Median Maternal Hepcidin at 32 Weeks Gestation | Anemia of inflammation was assessed via maternal urine hepcidin levels. In response to inflammation, elevated serum levels of hepcidin is synthesized. Hepcidin causes sequestration of iron from bio-available forms to storage forms such as ferritin and decreases intestinal absorption of iron. Hepcidin was measured in participants' urine at 32 weeks gestation. | 32 weeks gestation | 
| Mean Change in Maternal Weight From 14 to 32 Weeks Gestation | Maternal weight gain was assessed by measuring participants' weight in kilograms. The weight increase from 14 to 32 weeks was determined for each participant, and the mean and standard deviation calculated. | 14 and 32 weeks gestation | 
| Mean Change in Maternal Thigh Skinfold Thickness From 14 to 32 Weeks Gestation | Maternal fat stores were measured by thigh skinfold thickness obtained using a Holtain skinfold caliper. The thickness increase from 14 to 32 weeks was determined for each participant, and the mean and standard deviation calculated. | 14 and 32 weeks gestation | 
| Newborn Median Serum Transferrin Receptor:Ferritin Ratio | To assess total body iron, the serum transferrin receptor:ferritin ratio was assessed in the infant. At delivery, a heel stick blood sample and a cord blood sample were collected for assessment of total body iron by determination of the transferrin receptor:ferritin ratio. | 0-6 days after delivery. | 
| Number of Subjects With Reduction in S. Japonicum Egg Counts From Screening to 22 Weeks Gestation of Greater Than 90 Percent | Parasitologic response to treatment was evaluated by counting S. japonicum eggs per gram of stool at screening and again at 22 weeks gestation. Success of treatment was pre-specified as greater than 90 percent reduction in egg count from screening to 22 weeks gestation. | Screening and 22 weeks gestation | 
| Number of Participants Reporting Serious Adverse Events Within 24 Hours of Dosing | Participants were observed in hospital for 24 hours after dosing for serious adverse events. Serious adverse events included any untoward medical occurrence that resulted in death; was life threatening; was a persistent/significant disability/incapacity; required in-patient hospitalization or prolongation thereof (for reasons other than the 24-hour observation period); resulted in a congenital anomaly/birth defect; or may have jeopardized the participant, or required intervention to prevent one of these outcomes. | Within 24 hours of dosing | 
| Number of Participants Experiencing Fetal Loss by Abortion | Abortion was defined by the protocol as bleeding followed by fetal loss as supported by ultrasound before 20 weeks gestation. Abortion was an important safety outcome measure due to the fact that abortion would occur closer to the time of dosing than miscarriage or stillbirth. Participants were observed in hospital for 24 hours after dosing and asked to return for any bleeding at any time. | After dosing and before 20 weeks gestation | 
| Number of Participants Reporting Abnormalities in Hematology Assessments Within 24 Hours of Dosing | Toxicity to maternal bone marrow, kidney, and liver was assessed by laboratory parameters collected just before and 24 hours after dosing. Specifically, blood was drawn just before the dose at 12-16 weeks gestation to determine baseline complete blood count, including white blood count (WBC), platelets, and hemoglobin. Blood was then drawn 24 hours after the second part of the split dose and before discharge from the hospital to assess any changes in these parameters. White blood count was abnormal at or above 10,800 or at or below 3500 cells/square millimeter (sq mm), platelets were abnormal at or below 140,000 cells/sq mm, and hemoglobin was abnormal at or below 10.9 grams/deciliter (g/dL). | Just before and 24 hours after dosing | 
| Number of Participants Reporting Abnormalities in Clinical Chemistry Assessments Within 24 Hours of Dosing | Toxicity to maternal kidney and liver was assessed by laboratory parameters collected just before and 24 hours after dosing. Specifically, blood was drawn just before the dose at 12-16 weeks gestation to determine baseline blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin. Blood was then drawn 24 hours after the second part of the split dose and before discharge from the hospital to assess any changes in these parameters. Any values that were 1.1 times the upper limit of normal or greater for the parameter were considered abnormal. | Just before and 24 hours after dosing | 
