Efficacy, Pharmacokinetics, Safety, and Tolerability of IGSC 20% in Subjects With Primary Immunodeficiency

• Sponsor: Grifols Therapeutics LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02806986
• Collaborator: (none)
• Enrollment: 61
• Locations: 23
• Arm: 1
• Actual Duration (Months): 35.4
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Approximately 60 subjects will be enrolled in order to have approximately 20 adult subjects and 20 pediatric subjects treated with subcutaneously administered Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) who complete the entire study. This study will include 3 study stages: Screening/Previous Regimen Phase, IGSC 20% Treatment Stage 1 (13 IGSC 20% weekly doses), and IGSC 20% Treatment Stage 2 (39 IGSC 20% weekly doses). A total of 52 doses of IGSC 20% will be administered with a final follow-up visit 1 week after the last dose at Week 53. Subjects/caregivers will be trained on self-administration of IGSC 20% by the clinical site personnel.

Condition or Disease	Intervention/Treatment	Phase
Primary Immunodeficiency	Biological: IGSC 20%	Phase 3

Detailed Description

This is a prospective, multi-center, open-label, single-arm, efficacy, PK, safety and tolerability study of IGSC 20% in subjects with PI. Approximately 60 subjects will be enrolled in order to have approximately 20 adult subjects and 20 pediatric subjects treated with subcutaneously administered IGSC 20% who complete the entire study.

This study will include 3 study stages: Screening/Previous Regimen Phase, IGSC 20% Treatment Stage 1 (13 IGSC 20% weekly doses), and IGSC 20% Treatment Stage 2 (39 IGSC 20% weekly doses).

Previous Regimen Phase: Subjects will be infused with their current ongoing ("previous regimen") intravenous immune globulin/subcutaneous immune globulin (IVIG/SCIG) regimen (pIV/pSC) in the clinic to obtain 2 trough immunoglobulin G (IgG) levels (obtained prior to each pIV/pSC infusion) on each subject's "previous regimen".

20% IGSC Treatment Stage 1: The first dose of IGSC 20% will be administered at the clinical site immediately after Baseline assessments are complete (SC#1). All subjects will receive 13 IGSC 20% infusions at weekly intervals. IgG trough blood levels will be measured at all (except SC#3) study visits All other doses of IGSC 20% may be infused at home (once properly trained) or in the clinic. The Treatment Stage 1 dose will continue into IGSC 20% Treatment Stage 2.

IGSC 20% Treatment Stage 2: The IGSC 20% dose (mg/kg) will remain constant with no dose adjustment permitted in this phase, unless it is absolutely medically necessary. While all subjects will have a SC#17 clinic visit and standard assessments, serial pharmacokinetics (PK) sampling will only be performed in a subset of adult subjects:

Study Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-Center, Open-Label, Single-Arm Trial to Evaluate Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects With Primary Immunodeficiency
• Actual Study Start Date: Jun 1, 2016
• Actual Primary Completion Date: May 15, 2019
• Actual Study Completion Date: May 15, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IGSC 20% 13 doses of IGSC 20% in Treatment Stage 1 and 39 doses of IGSC 20% in Treatment Stage 2 for a total of 52 doses if IGSC 20%	Biological: IGSC 20%; Weekly administration of IGSC 20% via intravenous infusion; Other Names: Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography

Outcome Measures

Primary Outcome Measures

1. Rate of Serious Bacterial Infection (SBI) Per Participant Per Year [IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53]

   The rate of SBI events per participant per year during IGSC 20% treatment was calculated as the total number of SBI events divided by the total duration of exposure in years across all participants. The 2-sided 98% confidence interval (CI) was determined from a generalized linear model for poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable.

