A Study of Immune Globulin Subcutaneous (Human), 20% Solution (IGSC, 20%) in Japanese Participants With Primary Immunodeficiency Diseases (PID)

A Phase 3, Open-label, Non-controlled, Multi-dose Study to Evaluate the Pharmacokinetics, Safety and Tolerability, and Efficacy of Immune Globulin Subcutaneous (Human), 20% Solution (IGSC, 20%) in Japanese Subjects With Primary Immunodeficiency Diseases (PID)

In this study, Japanese participants with primary immunodeficiency diseases were treated with Immune Globulin Subcutaneous (Human), 20% solution, (IGSC, 20%). This study will be in 3 parts:

Part 1: Infusions with Immunoglobulin Intravenous (IGIV) every 3 or 4 weeks for 13 weeks.

Part 2: Participants will switch to weekly subcutaneous infusions with IGSC, 20% for 24 weeks.

Part 3: A subset will receive biweekly subcutaneous infusions with IGSC, 20% for 12 weeks.

The main aim of the study is to assess base levels of Immunoglobulin globulin G (IgG) levels in the blood of the participants after weekly and biweekly treatment with IGSC, 20% (in Parts 2 and 3 of the study). Their PID will be treated by their doctor according to their doctor's usual clinical practice.

Study Overview

• Status: Completed
• Conditions: Primary Immunodeficiency Diseases (PID)
• Intervention / Treatment: Biological: Immune Globulin Intravenous (IGIV); Biological: Immune Globulin Subcutaneous, 20% Solution (IGSC, 20%)

Detailed Description

This study consists of 3 treatment parts (Epoch 1, 2, 3). The total evaluation period of the study will be 57 weeks in which screening period is for 2-8 weeks and Epoch 1 is from Week 8 to Week 21, Epoch 2 is from Week 21 to Week 45, Epoch 3 is from Week 45 to Week 57.

Each participant will receive IGIV treatment in Epoch 1 for a total of 13 weeks, then switch to weekly subcutaneous (SC) treatment with IGSC, 20% in Epoch 2 for a total of 24 weeks and will continue into Epoch 3 for a total of 12 weeks of biweekly SC treatment with IGSC, 20%. Drug dose in Epoch 2 and Epoch 3 will be adjusted so that it will be an equivalent weekly dose of the dose administered in Epoch 1 and twice the dose administrated in Epoch 2 respectively. Epoch 2 will contain two periods, period 1: dose adjustment period (first 12 weeks) and period 2: evaluation period (second 12 weeks).

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Aichi
    • Nagoya-shi, Aichi, Japan, 466-8560
      • Nagoya University Hospital
  • Fukuoka
    • Fukuoka-shi, Fukuoka, Japan, 812-8582
      • Kyushu University Hospital
    • Kurume-shi, Fukuoka, Japan, 830-0011
      • Kurume University Hospital
  • Gifu
    • Gifu-shi, Gifu, Japan, 501-1194
      • Gifu University Hospital
  • Hiroshima
    • Hiroshima-shi, Hiroshima, Japan, 734-8551
      • Hiroshima University Hospital
  • Ishikawa
    • Kanazawa-shi, Ishikawa, Japan, 920-8641
      • Kanazawa University Hospital
  • Saitama
    • Tokorozawa-shi, Saitama, Japan, 359-8513
      • National Defense Medical College Hospital
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 113-8519
      • Tokyo Medical Dental University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Be of Japanese descent, defined as born in Japan and having Japanese parents and Japanese maternal and paternal grandparents.
• Participants must have a documented diagnosis of a form of primary humoral immunodeficiency involving antibody formation and requiring gammaglobulin replacement. The diagnosis must be confirmed by the medical director prior to treatment with IGIV.
• Participant is 2 years or older at the time of screening.
• Written informed consent is obtained from either the participants or the participants legally authorized representative prior to any study-related procedures and study product administration.
• Participant has been receiving a consistent dose of IGIV over a period of at least 3 months prior to screening equivalent to approximately 200-600 mg/kg-body weight (BW) per 3- 4 week period, as according to the product package insert
• Participant has a serum trough level of IgG >= 5 gram per liter (g/L) at screening.
• Participant has not had a serious bacterial infection within the 3 months prior to screening.
• Participant is willing and able to comply with the requirements of the protocol.

