KW-3357 Study in Patients With Early Onset Severe Preeclampsia

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of intravenous KW-3357 in patients with early-onset severe preeclampsia by comparing the prolongation days of pregnancy with that of placebo.

Official Title
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A Phase 3, Randomized, Placebo-controlled, Double Blind Study of KW-3357 in Patients With Early Onset Severe Preeclampsia

Conditions
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Preeclampsia

Intervention / Treatment
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* Drug: Antithrombin gamma
* Drug: physiological saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who gave written consent to participate in the clinical trial by their own free will. Patients aged 18 years or older at the time of obtaining informed consent Patients with early-onset PE* 24 weeks 0 days to 31 weeks 6 days of gestation at the time of enrollment *: Determine the definition of gestational age based on the Guidelines for Obstetrics and Gynecology, Obstetrics, 2020 Patients diagnosed with severe PE* *: Follow the diagnostic criteria of the Japan Society for the Study of Hypertension in Pregnancy Patients with AT activity of 100% or less in the preliminary examination Exclusion Criteria: Patients who are judged to require immediate delivery* *Best Practice Guide 2015 for Care and Treatment of Hypertension in Pregnancy Requirements for Considering Pregnancy Termination Regardless of Pregnancy Weeks in Pregnancy-induced Hypertension Syndrome Cases will be consulted for judgment. Patients with right hypochondralgia or epigastralgia Patients with HELLP syndromes Patients with pulmonary edema Patients with severe pleural effusion, severe ascites, or serous retinal detachment Patients with central nervous system disorders (eclampsia, stroke) or visual disorders (cortical blindness) Patients with severe headache or urge eclampsia Patients with abruptio placentae Suspected patients with 8 or more obstetric DIC scores Patients with a definitive diagnosis of congenital AT deficiency Patients with diseases or symptoms other than the primary disease requiring immediate delivery Patients on ongoing treatment with nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., aspirin) or who require NSAIDs use during the course of the study. Patients who have received the following drugs within 72 hours before administration of the investigational product, etc., or who require administration of the following drugs during the study period (from the start of administration of the investigational product, etc., until the date of termination of pregnancy); heparin, low-molecular-weight heparin (e.g., enoxaparin ordalteparin), fondaparinux, antiplatelet drugs (e.g., clopidogrel, prasugrel, aspirin), direct thrombin inhibitors (e.g., dabigatran), or anticoagulants (e.g., AT preparations). Patients with a current or past history of serious drug allergy Patients with a history or complication of drug dependence or alcoholism Patients with hypersensitivity to AT preparations Patients who are pregnant with a fetus with a chromosomal abnormality or a fetus suspected of having a serious malformation syndrome Patients with multiple pregnancies Patients with a history or complication of antiphospholipid antibody syndrome Patients with diabetes complicated pregnancy or obvious diabetes mellitus Patients with uncontrollable or significant complications, including the following Clinically significant cardiovascular diseases, etc. (New York Heart Association cardiac function classifications Class III or higher) Serious hepatic disease Serious renal disease Pneumonia, interstitial lung disease or other severe respiratory disease Blood disorders such as idiopathic thrombocytopenic purpura Psycho-central nervous system disorders that may affect informed consent Endocrine disorders such as hyperthyroidism Autoimmune diseases such as systemic lupus erythematosus Patients with active malignancy or patients with a history of onset or treatment of malignancy within 5 years before pregnancy (excluding excised or surgically cured basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or ductal carcinoma of the breast, and excluding cervical intraepithelial neoplasia regardless of excised or surgically cured or not) Patients with active infections (e.g., toxoplasma infection, genital chlamydia, genital herpes, cytomegalovirus infection) Patients with a positive history for HIV antibody. Patients with a positive history for HBs antigen and HCV antibody and with active infection presenting with hepatitis symptoms. Patients with any of the following laboratory abnormalities in preliminary examinations Patients with AST or ALT 2 times the upper limit of the reference level of the trial site Cr >=1.1 mg/dL Patients who have participated in a clinical trial or equivalent study of a drug or medical device within 4 months before pregnancy (within 6 months for biologics) and have received the investigational drug or used an unapproved medical device Other patients whom the principal investigator or the subinvestigator judges to be unfavorable for participation in the clinical trial

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: KW-3357<br>72 IU/kg | Drug: Antithrombin gamma<br>* Intravenous infusion, once a day, 7 days<br>|
| Placebo Comparator: placebo<br> | Drug: physiological saline<br>* Intravenous infusion, once a day, 7 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days of maintaining pregnancy |  | Subjects will be observed until maternal and/or fetal indications for delivery necessitate cessation of expectant management or until approximately 34 0/7 weeks of gestation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence or absence of achievement of 32 weeks of gestation |  | 28 days before the end of study | 
| Presence or absence of achievement of 34 weeks of gestation |  | 28 days before the end of study | 
| Presence or absence of achievement of 28 weeks of gestation in subjects enrolled in the period of less than 28 weeks of gestation |  | 28 days before the end of study | 
| Change in AT activity |  | From baseline to Day 8 at all time points and 3 days after termination of pregnancy | 
| Change in PLT concentration |  | From baseline to Day 8 at all time points and 3 days after termination of pregnancy | 
| Change on D-dimer concentration |  | From baseline to Day 8 at all time points | 
| Change in FDP concentration |  | From baseline to Day 8 at all time points | 
| Sitting systolic blood pressure and sitting diastolic blood pressure |  | From baseline to Day 8 at each time point, 3 days after termination of pregnancy, and 28 days after termination of pregnancy | 
| Proteinuria/creatinine ratio |  | From baseline to Day 8 at each time point, 3 days after termination of pregnancy, and 28 days after termination of pregnancy | 
| Amount of blood lost during delivery |  | 28 days before the end of study | 
| Biophysical Profile Score | Minimum is 0, max is 10. Higher score means better condition. | From baseline to Day 8 at each time point | 
| Fetal growth rate |  | 28 days before the end of study | 
| Apgar score | Minimum is 0, max is 10. Higher score means better condition. | At 1 minute and 5 minutes after birth | 
| Presence or absence of neonatal asphyxia |  | At 1 minute and 5 minutes after birth | 
| Birth weight |  | 28 days before the end of study | 
| Neonatal growth | Fetal growth is classified into small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA). | 28 days before the end of study | 
| Head and chest circumferences at birth |  | 28 days before the end of study | 
| Short-term prognosis of neonates (incidence of bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukolame, retinopathy of prematurity, sepsis, necrotizing enteritis, death, etc) |  | 28 days after termination of pregnancy | 
| The number of neonates who was hospitalized in the NICU |  | 28 days after termination of pregnancy | 
| The number of days in the NICU |  | 28 days after termination of pregnancy | 
| The number of neonates with respiratory management at the time of admission to the NICU |  | 28 days after termination of pregnancy | 
| The number of days of respiratory management at the time of admission to the NICU |  | 28 days after termination of pregnancy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preeclampsia, Antithrombin