Secondary Outcome Measures

1. Mean Trough Total IgG Concentration [Previous Regimen Phase: 2 timepoints pre-dose of pIV or pSC between Screening and Baseline (up to 8 weeks). IGSC 20% Phase: Pre-dose of IGSC 20% at Baseline (Week 1), Weeks 2, 5, 9, 13, 17, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Week 53]

   Mean trough total IgG concentration during the previous regimen phase was calculated as the average of the trough concentrations at the previous IVIG (pIV)#1 and pIV#2 visits for participants entering the study on a previous IVIG regimen, or at the previous subcutaneous immune globulin (SCIG) (pSC)#1 and baseline/SC#1 visits for participants entering the study on a previous SCIG regimen. Mean trough total IgG concentration during the IGSC 20% phase was calculated as the average of all steady state trough concentrations measured during the IGSC 20% treatment stage 2 at the visits corresponding to Weeks 17, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 53.

2. Rate of Infection of Any Kind Per Participant Per Year [IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53]

   The total number of infections of any kind (serious/non-serious including acute sinusitis, exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, infectious diarrhea, etc.) as determined by the investigator were evaluated. The rate of infection events per participant per year during IGSC 20% treatment was calculated as the total number of infection events divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable.

3. Rate of Days on Antibiotics Per Participants Per Year [IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53]

   The rate of days on antibiotics per participants per year during IGSC 20% treatment was calculated as the total number of days on antibiotic divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log transformed number of days with log-transformed duration of exposure in years as an offset variable.

4. Rate of Hospitalization Due to Infection Per Participants Per Year [IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53]

   The rate of hospitalization due to infection events per participant per year during IGSC 20% treatment was calculated as the total number of hospitalization due to infection events divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable.

5. Rate of Days of Work/School/Daily Activities Missed Per Participants Per Year Due to Infections and Related Treatment [IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53]

   The rate of days of work, school or daily activities missed per participant per year during IGSC 20% treatment was calculated as the total number of days of work/school/daily activities missed divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log-transformed number of days with log transformed duration of exposure in years as an offset variable.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Pre-existing diagnosis of PI with features of hypogammaglobulinemia requiring IgG replacement therapy

• No serious bacterial infection within the 3 months prior to Screening and has no serious bacterial infections (SBIs) up to the time of the Baseline Visit

• Currently on IgG replacement therapy (stable regimen [dose and dosing interval] via IV or SC infusion) for ≥ 3 consecutive months at a dosage of at least 200 mg/kg per infusion

• Documented (within previous 3 months) of an IgG trough level of ≥ 500 mg/dL on current IgG replacement therapy regimen

• Screening/pre-Baseline trough IgG levels must be ≥ 500 mg/dL.

Exclusion Criteria:

• Known serious adverse reaction to immunoglobulin or any severe anaphylactic reaction to blood or any blood-derived product

• History of blistering skin disease, clinically significant thrombocytopenia, bleeding disorder, diffuse rash, recurrent skin infections, or other disorders where SC therapy would be contraindicated during the study

• Isolated IgG subclass deficiency, isolated specific antibody deficiency disorder, or transient hypogammaglobulinemia of infancy

• Nephrotic syndrome, and/or a history of acute renal failure, and/or severe renal impairment, and/or is on dialysis

• Known previous infection with or clinical signs and symptoms consistent with current hepatitis B virus or hepatitis C virus infection

• History of (year prior to Screening or 2 episodes in lifetime) or current diagnosis of deep venous thrombosis or thromboembolism (e.g., myocardial infarction, cerebrovascular accident, or transient ischemic attack)

• Acquired medical condition known to cause secondary immune deficiency, such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, chronic or recurrent neutropenia (absolute neutrophil count less than 1000/μL [1.0 x 10^9/L]), or human immunodeficiency virus infection/acquired immune deficiency syndrome

• HIV positive by nucleic acid amplification technology based on a Screening blood sample

• Uncontrolled arterial hypertension (adult subjects: systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 100 mmHg)

