Follow-up Study of Subcutaneous Immune Globulin in Patients Requiring IgG Replacement Therapy (Japan Study)

• Sponsor: CSL Behring (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01458171
• Collaborator: (none)
• Enrollment: 23
• Locations: 9
• Arm: 1
• Duration (Months): 12
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The objective of this study is to assess the long-term safety, tolerability, and efficacy of IgPro20 in subjects with primary immunodeficiency (PID) as a follow-up to the pivotal study ZLB06_002CR (NCT01199705).

Condition or Disease	Intervention/Treatment	Phase
Primary Immune Deficiency Disorder	Biological: Immune globulin subcutaneous (Human)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter Follow-up Study of Long-term Safety, Tolerability, and Efficacy of Immune Globulin Subcutaneous (Human) IgPro20 in Subjects With Primary Immunodeficiency
• Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IgPro20	Biological: Immune globulin subcutaneous (Human); IgPro20 is a 20% (weight per volume [w/v]) liquid formulation of human immunoglobulin for subcutaneous (SC) use. Subjects will receive weekly infusions of IgPro20 for a total of 24 weeks at a dose based on the subject's IgPro20 dose in the pivotal study ZLB06_002CR (NCT01199705).; Other Names: Hizentra

Outcome Measures

Primary Outcome Measures

1. Median of the Individual Subject's Rate of Adverse Events (AEs) Per Infusion [24 weeks]

   The rate was calculated by counting all newly developed or worsened AEs within a subject and dividing by the total number of IgPro20 infusions administered to this subject. Subsequently, the median of these individual AE rates per infusion was calculated. AE rates were classified (i) by severity (mild, moderate, severe) and (ii) by causal relationship to study medication (not related or unlikely related; at least possibly related [i.e., possibly related, probably related, or related]).

Secondary Outcome Measures

1. Overall Rate of AEs Per Infusion [24 weeks]

   The rate was calculated by counting all newly developed or worsened AEs during the treatment period in all subjects and dividing the total number of AEs by the total number of IgPro20 infusions administered. In addition, individual AEs were classified (i) by severity (mild, moderate, severe) and (ii) by causal relationship to study medication (not related or unlikely related; at least possibly related [i.e., possibly related, probably related, or related]). The AE rates per infusion by severity and causal relationship to study medication were calculated by dividing the number of AEs in each category by the total number of IgPro20 infusions.

2. Number of Subjects With Newly Developing or Worsening AEs [24 weeks]

   Number of subjects with AEs, overall and classified (i) by severity (mild, moderate, severe) and (ii) by causal relationship to study medication (not related or unlikely related; at least possibly related [i.e., possibly related, probably related, or related]).

3. Percentage of Infusions With Subject-assessed Tolerability of at Least 'Good' [24 to 72 hours after infusion]

   Subjects assessed their overall perception of local tolerability at the infusion site throughout the study in the subject diary within a time window of 24 h to 72 h after the end of the latest infusion by assessing it as "very good", "good", "fair", or "poor". The reported percentage represents the percentage of subjects with local tolerability assessments of "very good" or "good" at any given study infusion.

4. IgG Trough Level [24 weeks]

   Serum IgG trough levels at the completion visit compared to the baseline visit of the follow-up study. IgG trough levels at baseline, at the completion visit, and the change from baseline to the completion visit are shown

5. Annualized Rate of Clinically Documented Serious Bacterial Infections (SBIs) [24 weeks]

   SBIs are defined as bacterial pneumonia, bacteremia and septicemia, osteomyelitis/septic arthritis, bacterial meningitis, or visceral abscess. The annualized rate was based on the total number of SBIs and the total number of subject study days for all subjects in the FAS and PPS and adjusted to 365 days.

6. Number of Infection Episodes (Serious and Non-serious) [24 weeks]

7. Number of Days Out of Work/School/Kindergarten/Day Care or Unable to Perform Normal Daily Activities Due to Infections. [24 weeks]

   Median number of days out of work/school/kindergarten/day care or unable to perform normal daily activities due to infections.

