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A Phase 3, randomized, placebo-controlled, double blind study of KW-3357 in patients with early onset severe preeclampsia

A Phase 3 study of KW-3357 in patients with early onset severe preeclampsia

181

There were no significant differences in demographic characteristics between the KW-3357 and placebo groups. Age at the time of informed consent (mean +- standard deviation, similar hereafter) was 34.9 +- 4.71 years for the KW-3357 group and 34.4 +- 5.07 years for the placebo group. The gestational age was 29.02 +- 2.171 weeks in the KW-3357 group and 28.94 +- 2.204 weeks in the placebo group. 31 subjects (34.4%) in the KW-3357 group and 30 subjects (33.0%) in the placebo group had the gestational age of less than 28 weeks. There were no significant differences in laboratory values related to disease status between the KW-3357 and placebo groups. Baseline AT activity was 81.07+-17.287% in the KW-3357 group and 79.37+-11.625% in the placebo group. Urinary protein was 271.9 +- 374.44 mg/dL in the KW-3357 group and 320.8 +- 571.34 mg/dL in the placebo group, and the urine protein to creatinine ratio was 2.2711 +- 2.57572 g/g in the KW-3357 group and 2.9466 +- 3.74099 g/g in the placebo group. The diagnosis of proteinuria was not significantly different between the KW-3357 group (78 subjects, 86.7%) and the placebo group (77 subjects, 84.6%). The baseline sFlt-1/PlGF ratio was 465.3361 +- 448.84788 in the KW-3357 group and 517.0820 +- 458.16234 in the placebo group. The number of subjects with severe hypertension (systolic blood pressure >= 160 mmHg and/or diastolic blood pressure >= 110 mmHg) at baseline was 74 subjects (82.2%) in the KW-3357 group and 76 subjects (83.5%) in the placebo group. Systolic blood pressure at diagnosis was 165.4 +- 22.46 mmHg in the KW-3357 group and 166.8 +- 17.40 mmHg in the placebo group; diastolic blood pressure at diagnosis was 99.4 +- 16.55 mmHg in the KW-3357 group and 98.9 +- 13.01 mmHg in the placebo group.

The 183 enrolled subjects were randomized, with 91 subjects in the KW-3357 group and 92 subjects in the placebo group, respectively. One subject in each group withdrew from the study prior to initiation of investigational drug administration, and 90 subjects (98.9%) in the KW-3357 group and 91 subjects (98.9%) in the placebo group were included in the safety analysis population and the Full Analysis Set (FAS). Of these subjects, one subject in the placebo group who used a concomitant prohibited drug, one subject in the placebo group who used a concomitant restricted drug, one subject in the KW-3357 group who received an investigational drug that deviated from the dose specified in the study protocol, and one subject in the placebo group who violated the exclusion criteria were excluded from the Per Protocol Set (PPS). 89 subjects (97.8%) in the KW-3357 group and 88 subjects (95.7%) in the placebo group were included in the PPS. Since there were no multiple deliveries and no fetal deaths or stillbirths prior to delivery in this study, the number of subjects and their fetuses and newborns was the same.

