S. Japonicum and Pregnancy Outcomes - Full Text View

Sponsor:	National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00486863

Purpose

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 420 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.

Condition	Intervention	Phase
Schistosomiasis [Bilharziasis]	Drug: Praziquantel Drug: Placebo	Phase II

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	S. Japonicum and Pregnancy Outcomes: A Randomized, Double Blind, Placebo Controlled Trial (RCT)

Resource links provided by NLM:

Drug Information available for: Praziquantel

U.S. FDA Resources

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Newborn birth weight. [ Time Frame: Within 24 hours of delivery. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Birth weight adjusted for gestational age and gender [ Time Frame: Ultrasound at enrollment, calculation of gestational age within 24 hours of delivery. ] [ Designated as safety issue: No ]
Dichotomous low birth weight [ Time Frame: At delivery ] [ Designated as safety issue: No ]
Maternal weight gain and fat stores [ Time Frame: Weight and thigh/upper arm skin fold thickness at enrollment and 32 weeks gestation. ] [ Designated as safety issue: No ]
Parasitologic response to treatment: reduction in S. japonicum egg counts in stool. [ Time Frame: Stool egg counts at screening and 22 weeks gestation. ] [ Designated as safety issue: No ]
Newborn hemoglobin and iron status via serum transferrin receptor:ferritin ratio. [ Time Frame: 2-6 days after delivery. ] [ Designated as safety issue: No ]
Praziquantel (PZQ) safety for mother, fetus and newborn: Adverse events. [ Time Frame: Adverse events collected during hospitalization ] [ Designated as safety issue: Yes ]
Assessment of anemia of inflammation via urine hepcidin levels. [ Time Frame: Urine hepcidin levels at 32 weeks gestation. ] [ Designated as safety issue: No ]
Maternal hemoglobin (via serum transferrin receptor/ferritin ratio). [ Time Frame: Hemoglobin measured at 14 and 32 weeks gestation, then 24 hours after second part of the split drug dose. ] [ Designated as safety issue: No ]
Praziquantel (PZQ) safety/toxicology for mother, fetus, and newborn. Labs: complete blood count, blood urea nitrogen, creatinine, and liver function tests (aspartate aminotransferase, alanine aminotransferase, and bilirubin) [ Time Frame: Collected just before and 24 hours after the 12-16 week dose. ] [ Designated as safety issue: Yes ]
Maternal iron status (via serum transferrin receptor/ferritin ratio) [ Time Frame: Iron status measured at 14 and 32 weeks gestation. ] [ Designated as safety issue: No ]
Pre-eclampsia determination: via proteinuria and blood pressure reading. [ Time Frame: 22 weeks and 32 weeks. ] [ Designated as safety issue: Yes ]
Newborn congenital anomalies. [ Time Frame: Determined at delivery, within 2-6 days of delivery, and at 28 days. ] [ Designated as safety issue: Yes ]
Praziquantel and 4-hydroxy praziquantel pharmacokinetic studies. [ Time Frame: 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). ] [ Designated as safety issue: No ]
Placental mechanisms mediating improved outcomes in the PZQ group: placental blood cytokine levels and placental tissue for villous explant cultures. [ Time Frame: At delivery. ] [ Designated as safety issue: No ]
Extra-placental mechanisms mediating improved outcomes in the PZQ group: maternal serum cytokine levels (particularly TNF-alpha, TNF-alpha receptors I and II, IL-1, and IL-6) [ Time Frame: At 32 weeks gestation ] [ Designated as safety issue: No ]

Estimated Enrollment:	420
Study Start Date:	August 2007
Estimated Study Completion Date:	April 2013
Estimated Primary Completion Date:	April 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Praziquantel Praziquantel at 12-16 weeks gestation.	Drug: Praziquantel 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.
Placebo Comparator: Control Placebo at 12-16 weeks gestation.	Drug: Placebo Made with the same color coded gelatin capsules with the inert compound dextrose.

Detailed Description:

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 420 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 first secondary objective is to assess treatment efficacy with respect to maternal and newborn nutritional status and maternal parasitologic response to treatment. This will be assessed by evaluating: maternal iron status (ferritin and serum transferrin receptor) and hemoglobin at 32 weeks gestation; change in maternal nutritional status from first trimester to 32 week visit; newborn iron stores as assessed by cord blood ferritin and hemoglobin; and parasitologic response to treatment reported as percent reduction in egg counts from the mean S. japonicum eggs per gram of stool at screening to the mean S. japonicum eggs per gram of stool at 22 weeks gestation. "Successful" treatment will be defined as a 90% or greater reduction in egg counts from pre-treatment to 22 weeks gestation. The second secondary objective is to collect preliminary safety and toxicity data on use of PZQ among pregnant women and their newborns. This will be assessed by evaluating: incidence of maternal convulsion after PZQ dosing; toxicity to maternal bone marrow, kidney, and liver as measured by laboratory parameters collected just before, and 24-48 hours after dose; immediate toxicity to the fetus as assessed by abortion (fetal demise before 20 weeks gestation); long-term toxicity to the fetus as assessed by rates of pre-maturity measured by modified Dubowitz exam at delivery, low-birth weight, stillbirth as defined by fetal demise after 20 weeks gestation, congenital anomalies as determined by physical exam performed by a pediatrician at 28 days of life; and pharmacokinetics of PZQ during pregnancy as assessed by 2 blood draws (4.5 and 8 hours after the first dose or 6 and 10 hours after the first dose). The third secondary objective is to identify extra-placental mechanisms mediating the hypothesized beneficial effect of PZQ on birth outcomes. The hypothesized mechanisms include: improved maternal iron bio-availability for transfer to the developing fetus and improved maternal nutritional status as assessed by anthropometric measures of body size. The fourth secondary objective is to identify extra-placental mechanisms mediating the hypothesized beneficial effect of PZQ on birth outcomes. The hypothesized mechanisms include: decreased concentrations of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-6 and increased concentrations of IL-10 compared in placental blood from S. japonicum infected, PZQ treated mothers compared to untreated mothers; decreased secretion of TNF-alpha, IFN-gamma, and IL-6 and more IL-10 secretion from placental explants from S. japonicum infected, PZQ treated women when stimulated with soluble parasite egg antigen compared to placental explants from S. japonicum infected, PZQ untreated mothers; and lower level of apoptosis in cultured trophoblasts exposed to peripheral serum as measured by cytokeratin 18 neo-epitope staining among S. japonicum infected, PZQ treated mothers versus untreated mothers. 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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

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:
1. History of seizures or other neurologic disorder, chronic medical problem determined by history or physical examination, e.g. active hepatitis, tuberculosis, heart disease.
2. 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.
3. 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.
4. 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.
5. 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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00486863

Contacts

Contact: Jennifer Friedman

(401) 863-2127

jennifer_friedman@brown.edu

Locations

Philippines
Research Institute for Tropical Medicine	Recruiting
Muntinlupa City, Philippines, 1781

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

More Information

No publications provided

Responsible Party:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00486863 History of Changes
Other Study ID Numbers:	06-0039, 4U01AI066050-06
Study First Received:	June 14, 2007
Last Updated:	February 9, 2012
Health Authority:	Philippines: Department of Health; Philippines: Institutional and Ethical Review Board; United States: Food and Drug Administration; United States: Institutional Review Board; United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Philippines, Schistosoma japonicum, Schistosomiasis, pregnant women

Additional relevant MeSH terms:

Schistosomiasis
Trematode Infections
Helminthiasis
Parasitic Diseases
Praziquantel

Anthelmintics
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on February 12, 2012