Exclusion Criteria:

• Participant has a known history of or is positive at screening for one or more of the following: hepatitis B surface antigen (HBsAg), polymerase chain reaction (PCR) for hepatitis C virus (HCV), PCR for human immunodeficiency virus (HIV) Type 1/2.

• Abnormal laboratory values at screening meeting any one of the following criteria (abnormal tests may be repeated once to determine if they are persistent):

  • Persistent alanine aminotransferase (ALT) and aspartate amino transferase (AST) > 2.5 times the upper limit of normal (ULN) for the testing laboratory
  • Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] <= 500/milli cubic meter [mm^3]).
• Participant has presence of renal function impairment defined by estimated glomerular filtration rate (eGFR) is <60 milliliter per minute/ 1.73 square meter (mL/min/1.73m^2).
• Participant has been diagnosed with or has a malignancy (other than adequately treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix), unless the disease-free period prior to screening exceeds 5 years.
• Participant is receiving anti-coagulation therapy or has a history of thrombotic episodes (including deep vein thrombosis, myocardial infarction, cerebrovascular accident, pulmonary embolism) within 12 months prior to screening or a history of thrombophilia.
• Participant has abnormal protein loss (protein losing enteropathy, nephrotic syndrome).
• Participant has anemia that would preclude phlebotomy for laboratory studies according to standard practice at the site.
• Participant has an ongoing history of hypersensitivity or persistent reactions (urticaria, breathing difficulty, severe hypotension, or anaphylaxis) following IV immunoglobulin, SC immunoglobulin, and/or Immune Serum Globulin (ISG) infusions.
• Participant has immunoglobulin A (IgA) deficiency (IgA less than 0.07 g/L), known anti IgA antibodies, and a history of hypersensitivity.
• Participant is on preventative (prophylactic) systemic antibacterial antibiotics at doses sufficient to treat or prevent bacterial infections, and cannot stop these antibiotics at the time of screening.
• Participant has active infection and is receiving antibiotic therapy for the treatment of infection at the time of screening.
• Participant has a bleeding disorder, or a platelet count less than 20,000/ microliter (mcL), or, in the opinion of the investigator, would be at significant risk of increased bleeding or bruising as a result of subcutaneous therapy.
• Participant has total protein > 9 gram per deciliter (g/dL) or myeloma, or macroglobulinemia (IgM) or paraproteinemia.

• Women of childbearing potential meeting any one of the following criteria:

  • Participant presents with a positive pregnancy test.
  • Participant is breast feeding.
  • Participant intends to begin nursing during the course of the study.
  • Participant does not agree to employ adequate birth-control measures (e.g. intrauterine device, diaphragm or condom [for male partner] with spermicidal jelly or foam, or birth control pills/patches) throughout the course of the study.
• Participant has participated in another clinical study and has been exposed to an IP or device within 30 days prior to study enrollment.
• Participant is scheduled to participate in another non-observational (interventional) clinical study involving an IP or device during the course of the study.
• Participant has severe dermatitis that would preclude adequate sites for safe product administration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Epoch 1: IGIV 200-600 mg/kg; Participants received 200 to 600 mg/kg of Immunoglobulin Intravenous (IGIV) infusion for every 3 or 4 weeks for up to 13 weeks.	Biological: Immune Globulin Intravenous (IGIV); Participants will receive IGIV infusion.; Other Names: Immune Globulin Infusion (Human)
Experimental: Epoch 2: IGSC (20%) 50-200 mg/kg; Participants who entered to Epoch 2 from Epoch 1 received 50-200 mg/kg of Immune Globulin Subcutaneous (Human) 20% infusion once a week up to approximately 24 weeks after Epoch 1.	Biological: Immune Globulin Subcutaneous, 20% Solution (IGSC, 20%); Participants will receive IGSC, 20% SC infusion.; Other Names: Immune Globulin Infusion (Human)
Experimental: Epoch 3: IGSC (20%) 100-400 mg/kg; Participants who entered to Epoch 3 from Epoch 1 received 100-400 mg/kg of Immune Globulin Subcutaneous (Human) 20% infusion biweekly up to approximately 12 weeks after Epoch 2.	Biological: Immune Globulin Subcutaneous, 20% Solution (IGSC, 20%); Participants will receive IGSC, 20% SC infusion.; Other Names: Immune Globulin Infusion (Human)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Epoch 2: Total Serum Trough Levels of Immune Globulin G (IgG) Antibodies During Period 2	Total serum trough levels of IgG antibodies measured during period 2 of Epoch 2 were assessed.	Epoch 2 (period 2): Up to 24 weeks
Epoch 3: Total Serum Trough Levels of IgG Antibodies	Total serum trough levels of IgG antibodies measured during Epoch 3 were assessed.	Epoch 3: Up to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Epoch 1: Total Serum Trough Levels of IgG Antibodies	Total serum trough levels of IgG antibodies measured during Epoch 1 were assessed.	Epoch 1: Up to Week 13
Epoch 2: Area Under the Curve From Time 0 to Last Interval (AUC0-last) for Total Serum Levels of IgG		Epoch 2: Week 21
Epoch 2: AUC0-last for Total Serum Levels of IgG Subclasses	Total serum levels of IgG subclasses IgG 1, IgG 2, IgG 3, and IgG 4 were determined.	Epoch 2: Week 21
Epoch 2: Apparent Clearance (CL/F) for Total Serum Levels of IgG		Epoch 2: Week 21
Epoch 2: CL/F for Total Serum Levels of IgG Subclasses	Total serum levels of IgG subclasses IgG 1, IgG 2, IgG 3, and IgG 4 were determined.	Epoch 2: Week 21
Epoch 2: Maximum Concentration (Cmax) for Total Serum Levels of IgG		Epoch 2: Week 21
Epoch 2: Cmax for Total Serum Levels of IgG Subclasses	Total serum levels of IgG subclasses IgG 1, IgG 2, IgG 3, and IgG 4 were determined.	Epoch 2: Week 21
Epoch 2: Minimum Concentration (Cmin) for Total Serum Levels of IgG		Epoch 2: Week 21
Epoch 2: Cmin for Total Serum Levels of IgG Subclasses	Total serum levels of IgG subclasses IgG 1, IgG 2, IgG 3, and IgG 4 were determined.	Epoch 2: Week 21
Epoch 2: Time to Maximum Concentration (Tmax) for Total Serum Levels of IgG		Epoch 2: Week 21
Epoch 2: Tmax for Total Serum Levels of IgG Subclasses	Total serum levels of IgG subclasses IgG 1, IgG 2, IgG 3, and IgG 4 were determined.	Epoch 2: Week 21
Trough Levels of Specific Antibodies to Clinically Relevant Pathogens: Clostridium Tetani Toxoid and Hepatitis B Virus (HBV)	Trough levels of specific antibodies to clinically relevant pathogen (Clostridium tetani toxoid and HBV) were assessed in Epoch 1, Epoch 2 and Epoch 3. Data was analyzed per interval in each Epoch for this outcome measure.	Epoch 1 (Week 1); Epoch 2 (Week 1, 24); Epoch 3 (Week 1, 13)
Trough Levels of Specific Antibodies to Clinically Relevant Pathogen: Haemophilus Influenzae (HIB)	Trough levels of specific antibodies to clinically relevant pathogens (HIB) were assessed in Epoch 1, Epoch 2, and Epoch 3. Data was analyzed per interval in each Epoch for this outcome measure.	Epoch 1 (Week 1); Epoch 2 (Week 1, 24); Epoch 3 (Week 1, 13)