• Receiving any of the following medications: (a) immunosuppressants including chemotherapeutic agents, (b) immunomodulators, (c) long-term systemic corticosteroids defined as daily dose > 1 mg of prednisone equivalent/kg/day for > 30 days Note: Intermittent courses of corticosteroids of not more than 10 days would not exclude a subject. Inhaled or topical corticosteroids are allowed.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Wesley Medical Research	Auchenflower		Australia	4066
2	Royal Melbourne Hospital	Parkville		Australia	3050
3	University Hospital	Hradec Kralove		Czechia	50005
4	CHU de Montpellier	Montpellier		France	34295
5	Klinikum Dortmund gGmbH	Dortmund		Germany	44137
6	Universitätsklinikum Hamburg-Eppendorf	Hamburg		Germany	20246
7	Children's Hospital at Municipal Hospital St. Georg	Leipzig		Germany	04129
8	University Hospital of Mainz	Mainz		Germany	55131
9	Asklepios Klinik Sankt Augustin	Sankt Augustin		Germany	53757
10	United St Istvan and St Laszlo Hospital	Budapest		Hungary
11	Josa Andras County Hospital	Nyiregyháza		Hungary	H-4400
12	The Children's Memorial Health Institute	Warsaw		Poland	4736
13	Hospital Universitario Vall d'Hebron	Barcelona		Spain	08025
14	Vall d'Hebron University Hospital	Barcelona		Spain	08035
15	Hospital Universitari Sant Joan de Déu	Barcelona		Spain	08950
16	Hospital Universitario Reina Sofia	Cordoba		Spain	14004
17	Hospital Clinico San Carlos	Madrid		Spain	28040
18	Hospital 12 Octubre	Madrid		Spain	28041
19	Hospital Virgen del Rocio	Sevilla		Spain	41013
20	Stockholm	Stockholm		Sweden	SE-14186
21	Addenbrooke's Hospital	Cambridge		United Kingdom	CB2 0QQ
22	St Bartholomew's Hospital	London		United Kingdom	E1 2ES
23	Derriford Hospital	Plymouth		United Kingdom	PL6 8DH

Sponsors and Collaborators

• Grifols Therapeutics LLC

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 22, 2016
• Statistical Analysis Plan - Jul 16, 2019

More Information

Publications

None provided.

• Responsible Party: Grifols Therapeutics LLC
• ClinicalTrials.gov Identifier: NCT02806986
• Other Study ID Numbers: GTI1503; 2015-003290-15
• First Posted: Jun 21, 2016
• Last Update Posted: Jun 16, 2020
• Last Verified: Jun 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Immunoglobulins; gamma-Globulins; Immunoglobulins, Intravenous; Rho(D) Immune Globulin

Study Results

Participant Flow

Recruitment Details	Participants with primary immunodeficiency (PI) requiring IgG replacement were enrolled. Study has 3 stages: Screening/Previous Regimen Phase, Treatment Stage 1 and 2. Total 62 participants entered Previous Regimen Phase, of which 61 entered in Treatment Stage 1 to receive IGSC 20%. Study was conducted in 8 countries from June 2016 to May 2019.
Pre-assignment Detail	Participants had no SBI within last 3 months prior to screening and were on immunoglobulin G (IgG) replacement therapy (stable regimen via intravenous [IV] or subcutaneous [SC] infusion) for ≥3 consecutive months prior to screening. Participants receiving IVIG prior to study entry must have received a dosage of ≥200 mg/kg per infusion.

