KW-3357 Study in Patients With Early Onset Severe Preeclampsia

Preeclampsia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04182373
• Other study ID #: 3357-101
• Status: Completed
• Phase: Phase 3
• Start date: November 19, 2019
• Est. completion date: June 16, 2023

Study information

• Verified date: November 2023
• Source: Kyowa Kirin Co., Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 181
• Est. completion date: June 16, 2023
• Est. primary completion date: May 17, 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Patients who gave written consent to participate in the clinical trial by their own free will.

2. Patients aged 18 years or older at the time of obtaining informed consent

3. 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""

4. Patients diagnosed with severe PE*

*: Follow the diagnostic criteria of the Japan Society for the Study of Hypertension in Pregnancy

5. Patients with AT activity of 100% or less in the preliminary examination

Exclusion Criteria:

1. 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.

2. Patients with right hypochondralgia or epigastralgia

3. Patients with HELLP syndromes

4. Patients with pulmonary edema

5. Patients with severe pleural effusion, severe ascites, or serous retinal detachment

6. Patients with central nervous system disorders (eclampsia, stroke) or visual disorders (cortical blindness)

7. Patients with severe headache or urge eclampsia

8. Patients with abruptio placentae

9. Suspected patients with 8 or more obstetric DIC scores

10. Patients with a definitive diagnosis of congenital AT deficiency

11. Patients with diseases or symptoms other than the primary disease requiring immediate delivery

12. Patients on ongoing treatment with nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., aspirin) or who require NSAIDs use during the course of the study.

13. 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).

14. Patients with a current or past history of serious drug allergy

15. Patients with a history or complication of drug dependence or alcoholism

16. Patients with hypersensitivity to AT preparations

17. Patients who are pregnant with a fetus with a chromosomal abnormality or a fetus suspected of having a serious malformation syndrome

18. Patients with multiple pregnancies

19. Patients with a history or complication of antiphospholipid antibody syndrome

20. Patients with diabetes complicated pregnancy or obvious diabetes mellitus

21. 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

22. 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)

23. Patients with active infections (e.g., toxoplasma infection, genital chlamydia, genital herpes, cytomegalovirus infection)

24. 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.

25. 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

26. 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

27. Other patients whom the principal investigator or the subinvestigator judges to be unfavorable for participation in the clinical trial

Related Conditions & MeSH terms

• Pre-Eclampsia
• Preeclampsia

Intervention

Drug:
• Antithrombin gamma
Intravenous infusion, once a day, 7 days
• physiological saline
Intravenous infusion, once a day, 7 days

Locations

Country	Name	City	State
Japan	Osaka Metropolitan University Hospital	Abeno-ku	Osaka
Japan	Aomori Prefectural Central Hospital	Aomori
Japan	The University of Tokyo Hospital	Bunkyo	Tokyo
Japan	Juntendo University Hospital	Bunkyo-ku	Tokyo
Japan	Tokyo Metropolitan Tama Medical Center	Fuchu	Tokyo
Japan	Fukuoka University Hospital	Fukuoka
Japan	Hakodate Central General Hospital	Hakodate	Hokkaido
Japan	Hamamatsu Medical Center	Hamamatsu	Shizuoka
Japan	Hamamatsu University Hospital	Hamamatsu	Shizuoka
Japan	Japanese Red Cross Society Himeji Hospital	Himeji	Hyogo
Japan	Kansai Medical University Hospital	Hirakata	Osaka
Japan	Osaka Women's and Children's Hospital	Izumi	Osaka
Japan	Rinku General Medical Center	Izumisano	Osaka
Japan	Juntendo University Shizuoka Hospital	Izunokuni	Shizuoka
Japan	Kagoshima City Hospital	Kagoshima
Japan	Ishikawa Prefectural Central Hospital	Kanazawa	Ishikawa
Japan	Nara Medical University Hospital	Kashihara	Nara
Japan	Saitama Medical Center	Kawagoe	Saitama
Japan	St. Marianna University School of Medicine	Kawasaki	Kanagawa
Japan	National Hospital Organization Kokura Medical Center	Kitakyushu	Fukuoka
Japan	Kobe University Hospital	Kobe	Hyogo
Japan	Yamanashi Prefectural Central Hospital	Kofu	Yamanashi
Japan	Kumamoto University Hospital	Kumamoto
Japan	Kurume University Hospital	Kurume	Fukuoka
Japan	Our Lady of the Snow Social Medical Corporation St. Mary's Hospital	Kurume	Fukuoka
Japan	Kyoto University Hospital	Kyoto
Japan	University Hospital Kyoto Prefectural University of Medicine	Kyoto
Japan	Shinshu University Hospital	Matsumoto	Nagano
Japan	Dokkyo Medical University Hospital	Mibu	Tochigi
Japan	Aiiku Hospital	Minato	Tokyo
Japan	Kyorin University Hospital	Mitaka	Tokyo
Japan	Faculty of Medicine, University of Miyazaki Hospital	Miyazaki
Japan	Nagasaki University Hospital	Nagasaki
Japan	Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital	Nagoya	Aichi
Japan	Nara Prefecture General Medical Center	Nara
Japan	Niigata University Medical & Dental Hospital	Niigata
Japan	Obihiro Kosei General Hospital	Obihiro	Hokkaido
Japan	Oita Prefectural Hospital	Oita
Japan	Okayama University Hospital	Okayama
Japan	National Hospital Organization Nagasaki Medical Center	Omura	Nagasaki
Japan	Osaka City General Hospital	Osaka
Japan	The Kitasato Institute Kitasato University Hospital	Sagamihara	Kanagawa
Japan	Hokkaido University Hospital	Sapporo	Hokkaido
Japan	Sapporo City General Hospital	Sapporo	Hokkaido
Japan	Sendai Red Cross Hospital	Sendai	Miyagi
Japan	National Center for Child Health and Development	Setagaya	Tokyo
Japan	Japanese Red Cross Medical Center	Shibuya	Tokyo
Japan	Jichi Medical University Hospital	Shimotsuke	Tochigi
Japan	Showa University Hospital	Shinagawa	Tokyo
Japan	Iwate Medical University Hospital	Shiwa	Iwate
Japan	National Cerebral and Cardiovascular Center	Suita	Osaka
Japan	Tokyo Metropolitan Bokutoh Hospital	Sumida	Tokyo
Japan	Ehime University Hospital	Toon	Ehime
Japan	Toyama University Hospital	Toyama
Japan	Fujita Health University Hospital	Toyoake	Aichi
Japan	Toyota Memorial Hospital	Toyota	Aichi
Japan	Mie University Hospital	Tsu	Mie
Japan	Yamaguchi University Hospital	Ube	Yamaguchi
Japan	Juntendo University Urayasu Hospital	Urayasu	Chiba
Japan	Okinawa prefectural Chubu Hospital	Uruma	Okinawa
Japan	Tokyo Women's Medical University Yachiyo Medical Center	Yachiyo	Chiba
Japan	Yokohama City University Medical Center	Yokohama	Kanagawa
Japan	National Hospital Organization Shikoku Medical Center for Children and Adults	Zentsuji	Kagawa