Health Related Quality of Life: Treatment Preference	Treatment preference questionnaire is a self-administered questionnaire developed to assess participants' preference towards the administration of new IGSC therapy. There are 4-items on the questionnaire, which investigate a participant's preference on the clinic/hospital/home setting of receiving the immunoglobulin therapy, the participant's rating on the frequency and method of administration, and the participant's preference to continue receiving the IGSC treatment. The questionnaire included following categories: Where do you prefer to receive your immunoglobulin therapy, The frequency of administration, as pre-specified in protocol, data is reported as per age (2-13 years and >=14 years).	Up to approximately 1.5 years
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	TEAEs was defined as adverse events (AEs) with onset after date-time of first dose of study drug, or medical conditions present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP. Any TEAE that is recorded by the investigator as "possibly related" or "probably related" to IP was considered as IGSC, 20%-related AE, and any AE recorded as "unlikely related" or "not related" was considered as unrelated AE. AEs included vital signs, clinical laboratory measurements.	From first dose of study drug up to end of study (up to approximately 1.5 years)
Number of Participants With Tolerability Events Related to the Infusion of Study Drug	An infusion is considered tolerable if the infusion rate was not reduced, or the infusion was not interrupted or stopped, due to TEAE related to study drug (IGIV or IGSC) infusion. A tolerability event is considered to have occurred if an infusion was not tolerable in Epoch 1, Epoch 2 and Epoch 3. Number of participants with tolerability events related to infusion of IP were assessed.	From first dose of study drug up to end of study (up to approximately 1.5 years)
Annual Rate of Validated Acute Serious Bacterial Infections (ASBI)	The ASBI rate was calculated as the mean number of acute serious bacterial infections per participants per year. Annual rate of validated acute serious bacterial infections per participant was assessed.	From first dose of study drug up to end of study (up to approximately 1.5 years)
Annual Rate of All Infections Per Year	Annual rate is the number of participants reporting any infection per year.	From first dose of study drug up to end of study (up to approximately 1.5 years)
Number of Days Participants Not Able to Attend School or Work to Perform Normal Daily Activities Due to Illness/Infection	Number of days not able to attend school or work to perform normal daily activities due to illness/infection are standardized per year (365.25 days). The number of days not able to attend school or work to perform normal daily activities due to illness/infection were assessed.	From first dose of study drug up to end of study (up to approximately 1.5 years)
Number of Days Participants Were on Antibiotics	Number of days on antibiotics is defined as the number of days those antibiotics were taken as concomitant medications and is standardized to per year (365.25 days). Antibiotics are defined as any medication under anatomical therapeutic chemical Level 2 therapeutic class "ANTIBACTERIALS FOR SYSTEMIC USE". If a participant took multiple antibiotics on a single day, that day is counted for only once. Protocol defined prophylactic antibiotics for viral, fungal or protozoal infections (e.g. trimethoprim/sulfamethoxazole twice a week for pneumocystis) which are not treated by immunoglobulin, were excluded from this analysis.	From first dose of study drug up to end of study (up to approximately 1.5 years)
Number of Participants Hospitalized Due to Illness or Infection	Number of participants with hospitalization are standardized to per year (365.25 days). A hospitalization is counted for a specific epoch only if that hospitalization started during that epoch.	From first dose of study drug up to end of study (up to approximately 1.5 years)
Length of Hospital Stay	Length of hospital stay per stay is standardized to per year (365.25 days). A hospitalization is counted for a specific epoch only if that hospitalization started during that epoch.	From first dose of study drug up to end of study (up to approximately 1.5 years)
Number of Acute Physician Visits Due to Illness/Infection	Number of acute physician visits is standardized to per year (365.25 days).	From first dose of study drug up to end of study (up to approximately 1.5 years)
Health-related Quality of Life (HRQoL): Pediatric Quality of Life Inventory (PedsQL) Total Scale Score	Peds-QL=generic HR QoL instrument designed specifically for pediatrics has domains as:general health/activities,feelings/emotional,social functioning,school functioning.In this study,2-7 years (parent as observer),8-13 years (participant as observer) for Peds-QL health questionnaire was analyzed.Higher scores=better QOL for all domains.This modular instrument used 5-point scale:0(never) to 4(almost always).Items are reversed scored;linearly transformed to 0-100 scale as follows:0=100,1=75,2=50,3=25,4=0.4 dimensions(physical, emotional, social, & school functioning) are scored.PEDS-QL Total Scale Score has 0-100 scale,higher scores=better HRQoL.	Baseline up to end of study (approximately 1.5 years)
