KW-3357 Study in Patients With Early Onset Severe Preeclampsia

Sponsor

Kyowa Kirin Co., Ltd. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04182373

Collaborator

Japan Blood Products Organization (Industry)

180

Enrollment

Locations

Arms

38.4

Anticipated Duration (Months)

2.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Preeclampsia	Drug: Antithrombin gamma Drug: physiological saline	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

180 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Nov 19, 2019

Anticipated Primary Completion Date :

Jan 31, 2023

Anticipated Study Completion Date :

Jan 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: KW-3357 72 IU/kg	Drug: Antithrombin gamma Intravenous infusion, once a day, 7 days
Placebo Comparator: placebo	Drug: physiological saline Intravenous infusion, once a day, 7 days

Arm

Intervention/Treatment

Experimental: KW-3357

72 IU/kg

Drug: Antithrombin gamma

Intravenous infusion, once a day, 7 days

Placebo Comparator: placebo

Drug: physiological saline

Intravenous infusion, once a day, 7 days

Outcome Measures

Primary Outcome Measures

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

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 [From baseline to Day 8 at each time point]
Minimum is 0, max is 10. Higher score means better condition.
Fetal growth rate [28 days before the end of study]
Apgar score [At 1 minute and 5 minutes after birth]
Minimum is 0, max is 10. Higher score means better condition.
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 [28 days before the end of study]
Fetal growth is classified into small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA).
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]

Other Outcome Measures

Change in TNF-alpha at the time of examination [From baseline to Day 8]
Change in interleukin (IL)-6 at the time of examination [From baseline to Day 8]
Change in IL-10 at the time of examination [From baseline to Day 8]
Change in hs-CRP at the time of examination [From baseline to Day 8]
Change in sFlt-1 at the time of examination [From baseline to Day 8]
Change in PlGF at the time of examination [From baseline to Day 8]
Change in sFlt-1/PlGF at the time of examination [From baseline to Day 8]
Pulsatility index of the umbilical artery and middle cerebral artery [At the time of examination from baseline to Day 8]
Change in findings of the umbilical artery and middle cerebral artery [At the time of examination from baseline to Day 8]
Distribution of reasons for termination of pregnancy [28 days before the end of study]
Prolongation days of pregnancy by reason of termination of pregnancy [28 days before the end of study]
Mode of delivery [28 days before the end of study]
Presence or absence of stillbirth [28 days before the end of study. Neonates will be assessed after delivery.]
Placental weight [28 days before the end of study]
Presence or absence of placental infarction [28 days before the end of study]
Umbilical arterial blood gas at termination of pregnancy [28 days before the end of study]
Presence or absence of HELLP syndromes and onset of symptoms [During the course of the clinical trial. Period from the day of commencement of administration of the investigational drug to Day 28 after the delivery]

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients who gave written consent to participate in the clinical trial by their own free will.
Patients aged 20 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, 2017"

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 or dalteparin), 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, obvious diabetes mellitus, or insulin use
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)
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