Arm/Group Title	IGSC 20%
Arm/Group Description	Following the previous regimen phase (screening), participants were enrolled to receive 13 immune globulin subcutaneous (human), 20% caprylate/chromatography purified (IGSC 20%) infusions at weekly intervals from baseline (Week 1) up to Week 13 in treatment stage 1. Participants were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 milligram per kilogram per week (mg/kg/week) if the derived 1:1 dose from the previous regimen was lower) and followed by 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52 in treatment stage 2. Dose adjustments were permitted per the study protocol and at the Investigator's discretion in the treatment stage 1. However, dose remained constant in treatment stage 2 unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor's Medical Monitor. A final follow-up visit occurred at Week 53.
Period Title: Treatment Stage 1
STARTED	61
COMPLETED	60
NOT COMPLETED	1
Period Title: Treatment Stage 1
STARTED	60
COMPLETED	55
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	IGSC 20%
Arm/Group Description	Following the previous regimen phase (screening), participants were enrolled to receive 13 IGSC 20% infusions at weekly intervals from baseline (Week 1) up to Week 13 in treatment stage 1. Participants were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower) and followed by 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52 in treatment stage 2. Dose adjustments were permitted per the study protocol and at the Investigator's discretion in the treatment stage 1. However, dose remained constant in treatment stage 2 unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor's Medical Monitor. A final follow-up visit occurred at Week 53.
Overall Participants	61
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.3 (19.97)
Sex: Female, Male (Count of Participants)
Female	19 31.1%
Male	42 68.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 16.4%
Not Hispanic or Latino	49 80.3%
Unknown or Not Reported	2 3.3%
Race/Ethnicity, Customized (Count of Participants)
White	57 93.4%
American Indian or Alaska Native	2 3.3%
Unknown	2 3.3%
Subject Entry Status (Count of Participants)
Entered on intravenous immune globulin (IVIG)	40 65.6%
Entered on subcutaneous immune globulin (SCIG)	21 34.4%

Outcome Measures

1. Primary Outcome

Title	Rate of Serious Bacterial Infection (SBI) Per Participant Per Year
Description	The rate of SBI events per participant per year during IGSC 20% treatment was calculated as the total number of SBI events divided by the total duration of exposure in years across all participants. The 2-sided 98% confidence interval (CI) was determined from a generalized linear model for poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable.
Time Frame	IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53

Outcome Measure Data

Analysis Population Description

Analysis was performed on the efficacy evaluable population which included all participants who received at least 1 dose of IGSC 20%.

Arm/Group Title	IGSC 20% Treatment Stage 1	IGSC 20% Treatment Stage 2	IGSC 20% Overall
Arm/Group Description	Following previous regimen phase (screening), participants were enrolled to receive 13 IGSC 20% infusions at weekly intervals from baseline (Week 1) up to Week 13. Participants were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower). Dose adjustments were permitted in this phase per the study protocol and at the Investigator's discretion.	Following treatment stage 1, participants received 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52. The IGSC 20% dose (mg/kg) remained constant with no dose adjustment permitted in this phase, unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor's Medical Monitor. A final follow-up visit occurred at Week 53.	Following previous regimen phase (screening), participants were enrolled to receive 13 IGSC 20% infusions at weekly intervals from baseline (Week 1) up to Week 13 in treatment stage 1. Participants were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower) and followed by 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52 in treatment stage 2. Dose adjustments were permitted per the study protocol and the at Investigator's discretion in the treatment stage 1. However, dose remained constant in treatment stage 2 unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor's Medical Monitor. A final follow-up visit occurred at Week 53.
Measure Participants	61	60	61
Number (98% Confidence Interval) [Rate of events per participant per year]	0	0.023	0.017

2. Secondary Outcome

Title	Mean Trough Total IgG Concentration
Description	Mean trough total IgG concentration during the previous regimen phase was calculated as the average of the trough concentrations at the previous IVIG (pIV)#1 and pIV#2 visits for participants entering the study on a previous IVIG regimen, or at the previous subcutaneous immune globulin (SCIG) (pSC)#1 and baseline/SC#1 visits for participants entering the study on a previous SCIG regimen. Mean trough total IgG concentration during the IGSC 20% phase was calculated as the average of all steady state trough concentrations measured during the IGSC 20% treatment stage 2 at the visits corresponding to Weeks 17, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 53.
Time Frame	Previous Regimen Phase: 2 timepoints pre-dose of pIV or pSC between Screening and Baseline (up to 8 weeks). IGSC 20% Phase: Pre-dose of IGSC 20% at Baseline (Week 1), Weeks 2, 5, 9, 13, 17, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Week 53

Outcome Measure Data

Analysis Population Description

Analysis was performed on the IgG population which consisted of all participants who received any amount of IGSC 20% and had total IgG concentration data to facilitate the comparison of mean trough IgG concentration during the IGSC 20% phase versus the pre-treatment phase.