EuroQoL (Quality of Life)-5 Dimensions 3 Levels (EQ-5D-3L) Total Scale Score	EQ-5D-3L health questionnaire=participant answered questionnaire scoring 5 dimensions -mobility,self-care,usual activities, pain/discomfort and anxiety/depression. n this study, 2-11 years (parent as observer),12 years and older (participant as observer) for EQ-5D-3L health questionnaire was analyzed.Health state index score range from 0 (worst health state) to 1 (perfect health state) and 1 reflects the best outcome.EQ visual analogue scale range from 0 to 100, where higher scores indicate better health status.Data is reported as per age groups (2-11 years and >=12 years).	Baseline up to end of the study (approximately 1.5 years)
Health-related Quality of Life (HRQoL): Short Form-36 Health Survey (SF-36) Score	SF-36=generic quality-of-life instrument that has been widely used to assess HRQL of participants.In this study, 14 years and older (participant as observer) for SF-36 health questionnaire was analyzed. Generic instruments are used in general populations to assess a wide range of domains applicable to a variety of health states, conditions, and diseases.SF-36=36 items aggregated into 8 multi-item scales (physical functioning, role - physical, bodily pain, general health, vitality, social functioning, role - emotional, and mental health), with scores ranging from 0 to 100.Higher scores=better HRQL. As pre-specified in protocol data is reported for participants with age group of 14 years or older.	Baseline up to end of the study (approximately 1.5 years)
Health Related Quality of Life: Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) Score	TSQM=is a global satisfaction scale used to assess the overall level of participant's satisfaction or dissatisfaction with their medications. In this study, 2-12 years (parent as observer), 13 years and older (participant as observer) for TSQM health questionnaire will be analyzed. TSQM-9 is a 9-item, validated, self-administered instrument used to assess participant's satisfaction with medication. The three domains assessed are effectiveness, convenience, and global satisfaction. The score of each of the 3 domains is based on an algorithm to create a score of 0 to 100. Higher score indicated greater satisfaction in that domain. As pre-specified in protocol, data is reported as per age group (2-12 years and >=13 years).	Baseline up to end of the study (approximately 1.5 years)
Health Related Quality of Life: Treatment Satisfaction Questionnaire for Life Quality Index (LQI) Score	LQI=self-administered questionnaire developed specifically for participants/legal guardians involved in IGIV treatments.2-13 years (parent as observer),14 years and older (participant as observer) for LQI health questionnaire was analyzed.LQI=15-items, divided into 4 domains: treatment interferences(TI)[6 items],therapy-related problems(TRP)[4 items],therapy setting(TS)[3 items];treatment costs(TC)[2 items].Items are rated on a 7-point Likert-type scale ranging from 1:"Extremely bad" to 7:"Extremely good".Total scores=0 to 100,higher scores=highest possible satisfaction with factors such as independence,therapy convenience,social/school/work activities;health and travel costs.As pre-specified in protocol, data is reported as per age (2-13 years and >=14 years).All-Treated Set included all enrolled participants of age group '2-13 years' and '>=14 years' who received at least 1 dose of study drug (IGIV or IGSC).'n'=Number analysed are participants with data available for analysis.	Baseline up to end of the study (approximately 1.5 years)

Collaborators and Investigators

• Sponsor: Baxalta now part of Shire
• Investigators: Study Director: Study Director, Shire

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2020
• Primary Completion (Actual): December 22, 2021
• Study Completion (Actual): December 22, 2021

Study Registration Dates

• First Submitted: April 10, 2020
• First Submitted That Met QC Criteria: April 10, 2020
• First Posted (Actual): April 15, 2020

Study Record Updates

• Last Update Posted (Actual): March 22, 2024
• Last Update Submitted That Met QC Criteria: September 21, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Genetic Diseases, Inborn; Immunologic Deficiency Syndromes; Primary Immunodeficiency Diseases; Physiological Effects of Drugs; Immunologic Factors; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous; gamma-Globulins; Rho(D) Immune Globulin; Immunoglobulin G
• Other Study ID Numbers: TAK-664-3001; JapicCTI-205162 (Registry Identifier: JapicCTI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No