In the maternal, treatment emergent adverse events (TEAEs) occurred in 69 of 90 subjects (76.7%) in the KW-3357 group and 70 of 91 subjects (76.9%) in the placebo group. Drug-related TEAEs occurred in 7 subjects (7.8%) in the KW-3357 group and 2 subjects (2.2%) in the placebo group. No TEAEs resulting in death occurred. Other serious TEAEs occurred in 25 subjects (27.8%) in the KW-3357 group and 15 subjects (16.5%) in the placebo group. Other serious drug-related TEAEs events occurred in 1 subject (1.1%) in the KW-3357 group and 1 subject (1.1%) in the placebo group. Other significant TEAEs occurred in 2 subjects (2.2%) in the KW-3357 group and 5 subjects (5.5%) in the placebo group. No other significant drug-related TEAEs occurred in either group. In the fetus, TEAEs occurred in 26 subjects (28.9%) in the KW-3357 group and 28 subjects (30.8%) in the placebo group. No drug-related TEAEs occurred. No TEAEs resulting in fetal death or other significant TEAEs occurred. Other serious TEAEs occurred in 26 subjects (28.9%) in the KW-3357 group and 27 subjects (29.7%) in the placebo group. In the neonatal, TEAEs occurred in 34 subjects (37.8%) in the KW-3357 group and 30 subjects (33.0%) in the placebo group. Drug-related TEAEs occurred in 1 subject (1.1%) in the KW-3357 group and none in the placebo group. TEAEs resulting in neonatal death occurred in 3 subjects (3.3%) in the KW-3357 group, but none in the placebo group. No drug-related TEAEs resulting in neonatal death occurred. Other serious TEAEs occurred in 15 subjects (16.7%) in the KW-3357 group and 14 subjects (15.4%) in the placebo group. No other serious drug-related TEAEs occurred in either group. Among maternal TEAEs, "anaemia" was the most common TEAEs in the KW-3357 group, occurring in 24 subjects (26.7%). The most common TEAEs in the placebo group was "constipation", occurring in 12 subjects (13.2%). TEAEs that occurred at least 10% more frequently in the KW-3357 group than in the placebo group was "anemia" (26.7% in the KW-3357 group and 9.9% in the placebo group). There were no TEAEs in the placebo group that occurred at least 10% more frequently than the KW-3357 group. The most common TEAEs occurring in the fetus was "fetal distress syndrome" in both groups, occurring in 26 subjects (28.9%) in the KW-3357 group and 27 subjects (29.7%) in the placebo group. No other TEAEs that occurred in more than one subject were observed in either group. The most common TEAEs occurring in the neonatal was "neonatal respiratory distress syndrome" in both groups, occurring in 9 (10.0%) subjects in the KW-3357 group and 7 (7.7%) subjects in the placebo group. Hemorrhage, defined as adverse events of special interest in the study, occurred in 25 subjects (27.8%) in the KW-3357 group and 8 subjects (8.8%) in the placebo group. The difference in incidence rates between treatment groups (KW-3357 group - placebo group, 95% CI) was 19.0% (4.3, 32.7%) and the risk ratio (95% CI) was 3.16 (1.51, 6.63), with a higher incidence rate in the KW-3357 group.

When the days of maintaining pregnancy was compared between the KW-3357 and placebo groups using a Kaplan-Meier curve and a generalized Wilcoxon test, there was no statistically significant difference between the treatment groups (p=0.0719). The mean of days of maintaining pregnancy by treatment group (95%CI) was 16.9 (13.8, 20.0) days for the KW-3357 group and 13.0 (10.4, 15.6) days for the placebo group. Even when the date of investigator's decision to terminate pregnancy was considered as the date of pregnancy termination, it was not possible to determine that the days of maintaining pregnancy was prolonged in the KW-3357 group. The median of the days of maintaining pregnancy estimated by Kaplan-Meier (95%CI) was 12.0 (9.0, 15.0) days in the KW-3357 group and 9.0 (8.0, 11.0) days in the placebo group. The hazard ratio by Stratified Cox proportional-hazard model was 0.756 (0.556, 1.030). The hazard ratio of the days of maintaining pregnancy (95%CI) was estimated between treatment groups and for each explanatory variable from a Cox regression model using the allocation factors (gestational age at enrollment, baseline AT activity, and proteinuria) as explanatory variables, and was 0.670 (0.496, 0.906) for AT activity and 0.541 (0.346, 0.847) for the presence of proteinuria.

Baseline AT activity (mean +- standard deviation) was 81.07 +- 17.287% in the KW-3357 group and 79.37 +- 11.625% in the placebo group. The mean difference between treatment groups (KW-3357 group - placebo group, 95% CI) was 1.69% (-2.62, 6.01%), showing no significant difference. AT activity of the KW-3357 group and the placebo group after the initiation of investigational drug administration (15 minutes after Day 1 administration - Day 8) ranged from 136.74% to 211.52% and from 77.62% to 80.17%, respectively. At all of these time points, AT activity in the KW-3357 group was higher than in the placebo group. AT activity at 3 days after pregnancy termination was 103.13 +- 26.853% in the KW-3357 group and 78.43 +- 13.426% in the placebo group. The mean difference between the treatment groups was 24.70% (18.35, 31.04%), with higher AT activity in the KW-3357 group compared to the placebo group. There was no strong correlation between the days of maintaining pregnancy and AT activity after the investigational drug administration.