Arm/Group Title	IGSC 20% Overall	Previous Regimen
Arm/Group Description	Following previous regimen phase (screening), participants were enrolled to receive 13 IGSC 20% infusions at weekly intervals from baseline (Week 1) up to Week 13 in treatment stage 1. Participants were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower) and followed by 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52 in treatment stage 2. Dose adjustments were permitted per the study protocol and the at Investigator's discretion in the treatment stage 1. However, dose remained constant in treatment stage 2 unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor's Medical Monitor. A final follow-up visit occurred at Week 53.	Participants were required to attend the clinic for infusion with their previous ongoing ("previous regimen") IVIG/SCIG regimen (pIV/pSC) to obtain 2 trough IgG levels (obtained prior to each pIV/pSC infusion) on each participant's "previous regimen". Trough levels for total IgG determined during the Previous Regimen Phase were used to confirm final eligibility for participants entering the study to receive treatment with IGSC 20% (must be ≥500 milligrams per deciliter [mg/dL]).
Measure Participants	59	59
Mean (Standard Deviation) [milligram per deciliter (mg/dL)]	947.64 (150.262)	891.37 (165.943)

3. Secondary Outcome

Title	Rate of Infection of Any Kind Per Participant Per Year
Description	The total number of infections of any kind (serious/non-serious including acute sinusitis, exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, infectious diarrhea, etc.) as determined by the investigator were evaluated. The rate of infection events per participant per year during IGSC 20% treatment was calculated as the total number of infection events divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable.
Time Frame	IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53

Outcome Measure Data

Analysis Population Description

Analysis was performed on the efficacy evaluable population which included all participants who received at least 1 dose of IGSC 20%.

Arm/Group Title	IGSC 20% Treatment Stage 1	IGSC 20% Treatment Stage 2	IGSC 20% Overall
Arm/Group Description	Following previous regimen phase (screening), participants were enrolled to receive 13 IGSC 20% infusions at weekly intervals from baseline (Week 1) up to Week 13. Participants were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower). Dose adjustments were permitted in this phase per the study protocol and at the Investigator's discretion.	Following treatment stage 1, participants received 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52. The IGSC 20% dose (mg/kg) remained constant with no dose adjustment permitted in this phase, unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor's Medical Monitor. A final follow-up visit occurred at Week 53.	Following previous regimen phase (screening), participants were enrolled to receive 13 IGSC 20% infusions at weekly intervals from baseline (Week 1) up to Week 13 in treatment stage 1. Participants were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower) and followed by 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52 in treatment stage 2. Dose adjustments were permitted per the study protocol and the at Investigator's discretion in the treatment stage 1. However, dose remained constant in treatment stage 2 unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor's Medical Monitor. A final follow-up visit occurred at Week 53.
Measure Participants	61	60	61
Number (95% Confidence Interval) [Rate of events per participant per year]	2.524	2.353	2.397

4. Secondary Outcome

Title	Rate of Days on Antibiotics Per Participants Per Year
Description	The rate of days on antibiotics per participants per year during IGSC 20% treatment was calculated as the total number of days on antibiotic divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log transformed number of days with log-transformed duration of exposure in years as an offset variable.
Time Frame	IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53

Outcome Measure Data

Analysis Population Description

Analysis was performed on the efficacy evaluable population which included all participants who received at least 1 dose of IGSC 20%.