| Number of Participants Whose Infant Was Born With Congenital Anomalies | The newborn was examined by the midwife at delivery and within 2-6 days of delivery to assess the presence of congenital anomalies and well-being. The newborn was also examined by study pediatrician at 28 days of life. | At delivery, within 2-6 days of delivery, and at 28 days | 
| Number of Participants With Pre-eclampsia | Participants were assessed for the presence of pre-eclampsia at both the 22 and 32 week visits. Pre-eclampsia was defined by the presence of proteinurea (2+ protein on urine dipstick) and a single diastolic blood pressure reading of 100 millimiters of mercury (mm Hg) or above OR more than one reading, four hours apart, of 90 mm Hg or above. | 22 weeks and 32 weeks | 
| Maternal Serum Cytokine Levels of TNF-alpha, TNF-alpha Receptors I and II, IL-1, and IL-6 | Extra-placental mechanisms mediating improved outcomes in the PZQ group were planned to be evaluated with maternal serum cytokine levels, particularly TNF-alpha, TNF-alpha receptors I and II, IL-1, and IL-6. These assays were intended to be performed only if the primary objective of the study was met; therefore, there will be no results reported for this outcome measure. | At 32 weeks gestation | 
| Placental Blood Cytokine Levels | Cytokine assays were planned to be performed with culture supernatant harvested from placental explant cultures. The cytokines were to be measured with a multi-analyte analyzer. These assays were intended to be performed only if the primary objective of the study was met; therefore, there will be no results reported for this outcome measure. | At delivery | 
| Cytokeratin 18 Neo-epitope Staining as a Measure of Apoptosis | A study hypothesis was that peripheral serum obtained from S. japonicum infected, treated mothers would induce a lower level of apoptosis (programmed cell death) in cultured trophoblasts as measured by cytokeratin 18 neo-epitope staining compared to peripheral serum obtained from S. japonicum infected, PZQ untreated mothers. This assay was planned to be completed only if the primary objective was met; therefore, there will be no data for this outcome measure. | 32 weeks gestation | 
| Praziquantel Pharmacokinetic Concentrations | Two plasma samples were collected during the overnight hospitalization from approximately 200 subjects that remained at the time of study modification to incorporate PK studies. Subjects had samples collected based on one of two sample collection strategies: 4.5 and 8 hr after the first praziquantel dose or 6 and 10 hr after the first praziquantel dose. Subjects randomized to an even study number were assigned to the 4.5 and 8 hour schedule. Subjects randomized to an odd study number were assigned to the 6 and 10 hour schedule. Samples only from subjects randomized to receive praziquantel were analyzed for praziquantel. Samples drawn from subjects randomized to the control group were not analyzed. Praziquantel concentrations (ng/ml) were assayed using high performance liquid chromatography-electrospray mass spectrometry in the University of California at San Diego Pediatric Clinical Pharmacology Laboratory. | 4.5 and 8 hours after the first praziquantel dose (subjects assigned to an even study number) or 6 and 10 hours after the first praziquantel dose (subjects assigned to an odd study number). | 
| 4-hydroxy Praziquantel Pharmacokinetic Concentrations | Since pregnancy is associated with increased cytochrome P450 activity and physiologic changes in the gastrointestinal tract that tend to reduce drug absorption, praziquantel pharmacokinetics may be affected by pregnancy. Thus, the metabolite-to-parent drug ratio may serve as a differential marker to help determine if variability in drug exposure following oral administration during pregnancy is due to altered metabolism or drug absorption. Samples that were collected from subjects who were randomized to receive praziquantel were analyzed for praziquantel and 4-hydroxy praziquantel concentrations. Assays were performed using high performance liquid chromatography-electrospray mass spectrometry in the University of California at San Diego Pediatric Clinical Pharmacology Laboratory. Descriptive statistics were obtained for concentrations at each of the four sparse sampling timepoints. | 4.5 and 8 hours after the first praziquantel dose (subjects assigned to an even study number) or 6 and 10 hours after the first praziquantel dose (subjects assigned to an odd study number). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Philippines, Schistosoma japonicum, Schistosomiasis, pregnant women, fetuses, 08-0049