Clinical trial NCT04182373: KW-3357 Study in Patients With Early Onset Severe Preeclampsia
Official title: A Phase 3, Randomized, Placebo-controlled, Double Blind Study of KW-3357 in Patients With Early Onset Severe Preeclampsia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Preeclampsia
Keywords: Preeclampsia
Antithrombin
Lead sponsor: Kyowa Kirin Co., Ltd.
Sponsor class: INDUSTRY
Collaborators: name: Japan Blood Products Organization
First posted: 2019-12-02
Enrollment: 181
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Days of maintaining pregnancy
timeFrame: 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 outcomes:
measure: Presence or absence of achievement of 32 weeks of gestation
timeFrame: 28 days before the end of study
measure: Presence or absence of achievement of 34 weeks of gestation
timeFrame: 28 days before the end of study
measure: Presence or absence of achievement of 28 weeks of gestation in subjects enrolled in the period of less than 28 weeks of gestation
timeFrame: 28 days before the end of study
measure: Change in AT activity
timeFrame: From baseline to Day 8 at all time points and 3 days after termination of pregnancy
measure: Change in PLT concentration
timeFrame: From baseline to Day 8 at all time points and 3 days after termination of pregnancy
measure: Change on D-dimer concentration
timeFrame: From baseline to Day 8 at all time points
measure: Change in FDP concentration
timeFrame: From baseline to Day 8 at all time points
measure: Sitting systolic blood pressure and sitting diastolic blood pressure
timeFrame: From baseline to Day 8 at each time point, 3 days after termination of pregnancy, and 28 days after termination of pregnancy
measure: Proteinuria/creatinine ratio
timeFrame: From baseline to Day 8 at each time point, 3 days after termination of pregnancy, and 28 days after termination of pregnancy
measure: Amount of blood lost during delivery
timeFrame: 28 days before the end of study
measure: Biophysical Profile Score
timeFrame: From baseline to Day 8 at each time point
measure: Fetal growth rate
timeFrame: 28 days before the end of study
measure: Apgar score
timeFrame: At 1 minute and 5 minutes after birth
measure: Presence or absence of neonatal asphyxia
timeFrame: At 1 minute and 5 minutes after birth
measure: Birth weight
timeFrame: 28 days before the end of study
measure: Neonatal growth
timeFrame: 28 days before the end of study
measure: Head and chest circumferences at birth
timeFrame: 28 days before the end of study
measure: Short-term prognosis of neonates (incidence of bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukolame, retinopathy of prematurity, sepsis, necrotizing enteritis, death, etc)
timeFrame: 28 days after termination of pregnancy
measure: The number of neonates who was hospitalized in the NICU
timeFrame: 28 days after termination of pregnancy
measure: The number of days in the NICU
timeFrame: 28 days after termination of pregnancy
measure: The number of neonates with respiratory management at the time of admission to the NICU
timeFrame: 28 days after termination of pregnancy
measure: The number of days of respiratory management at the time of admission to the NICU
timeFrame: 28 days after termination of pregnancy
Other outcomes:
measure: Change in TNF-alpha at the time of examination
timeFrame: From baseline to Day 8
measure: Change in interleukin (IL)-6 at the time of examination
timeFrame: From baseline to Day 8
measure: Change in IL-10 at the time of examination
timeFrame: From baseline to Day 8
measure: Change in hs-CRP at the time of examination
timeFrame: From baseline to Day 8
measure: Change in sFlt-1 at the time of examination
timeFrame: From baseline to Day 8
measure: Change in PlGF at the time of examination
timeFrame: From baseline to Day 8
measure: Change in sFlt-1/PlGF at the time of examination
timeFrame: From baseline to Day 8
measure: Pulsatility index of the umbilical artery and middle cerebral artery
timeFrame: At the time of examination from baseline to Day 8
measure: Change in findings of the umbilical artery and middle cerebral artery
timeFrame: At the time of examination from baseline to Day 8
measure: Distribution of reasons for termination of pregnancy
timeFrame: 28 days before the end of study
measure: Prolongation days of pregnancy by reason of termination of pregnancy
timeFrame: 28 days before the end of study
measure: Mode of delivery
timeFrame: 28 days before the end of study
measure: Presence or absence of stillbirth
timeFrame: 28 days before the end of study. Neonates will be assessed after delivery.