8. Number of Days of Hospitalization Due to Infections. [24 weeks]

   Median number of days of hospitalization due to infections.

9. Duration of Use of Antibiotics for Infection Prophylaxis and Treatment [24 weeks]

   Median number of days of use of antibiotics for infection prophylaxis and/or treatment

Other Outcome Measures

1. Rate of Infection Episodes (Serious and Non-serious) [24 weeks]

   The annualized rate of infection episodes (serious and non-serious) was based on the total number of infection episodes and the total number of subject study days for all subjects in the FAS population and the PPS population and adjusted to 365 days.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects who have participated in study ZLB06_002CR and who have tolerated IgPro20 well.

• Written informed consent by the subject/parent/legally acceptable representative. Written assent for an underage subject (≥7 years at the time of obtaining informed consent), as far as possible.

Exclusion Criteria:

• Ongoing serious bacterial infections (SBIs) (pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, or visceral abscess) at the time of the first infusion.

• Hypoalbuminemia, protein-losing enteropathies, and any proteinuria (known total urine protein concentration >0.2 g/L or urine protein ++ by dipstick).

• Pregnancy or nursing mother.

• Participation in a study with an investigational medicinal product (IMP) within 3 months prior to enrollment except for ZLB06_002CR.

• Subjects who are planning to donate blood during the study.

• Re-entry of subjects previously participating in the current follow-up study.

• Known or suspected antibodies to the IMP, or to excipients of the IMP.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Study site	Nagoya city	Aichi Pref.	Japan	466-8560
2	Study site	Chiba city	Chiba Pref.	Japan	260-8677
3	Study site	Fukuoka city	Fukuoka	Japan	812-8582
4	Study site	Gifu city	Gifu Pref.	Japan	502-8558
5	Study site	Sapporo city	Hokkaido	Japan	060-8648
6	Study site	Moriguchi city	Osaka	Japan	570-8507
7	Study site	Koshigaya city	Saitama Pref.	Japan	343-8555
8	Study site	Tokorozawa city	Saitama Pref.	Japan	359-8513
9	Study site	Bunkyo-ku	Tokyo Metropolitan	Japan	113-8519

Sponsors and Collaborators

• CSL Behring

Investigators

• Study Director: Midori Kobayashi, CSL Behring K.K.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: CSL Behring
• ClinicalTrials.gov Identifier: NCT01458171
• Other Study ID Numbers: ZLB07_001CR
• First Posted: Oct 24, 2011
• Last Update Posted: Apr 9, 2013
• Last Verified: Feb 1, 2013

• Keywords provided by CSL Behring: Immune globulin subcutaneous; SCIG; Primary immunodeficiency; PID
• Additional relevant MeSH terms: Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Immunoglobulins; Antibodies; gamma-Globulins; Immunoglobulins, Intravenous; Rho(D) Immune Globulin

Study Results

Participant Flow

Recruitment Details	This multicenter study enrolled subjects at nine study centers in Japan who had participated in the preceding pivotal study ZLB06_002CR (CT.gov identifier: NCT01199705).
Pre-assignment Detail	Only subjects participating in the preceding pivotal study ZLB06_002CR (NCT01199705) were eligible. The enrolment visit of this study was on the same day as the completion visit of the preceding pivotal study ZLB06_002CR.

Arm/Group Title	IgPro20
Arm/Group Description	Immune globulin subcutaneous (Human): IgPro20 is a 20% (weight per volume [w/v]) liquid formulation of human immunoglobulin for subcutaneous (SC) use. Subjects will receive weekly infusions of IgPro20 for a total of 24 weeks at a dose based on the subject's IgPro20 dose in the pivotal study ZLB06_002CR (NCT01199705).
Period Title: Overall Study
STARTED	23
COMPLETED	22
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	IgPro20
Arm/Group Description	Immune globulin subcutaneous (Human): IgPro20 is a 20% (weight per volume [w/v]) liquid formulation of human immunoglobulin for subcutaneous (SC) use. Subjects will receive weekly infusions of IgPro20 for a total of 24 weeks at a dose based on the subject's IgPro20 dose in the pivotal study ZLB06_002CR (NCT01199705).
Overall Participants	23
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	20.8 (13.68)
Sex: Female, Male (Count of Participants)
Female	9 39.1%
Male	14 60.9%