Contacts and Locations

Locations

	Site	City	State	Country
1	Japanese Red Cross Nagoya Daiichi Hospital	Nagoya	Aichi	Japan
2	Fujita Health University Hospital	Toyoake	Aichi	Japan
3	Toyota Memorial Hospital	Toyota	Aichi	Japan
4	Juntendo University Urayasu Hospital	Urayasu	Chiba	Japan
5	Tokyo Women's Medical University Yachiyo Medical Center	Yachiyo	Chiba	Japan
6	Ehime University Hospital	Toon	Ehime	Japan
7	National Hospital Organization Kokura Medical Center	Kitakyushu	Fukuoka	Japan
8	Kurume University Hospital	Kurume	Fukuoka	Japan
9	Our Lady of the Snow Social Medical Corporation St. Mary's Hospital	Kurume	Fukuoka	Japan
10	Hakodate Central General Hospital	Hakodate	Hokkaido	Japan
11	Obihiro Kosei General Hospital	Obihiro	Hokkaido	Japan
12	Hokkaido University Hospital	Sapporo	Hokkaido	Japan
13	Sapporo City General Hospital	Sapporo	Hokkaido	Japan
14	Japanese Red Cross Society Himeji Hospital	Himeji	Hyogo	Japan
15	Kobe University Hospital	Kobe	Hyogo	Japan
16	Ishikawa Prefectural Central Hospital	Kanazawa	Ishikawa	Japan
17	National Hospital Organization Shikoku Medical Center for Children and Adults	Zentsuji	Kagawa	Japan
18	St. Marianna University School of Medicine	Kawasaki	Kanagawa	Japan
19	The Kitasato Institute Kitasato University Hospital	Sagamihara	Kanagawa	Japan
20	Yokohama City University Medical Center	Yokohama	Kanagawa	Japan
21	Mie University Hospital	Tsu	Mie	Japan
22	Sendai Red Cross Hospital	Sendai	Miyagi	Japan
23	Shinshu University Hospital	Matsumoto	Nagano	Japan
24	National Hospital Organization Nagasaki Medical Center	Omura	Nagasaki	Japan
25	Nara Medical University Hospital	Kashihara	Nara	Japan
26	Okinawa prefectural Chubu Hospital	Uruma	Okinawa	Japan
27	Osaka City University Hospital	Abeno-ku	Osaka	Japan
28	Kansai Medical University Hospital	Hirakata	Osaka	Japan
29	Rinku General Medical Center	Izumisano	Osaka	Japan
30	Osaka Women's and Children's Hospital	Izumi	Osaka	Japan
31	National Cerebral and Cardiovascular Center	Suita	Osaka	Japan
32	Saitama Medical Center	Kawagoe	Saitama	Japan
33	Hamamatsu Medical Center	Hamamatsu	Shizuoka	Japan
34	Hamamatsu University Hospital	Hamamatsu	Shizuoka	Japan
35	Juntendo University Shizuoka Hospital	Izunokuni	Shizuoka	Japan
36	Dokkyo Medical University Hospital	Mibu	Tochigi	Japan
37	Jichi Medical University Hospital	Shimotsuke	Tochigi	Japan
38	Juntendo University Hospital	Bunkyo-ku	Tokyo	Japan
39	The University of Tokyo Hospital	Bunkyo	Tokyo	Japan
40	Tokyo Metropolitan Tama Medical Center	Fuchu	Tokyo	Japan
41	Aiiku Hospital	Minato	Tokyo	Japan
42	Kyorin University Hospital	Mitaka	Tokyo	Japan
43	National Center for Child Health and Development	Setagaya	Tokyo	Japan
44	Japanese Red Cross Medical Center	Shibuya	Tokyo	Japan
45	Showa University Hospital	Shinagawa	Tokyo	Japan
46	Tokyo Metropolitan Bokutoh Hospital	Sumida	Tokyo	Japan
47	Yamaguchi University Hospital	Ube	Yamaguchi	Japan
48	Yamanashi Prefectural Central Hospital	Kofu	Yamanashi	Japan
49	Aomori Prefectural Central Hospital	Aomori		Japan
50	Fukuoka University Hospital	Fukuoka		Japan
51	Kagoshima City Hospital	Kagoshima		Japan
52	Kumamoto University Hospital	Kumamoto		Japan
53	Kyoto University Hospital	Kyoto		Japan
54	University Hospital Kyoto Prefectural University of Medicine	Kyoto		Japan
55	Faculty of Medicine, University of Miyazaki Hospital	Miyazaki		Japan
56	Nagasaki University Hospital	Nagasaki		Japan
57	Nara Prefecture General Medical Center	Nara		Japan
58	Niigata University Medical & Dental Hospital	Niigata		Japan
59	Oita Prefectural Hospital	Oita		Japan
60	Okayama University Hospital	Okayama		Japan
61	Osaka City General Hospital	Osaka		Japan
62	Toyama University Hospital	Toyama		Japan