Sponsors (2)

Lead Sponsor	Collaborator
Kyowa Kirin Co., Ltd.	Japan Blood Products Organization

Country where clinical trial is conducted

Japan, 

References & Publications (1)

Saito S, Takagi K, Moriya J, Kobayashi T, Kanayama N, Sameshima H, Morikawa M, Sago H, Adachi T, Ohkuchi A, Takeda S, Masuyama H, Seki H. A randomized phase 3 trial evaluating antithrombin gamma treatment in Japanese patients with early-onset severe preeclampsia (KOUNO-TORI study): Study protocol. Contemp Clin Trials. 2021 Aug;107:106490. doi: 10.1016/j.cct.2021.106490. Epub 2021 Jun 24. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in TNF-alpha at the time of examination		From baseline to Day 8
Other	Change in interleukin (IL)-6 at the time of examination		From baseline to Day 8
Other	Change in IL-10 at the time of examination		From baseline to Day 8
Other	Change in hs-CRP at the time of examination		From baseline to Day 8
Other	Change in sFlt-1 at the time of examination		From baseline to Day 8
Other	Change in PlGF at the time of examination		From baseline to Day 8
Other	Change in sFlt-1/PlGF at the time of examination		From baseline to Day 8
Other	Pulsatility index of the umbilical artery and middle cerebral artery		At the time of examination from baseline to Day 8
Other	Change in findings of the umbilical artery and middle cerebral artery		At the time of examination from baseline to Day 8
Other	Distribution of reasons for termination of pregnancy		28 days before the end of study
Other	Prolongation days of pregnancy by reason of termination of pregnancy		28 days before the end of study
Other	Mode of delivery		28 days before the end of study
Other	Presence or absence of stillbirth		28 days before the end of study. Neonates will be assessed after delivery.
Other	Placental weight		28 days before the end of study
Other	Presence or absence of placental infarction		28 days before the end of study
Other	Umbilical arterial blood gas at termination of pregnancy		28 days before the end of study
Other	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
Primary	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	Presence or absence of achievement of 32 weeks of gestation		28 days before the end of study
Secondary	Presence or absence of achievement of 34 weeks of gestation		28 days before the end of study
Secondary	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
Secondary	Change in AT activity		From baseline to Day 8 at all time points and 3 days after termination of pregnancy
Secondary	Change in PLT concentration		From baseline to Day 8 at all time points and 3 days after termination of pregnancy
Secondary	Change on D-dimer concentration		From baseline to Day 8 at all time points
Secondary	Change in FDP concentration		From baseline to Day 8 at all time points
Secondary	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
Secondary	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
Secondary	Amount of blood lost during delivery		28 days before the end of study
Secondary	Biophysical Profile Score	Minimum is 0, max is 10. Higher score means better condition.	From baseline to Day 8 at each time point
Secondary	Fetal growth rate		28 days before the end of study
Secondary	Apgar score	Minimum is 0, max is 10. Higher score means better condition.	At 1 minute and 5 minutes after birth
Secondary	Presence or absence of neonatal asphyxia		At 1 minute and 5 minutes after birth
Secondary	Birth weight		28 days before the end of study
Secondary	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
Secondary	Head and chest circumferences at birth		28 days before the end of study
Secondary	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
Secondary	The number of neonates who was hospitalized in the NICU		28 days after termination of pregnancy
Secondary	The number of days in the NICU		28 days after termination of pregnancy
Secondary	The number of neonates with respiratory management at the time of admission to the NICU		28 days after termination of pregnancy
Secondary	The number of days of respiratory management at the time of admission to the NICU		28 days after termination of pregnancy