Outcome Measures

1. Primary Outcome

Title	Median of the Individual Subject's Rate of Adverse Events (AEs) Per Infusion
Description	The rate was calculated by counting all newly developed or worsened AEs within a subject and dividing by the total number of IgPro20 infusions administered to this subject. Subsequently, the median of these individual AE rates per infusion was calculated. AE rates were classified (i) by severity (mild, moderate, severe) and (ii) by causal relationship to study medication (not related or unlikely related; at least possibly related [i.e., possibly related, probably related, or related]).
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The All Treated (AT) set comprised all subjects receiving at least 1 IgPro20 infusion.

Arm/Group Title	IgPro20
Arm/Group Description	Immune globulin subcutaneous (Human): IgPro20 is a 20% (weight per volume [w/v]) liquid formulation of human immunoglobulin for subcutaneous (SC) use. Subjects will receive weekly infusions of IgPro20 for a total of 24 weeks at a dose based on the subject's IgPro20 dose in the pivotal study ZLB06_002CR (NCT01199705).
Measure Participants	23
All AEs	0.167
Mild AEs	0.125
Moderate AEs	0
Severe AEs	0
Not related or unlikely related AEs	0.125
At least possibly related AEs	0

2. Secondary Outcome

Title	Overall Rate of AEs Per Infusion
Description	The rate was calculated by counting all newly developed or worsened AEs during the treatment period in all subjects and dividing the total number of AEs by the total number of IgPro20 infusions administered. In addition, individual AEs were classified (i) by severity (mild, moderate, severe) and (ii) by causal relationship to study medication (not related or unlikely related; at least possibly related [i.e., possibly related, probably related, or related]). The AE rates per infusion by severity and causal relationship to study medication were calculated by dividing the number of AEs in each category by the total number of IgPro20 infusions.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The AT set comprised all subjects receiving at least 1 IgPro20 infusion.

Arm/Group Title	IgPro20
Arm/Group Description	Immune globulin subcutaneous (Human): IgPro20 is a 20% (weight per volume [w/v]) liquid formulation of human immunoglobulin for subcutaneous (SC) use. Subjects will receive weekly infusions of IgPro20 for a total of 24 weeks at a dose based on the subject's IgPro20 dose in the pivotal study ZLB06_002CR (NCT01199705).
Measure Participants	23
Measure Infusions	529
All AEs	0.346
Mild AEs	0.342
Moderate AEs	0.002
Severe AEs	0.002
Not related or unlikely related AEs	0.210
At least possibly related AEs	0.136

3. Secondary Outcome

Title	Number of Subjects With Newly Developing or Worsening AEs
Description	Number of subjects with AEs, overall and classified (i) by severity (mild, moderate, severe) and (ii) by causal relationship to study medication (not related or unlikely related; at least possibly related [i.e., possibly related, probably related, or related]).
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The AT set comprised all subjects receiving at least 1 IgPro20 infusion.

Arm/Group Title	IgPro20
Arm/Group Description	Immune globulin subcutaneous (Human): IgPro20 is a 20% (weight per volume [w/v]) liquid formulation of human immunoglobulin for subcutaneous (SC) use. Subjects will receive weekly infusions of IgPro20 for a total of 24 weeks at a dose based on the subject's IgPro20 dose in the pivotal study ZLB06_002CR (NCT01199705).
Measure Participants	23
All AEs	22 95.7%
Mild AEs	21 91.3%
Moderate AEs	1 4.3%
Severe AEs	1 4.3%
Not related or unlikely related	12 52.2%
At least possibly related	10 43.5%