measure: Placental weight
timeFrame: 28 days before the end of study
measure: Presence or absence of placental infarction
timeFrame: 28 days before the end of study
measure: Umbilical arterial blood gas at termination of pregnancy
timeFrame: 28 days before the end of study
measure: Presence or absence of HELLP syndromes and onset of symptoms
timeFrame: 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
Locations:
city: Nagoya
country: Japan
facility: Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital
state: Aichi
city: Toyoake
country: Japan
facility: Fujita Health University Hospital
state: Aichi
city: Toyota
country: Japan
facility: Toyota Memorial Hospital
state: Aichi
city: Urayasu
country: Japan
facility: Juntendo University Urayasu Hospital
state: Chiba
city: Yachiyo
country: Japan
facility: Tokyo Women's Medical University Yachiyo Medical Center
state: Chiba
city: Toon
country: Japan
facility: Ehime University Hospital
state: Ehime
city: Kitakyushu
country: Japan
facility: National Hospital Organization Kokura Medical Center
state: Fukuoka
city: Kurume
country: Japan
facility: Kurume University Hospital
state: Fukuoka
city: Kurume
country: Japan
facility: Our Lady of the Snow Social Medical Corporation St. Mary's Hospital
state: Fukuoka
city: Hakodate
country: Japan
facility: Hakodate Central General Hospital
state: Hokkaido
city: Obihiro
country: Japan
facility: Obihiro Kosei General Hospital
state: Hokkaido
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
state: Hokkaido
city: Sapporo
country: Japan
facility: Sapporo City General Hospital
state: Hokkaido
city: Himeji
country: Japan
facility: Japanese Red Cross Society Himeji Hospital
state: Hyogo
city: Kobe
country: Japan
facility: Kobe University Hospital
state: Hyogo
city: Kanazawa
country: Japan
facility: Ishikawa Prefectural Central Hospital
state: Ishikawa
city: Shiwa
country: Japan
facility: Iwate Medical University Hospital
state: Iwate
city: Zentsuji
country: Japan
facility: National Hospital Organization Shikoku Medical Center for Children and Adults
state: Kagawa
city: Kawasaki
country: Japan
facility: St. Marianna University School of Medicine
state: Kanagawa
city: Sagamihara
country: Japan
facility: The Kitasato Institute Kitasato University Hospital
state: Kanagawa
city: Yokohama
country: Japan
facility: Yokohama City University Medical Center
state: Kanagawa
city: Tsu
country: Japan
facility: Mie University Hospital
state: Mie
city: Sendai
country: Japan
facility: Sendai Red Cross Hospital
state: Miyagi
city: Matsumoto
country: Japan
facility: Shinshu University Hospital
state: Nagano
city: Omura
country: Japan
facility: National Hospital Organization Nagasaki Medical Center
state: Nagasaki
city: Kashihara
country: Japan
facility: Nara Medical University Hospital
state: Nara
city: Uruma
country: Japan
facility: Okinawa prefectural Chubu Hospital
state: Okinawa
city: Abeno-ku
country: Japan
facility: Osaka Metropolitan University Hospital
state: Osaka
city: Hirakata
country: Japan
facility: Kansai Medical University Hospital
state: Osaka
city: Izumisano
country: Japan
facility: Rinku General Medical Center
state: Osaka
city: Izumi
country: Japan
facility: Osaka Women's and Children's Hospital
state: Osaka
city: Suita
country: Japan
facility: National Cerebral and Cardiovascular Center
state: Osaka
city: Kawagoe
country: Japan
facility: Saitama Medical Center
state: Saitama
city: Hamamatsu
country: Japan
facility: Hamamatsu Medical Center
state: Shizuoka
city: Hamamatsu
country: Japan
facility: Hamamatsu University Hospital
state: Shizuoka
city: Izunokuni
country: Japan
facility: Juntendo University Shizuoka Hospital
state: Shizuoka
city: Mibu
country: Japan
facility: Dokkyo Medical University Hospital
state: Tochigi
city: Shimotsuke
country: Japan
facility: Jichi Medical University Hospital
state: Tochigi
city: Bunkyo-ku
country: Japan
facility: Juntendo University Hospital
state: Tokyo
city: Bunkyo
country: Japan
facility: The University of Tokyo Hospital
state: Tokyo
city: Fuchu
country: Japan
facility: Tokyo Metropolitan Tama Medical Center
state: Tokyo
city: Minato
country: Japan
facility: Aiiku Hospital
state: Tokyo
city: Mitaka
country: Japan
facility: Kyorin University Hospital
state: Tokyo
city: Setagaya
country: Japan
facility: National Center for Child Health and Development
state: Tokyo
city: Shibuya
country: Japan
facility: Japanese Red Cross Medical Center
state: Tokyo
city: Shinagawa
country: Japan
facility: Showa University Hospital
state: Tokyo
city: Sumida
country: Japan
facility: Tokyo Metropolitan Bokutoh Hospital
state: Tokyo
city: Ube
country: Japan
facility: Yamaguchi University Hospital
state: Yamaguchi
city: Kofu
country: Japan
facility: Yamanashi Prefectural Central Hospital
state: Yamanashi
city: Aomori
country: Japan
facility: Aomori Prefectural Central Hospital
city: Fukuoka
country: Japan
facility: Fukuoka University Hospital
city: Kagoshima
country: Japan
facility: Kagoshima City Hospital
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Kyoto
country: Japan
facility: Kyoto University Hospital
city: Kyoto
country: Japan
facility: University Hospital Kyoto Prefectural University of Medicine
city: Miyazaki
country: Japan
facility: Faculty of Medicine, University of Miyazaki Hospital
city: Nagasaki
country: Japan
facility: Nagasaki University Hospital
city: Nara
country: Japan
facility: Nara Prefecture General Medical Center
city: Niigata
country: Japan
facility: Niigata University Medical & Dental Hospital
city: Oita
country: Japan
facility: Oita Prefectural Hospital
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Osaka
country: Japan
facility: Osaka City General Hospital
city: Toyama
country: Japan
facility: Toyama University Hospital
Study officials:
References:
citation: 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.