Arm/Group Title	IGSC 20% Treatment Stage 1	IGSC 20% Treatment Stage 2	IGSC 20% Overall
Arm/Group Description	Following previous regimen phase (screening), participants were enrolled to receive 13 IGSC 20% infusions at weekly intervals from baseline (Week 1) up to Week 13. Participants were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower). Dose adjustments were permitted in this phase per the study protocol and at the Investigator's discretion.	Following treatment stage 1, participants received 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52. The IGSC 20% dose (mg/kg) remained constant with no dose adjustment permitted in this phase, unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor's Medical Monitor. A final follow-up visit occurred at Week 53.	Following previous regimen phase (screening), participants were enrolled to receive 13 IGSC 20% infusions at weekly intervals from baseline (Week 1) up to Week 13 in treatment stage 1. Participants were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower) and followed by 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52 in treatment stage 2. Dose adjustments were permitted per the study protocol and the at Investigator's discretion in the treatment stage 1. However, dose remained constant in treatment stage 2 unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor's Medical Monitor. A final follow-up visit occurred at Week 53.
Measure Participants	61	60	61
Prophylactic Antibiotic	43.240	44.846	44.432
Therapeutic Antibiotics	13.085	7.451	8.904

5. Secondary Outcome

Title	Rate of Hospitalization Due to Infection Per Participants Per Year
Description	The rate of hospitalization due to infection events per participant per year during IGSC 20% treatment was calculated as the total number of hospitalization due to infection events divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable.
Time Frame	IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53

Outcome Measure Data

Analysis Population Description

Analysis was performed on the efficacy evaluable population which included all participants who received at least 1 dose of IGSC 20%.

Arm/Group Title	IGSC 20% Treatment Stage 1	IGSC 20% Treatment Stage 2	IGSC 20% Overall
Arm/Group Description	Following previous regimen phase (screening), participants were enrolled to receive 13 IGSC 20% infusions at weekly intervals from baseline (Week 1) up to Week 13. Participants were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower). Dose adjustments were permitted in this phase per the study protocol and at the Investigator's discretion.	Following treatment stage 1, participants received 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52. The IGSC 20% dose (mg/kg) remained constant with no dose adjustment permitted in this phase, unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor's Medical Monitor. A final follow-up visit occurred at Week 53.	Following previous regimen phase (screening), participants were enrolled to receive 13 IGSC 20% infusions at weekly intervals from baseline (Week 1) up to Week 13 in treatment stage 1. Participants were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower) and followed by 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52 in treatment stage 2. Dose adjustments were permitted per the study protocol and the at Investigator's discretion in the treatment stage 1. However, dose remained constant in treatment stage 2 unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor's Medical Monitor. A final follow-up visit occurred at Week 53.
Measure Participants	61	60	61
Number (95% Confidence Interval) [Rate of events per person per year]	0	0.023	0.017

6. Secondary Outcome

Title	Rate of Days of Work/School/Daily Activities Missed Per Participants Per Year Due to Infections and Related Treatment
Description	The rate of days of work, school or daily activities missed per participant per year during IGSC 20% treatment was calculated as the total number of days of work/school/daily activities missed divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log-transformed number of days with log transformed duration of exposure in years as an offset variable.
Time Frame	IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53

Outcome Measure Data

Analysis Population Description

Analysis was performed on the efficacy evaluable population which included all participants who received at least 1 dose of IGSC 20%.