The efficacy of KW-3357 in subjects with early-onset severe preeclampsia (PE) was not validated in this clinical trial, and the safety of KW-3357 in subjects with early-onset severe PE requires caution regarding the occurrence of bleeding-related events and "anemia" in the maternal.

Yes

The datasets generated and/or analyzed during the study sponsored by Kyowa Kirin will be available in the Vivli repository, https://vivli.org/ourmember/kyowa-kirin/ as long as conditions of data disclosure specified in the policy section of the Vivli website are satisfied.

Kenichi Takagi

Kyowa Kirin Co., Ltd

1-9-2, Otemachi , Chiyoda-ku, Tokyo, Japan

clinical.info.jp@kyowakirin.com

Clinical trial information contact

Kyowa Kirin Co., Ltd

1-9-2, Otemachi , Chiyoda-ku, Tokyo, Japan

+81-3-5205-7200

clinical.info.jp@kyowakirin.com

completed

Nov. 19, 2019

Interventional

multicenter, randomized, placebo-controlled, double-blind study

treatment purpose

3

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 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 test

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 Case 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 gestation); 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).
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
- Severe 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

Female

Preeclampsia

investigational material(s)
Generic name etc : KW-3357
INN of investigational material : antithrombin gamma
Therapeutic category code : 634 Human blood preparations
Dosage and Administration for Investigational material : intraveneous infusion once a day

control material(s)
Generic name etc : physiological saline
INN of investigational material : -
Therapeutic category code : 331 Blood substitutes
Dosage and Administration for Investigational material : intraveneous infusion once a day

confirmatory
Days of maintaining pregnancy (Days from the start date of investigational drug to the date of pregnancy termination)

efficacy
Secondary endpoint:
1) Assessment of gestational age
- Presence or absence of achievement of 32 weeks of gestation, presence or absence of achievement of 34 weeks of gestation, and presence or absence of achievement of 28 weeks of gestation in subjects enrolled in the period of less than 28 weeks of gestation
2) Maternal efficacy endpoints
- Blood coagulation factors (AT activity, PLT, D-dimer, FDP) from baseline to Day 8 at all time points and 3 days after termination of pregnancy
- Sitting systolic blood pressure and sitting diastolic blood pressure from baseline to Day 8 at each examination 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
3) Efficacy endpoints for fetus
- Biophysical Profile Score from baseline to Day 8 at each time point
- Fetal growth rate during the period of administration of the investigational product, etc.
4) Efficacy endpoints in neonates
- Apgar score at 1 minute and 5 minutes after birth, presence or absence of neonatal asphyxia
- Birth weight and neonatal growth
- Head and chest circumferences at birth
- Short-term prognosis of neonates 28 days after termination of pregnancy
- Whether or not the neonates was hospitalized in the NICU at 28 days after termination of pregnancy and the number of days in the hospital
- Presence or absence of respiratory management and the number of days of management at the time of admission to the NICU 28 days after termination of pregnancy

Other efficacy endpoints:
- Biomarkers (TNF-alpha, interleukin (IL)-6, IL-10, and hs-CRP, and sFlt-1 and PlGF and sFlt-1/PlGF) at the time of examination from baseline to Day 8
- Pulsatility index and findings of the umbilical artery and middle cerebral artery at the time of examination from baseline to Day 8
- Reason for termination of pregnancy
- Prolongation days of pregnancy by reason of termination of pregnancy
- Labor findings (mode of delivery, presence or absence of stillbirth, placental weight, presence or absence of placental infarction)
- Umbilical arterial blood gas at termination of pregnancy
- Presence or absence of HELLP syndromes and onset of symptoms during the course of the clinical trial

+81-55-948-3111

Sept. 03, 2019