A Study of the Efficacy and Safety of GB-0998 in Patients With Unexplained Recurrent Miscarriage

A Double-Blind, Randomized, Placebo-Controlled Study of GB-0998 in Patients With Unexplained Recurrent Miscarriage.

The present survey was conducted to evaluate the efficacy and safety of GB-0998(immunoglobulin) in the treatment of unexplained recurrent miscarriage in comparison to placebo using a multicenter, double-blind, intergroup comparison method.

Study Overview

• Status: Completed
• Conditions: Recurrent Miscarriage
• Intervention / Treatment: Drug: Placebo; Drug: GB-0998

Detailed Description

Among the patients whose risk factors for recurrent miscarriage are unknown who repeatedly miscarry or patients who repeatedly miscarry despite treatment for risk factors, those who have never given birth and have had four or more miscarriages. Patients were assigned into two groups, GB-0998 or placebo, and received 8 ml/kg body weight of GB-0998 (400 mg/kg body weight) or placebo once a day for 5 days. The primary efficacy endpoint was ongoing pregnancy rate at 22 weeks of gestation (excluding miscarriages associated with fetal chromosomal abnormalities) and one of the secondary endpoint was live birth rate.

• Study Type: Interventional
• Enrollment (Actual): 99
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Tokyo, Japan
    • Japan Blood Products Organization

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 39 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria

1. Patients with primary recurrent miscarriage
2. Patients with a history of at least 4 miscarriages (not including biochemical pregnancy in the count of prior miscarriages)
3. Patients with any of the following risk factors for recurrent miscarriage

【Patients with unknown risk factors】 Patients with normal test results for each of the following risk factors who have experienced miscarriage of a fetus with normal chromosome karyotype

1. Abnormal uterine morphology
2. Thyroid dysfunction
3. Chromosome abnormality in the couple
4. Positive antiphospholipid antibody
5. Factor XII deficiency
6. Protein S deficiency
7. Protein C deficiency

【Patients determined to have risk factors】 Patients with the following risk factors who have experienced miscarriage of a fetus with normal chromosome karyotype despite receiving treatment for these factors

1. Abnormal uterine morphology (septate uterus): Patients who have undergone surgery
2. Thyroid dysfunction: Patients receiving medical treatment
3. Incidentally positive antiphospholipid antibody, factor XII deficiency, protein S deficiency, protein C deficiency:Patients receiving combination therapy with aspirin and heparin 4．Regardless of whether or not risk factors are present, patients should have experienced at least 1 a miscarriage of a fetus with normal chromosome karyotype 5．Patients below the age of 42 years at the time of obtaining informed consent 6．Patients who can be admitted for at least the period from the start date of administration of the study drug to the date of examination and assessment 1 week after the start of administration of the study drug 7．Patients who have given written informed consent to participate in this study

Exclusion Criteria:

1. Patients with chromosome abnormalities in themselves or their partners that are risk factors for recurrent miscarriage, patients with antiphospholipid syndrome, and patients with incidentally positive antiphospholipid antibody (when the latest test result is positive)
2. Patients in whom complications of diabetes mellitus or impaired glucose tolerance has been identified, but who have not received appropriate treatment for this condition
3. Patients who have received intravenous immunoglobulin therapy as treatment for recurrent miscarriage in the past
4. Patients with a history of stillbirth at 22 weeks of gestation or later
5. Patients receiving treatment for malignant tumor
6. Patients with a history of thromboembolism
7. Patients with a history of shock or hypersensitivity in response to the ingredients of this drug or patients with hereditary fructose intolerance
8. Patients who have been diagnosed with IgA deficiency in the past or patients who have a serum IgA level of <5 mg/dL at laboratory tests at registration
9. Patients who have received another study drug within the period of 12 weeks prior to informed consent or who are currently participating in another clinical trial
10. Patients who are unsuitable for this study for any other reason, in the opinion of a principal investigator or sub-investigators

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Infusion of normal saline	Drug: Placebo; Subjects received the same dose of saline as GB-0998 for 5 days after confirmation of the gestational sac by ultrasonography, up to 6 weeks and 6 days of gestation.; Other Names: normal saline
Experimental: GB-0998; Infusion of GB-0998 (Immunoglobulin)	Drug: GB-0998; Subjects received GB-0998 at 400 mg/kg body weight once daily for 5 days until 6 weeks and 6 days of gestation after confirmation of the gestational sac by ultrasonography.; Other Names: Intravenous Immunoglobulin （Venoglobulin®IH，2.5g/50ml）

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ongoing pregnancy rate (excluding miscarriages associated with fetal chromosomal abnormalities)	To evaluate the effectiveness of the drug in preventing miscarriages, we examined the ongoing pregnancy rate at 22 weeks and 0 days of gestation in cases excluding cases of fetal chromosome aberration miscarriages.	At 22 weeks of gestation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ongoing pregnancy rate(all patients)	To evaluate the effectiveness of the drug in preventing miscarriages, we examined the ongoing pregnancy rate at 22 weeks and 0 days of gestation in all patients.	At 22 weeks of gestation
Live birth rate (excluding miscarriages associated with fetal chromosomal abnormalities)	To evaluate the effectiveness of the drug in total outcome of pregnancy, we examined the live birth rate in cases excluding cases of fetal chromosome aberration miscarriages.	At the time of birth
Live birth rate(all patients)	To evaluate the effectiveness of the drug in total outcome of pregnancy, we examined the live birth rate in all patients.	At the time of birth

Collaborators and Investigators

• Sponsor: Japan Blood Products Organization
• Investigators: Principal Investigator: Hideto Yamada, Director, Center for Recurrent Pregnancy Loss, Teine Keijinkai Hospital; Principal Investigator: Shigeru Saito, Professor, University of Toyama

Publications and helpful links

General Publications

• Yamada H, Deguchi M, Saito S, Takeshita T, Mitsui M, Saito T, Nagamatsu T, Takakuwa K, Nakatsuka M, Yoneda S, Egashira K, Tachibana M, Matsubara K, Honda R, Fukui A, Tanaka K, Sengoku K, Endo T, Yata H. Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy losses: A double-blind, randomised, placebo-controlled trial. EClinicalMedicine. 2022 Jun 29;50:101527. doi: 10.1016/j.eclinm.2022.101527. eCollection 2022 Aug.

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2014
• Primary Completion (Actual): May 1, 2020
• Study Completion (Actual): September 1, 2020

Study Registration Dates

• First Submitted: July 3, 2014
• First Submitted That Met QC Criteria: July 8, 2014
• First Posted (Estimate): July 9, 2014

Study Record Updates

• Last Update Posted (Actual): January 28, 2022
• Last Update Submitted That Met QC Criteria: January 26, 2022
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: IVIG; Intravenous immunoglobulin; Unexplained Recurrent miscarriage; Primary Recurrent miscarriage
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Pregnancy Complications; Recurrence; Abortion, Spontaneous; Abortion, Habitual; Physiological Effects of Drugs; Immunologic Factors; Immunoglobulins; Immunoglobulins, Intravenous; gamma-Globulins; Rho(D) Immune Globulin
• Other Study ID Numbers: B211-11

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No