Arm/Group Title	IGSC 20% Treatment Stage 1	IGSC 20% Treatment Stage 2	IGSC 20% Overall
Arm/Group Description	Following previous regimen phase (screening), participants were enrolled to receive 13 IGSC 20% infusions at weekly intervals from baseline (Week 1) up to Week 13. Participants were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower). Dose adjustments were permitted in this phase per the study protocol and at the Investigator's discretion.	Following treatment stage 1, participants received 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52. The IGSC 20% dose (mg/kg) remained constant with no dose adjustment permitted in this phase, unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor's Medical Monitor. A final follow-up visit occurred at Week 53.	Following previous regimen phase (screening), participants were enrolled to receive 13 IGSC 20% infusions at weekly intervals from baseline (Week 1) up to Week 13 in treatment stage 1. Participants were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower) and followed by 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52 in treatment stage 2. Dose adjustments were permitted per the study protocol and the at Investigator's discretion in the treatment stage 1. However, dose remained constant in treatment stage 2 unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor's Medical Monitor. A final follow-up visit occurred at Week 53.
Measure Participants	61	60	61
Number (95% Confidence Interval) [Rate of days missed per person per year]	4.118	5.283	4.983

Adverse Events

Time Frame	Treatment-emergent adverse events (TEAEs) were collected from the beginning of treatment administration with IGSC 20% (Baseline/Week 1) until the Final Visit (Week 53). Up to 1 year overall.
Adverse Event Reporting Description	TEAEs are presented for the safety population which included all participants who received any amount of IGSC 20%.
Arm/Group Title	IGSC 20% Overall
Arm/Group Description	Following previous regimen phase (screening), participants were enrolled to receive 13 IGSC 20% infusions at weekly intervals from baseline (Week 1) up to Week 13 in treatment stage 1. Participants were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower) and followed by 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52 in treatment stage 2. Dose adjustments were permitted per the study protocol and the at Investigator's discretion in the treatment stage 1. However, dose remained constant in treatment stage 2 unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor's Medical Monitor. A final follow-up visit occurred at Week 53.
All Cause Mortality
	IGSC 20% Overall
	Affected / at Risk (%)	# Events
Total	0/61 (0%)
Serious Adverse Events
	IGSC 20% Overall
	Affected / at Risk (%)	# Events
Total	7/61 (11.5%)
Blood and lymphatic system disorders
Thrombocytopenia	1/61 (1.6%)
Cardiac disorders
Aortic valve incompetence	1/61 (1.6%)
General disorders
Medical device site joint pain	1/61 (1.6%)
Infections and infestations
Urinary tract infection	1/61 (1.6%)
Pneumonia	1/61 (1.6%)
Injury, poisoning and procedural complications
Joint dislocation	1/61 (1.6%)
Renal and urinary disorders
Nephrotic syndrome	1/61 (1.6%)
Other (Not Including Serious) Adverse Events
	IGSC 20% Overall
	Affected / at Risk (%)	# Events
Total	49/61 (80.3%)
Gastrointestinal disorders
Diarrhoea	6/61 (9.8%)
Vomiting	5/61 (8.2%)
Nausea	4/61 (6.6%)
General disorders
Infusion site erythema	10/61 (16.4%)
Infusion site pruritus	8/61 (13.1%)
Pyrexia	7/61 (11.5%)
Infusion site pain	5/61 (8.2%)
Infusion site swelling	4/61 (6.6%)
Infections and infestations
Nasopharyngitis	12/61 (19.7%)
Upper respiratory tract infection	9/61 (14.8%)
Bronchitis	8/61 (13.1%)
Rhinitis	7/61 (11.5%)
Sinusitis	7/61 (11.5%)
Gastroenteritis	6/61 (9.8%)
Lower respiratory tract infection	5/61 (8.2%)
Influenza	4/61 (6.6%)
Viral infection	4/61 (6.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/61 (8.2%)
Back pain	4/61 (6.6%)
Respiratory, thoracic and mediastinal disorders
Cough	9/61 (14.8%)
Headache	7/61 (11.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Site may publish results from the Study, after providing Sponsor thirty days' notice prior to submitting a manuscript or other materials related to the Study to any outside party. At Sponsors' request, Site will remove any Confidential Information (other than Study results), and Site will upon Sponsors' request, delay publication or presentation for a period of up to one hundred twenty days to allow Sponsor to protect its interests in any Sponsor Inventions.