4. Secondary Outcome

Title	Percentage of Infusions With Subject-assessed Tolerability of at Least 'Good'
Description	Subjects assessed their overall perception of local tolerability at the infusion site throughout the study in the subject diary within a time window of 24 h to 72 h after the end of the latest infusion by assessing it as "very good", "good", "fair", or "poor". The reported percentage represents the percentage of subjects with local tolerability assessments of "very good" or "good" at any given study infusion.
Time Frame	24 to 72 hours after infusion

Outcome Measure Data

Analysis Population Description

The FAS comprised all subjects receiving at least 1 IgPro20 infusion.

Arm/Group Title	IgPro20
Arm/Group Description	Immune globulin subcutaneous (Human): IgPro20 is a 20% (weight per volume [w/v]) liquid formulation of human immunoglobulin for subcutaneous (SC) use. Subjects will receive weekly infusions of IgPro20 for a total of 24 weeks at a dose based on the subject's IgPro20 dose in the pivotal study ZLB06_002CR (NCT01199705).
Measure Participants	23
Number [percentage of infusions]	85.4

5. Secondary Outcome

Title	IgG Trough Level
Description	Serum IgG trough levels at the completion visit compared to the baseline visit of the follow-up study. IgG trough levels at baseline, at the completion visit, and the change from baseline to the completion visit are shown
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised all subjects receiving at least 1 IgPro20 infusion. The Per Protocol Set (PPS) comprised all subjects with the disease under study who a) received uniformly repeated IgPro20 infusions at weekly intervals and b) who had at least 1 documented total serum IgG trough level.

Arm/Group Title	IgPro20 - FAS	IgPro20 - PPS
Arm/Group Description	The FAS comprised all subjects receiving at least 1 IgPro20 infusion.	The PPS comprised all subjects with the disease under study who a) received uniformly repeated IgPro20 infusions at weekly intervals and b) who had at least 1 documented total serum IgG trough level.
Measure Participants	23	19
Baseline	7.469 (1.3943)	7.586 (1.3363)
Completion visit	8.914 (4.0502)	8.227 (1.5458)
Change from baseline to the completion vist	1.445 (3.4379)	0.642 (0.7687)

6. Secondary Outcome

Title	Annualized Rate of Clinically Documented Serious Bacterial Infections (SBIs)
Description	SBIs are defined as bacterial pneumonia, bacteremia and septicemia, osteomyelitis/septic arthritis, bacterial meningitis, or visceral abscess. The annualized rate was based on the total number of SBIs and the total number of subject study days for all subjects in the FAS and PPS and adjusted to 365 days.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The FAS comprised all subjects receiving at least 1 IgPro20 infusion. The PPS comprised all subjects with the disease under study who a) received uniformly repeated IgPro20 infusions at weekly intervals and b) who had at least 1 documented total serum IgG trough level.

Arm/Group Title	IgPro20 - FAS	IgPro20 - PPS
Arm/Group Description	The FAS comprised all subjects receiving at least 1 IgPro20 infusion.	The PPS comprised all subjects with the disease under study who a) received uniformly repeated IgPro20 infusions at weekly intervals and b) who had at least 1 documented total serum IgG trough level.
Measure Participants	23	19
Measure Total Study Days	3739	3214
Number [SBIs per subject year]	0.00	0.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IgPro20
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Annualized Rate
	Estimated Value	0.00
	Confidence Interval	(1-Sided) 99%; to 0.450
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	IgPro20 - PPS
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Annualized Rate
	Estimated Value	0.00
	Confidence Interval	(1-Sided) 99%; to 0.523
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Number of Infection Episodes (Serious and Non-serious)
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The FAS comprised all subjects receiving at least 1 IgPro20 infusion. The PPS comprised all subjects with the disease under study who a) received uniformly repeated IgPro20 infusions at weekly intervals and b) who had at least 1 documented total serum IgG trough level.

Arm/Group Title	IgPro20 - FAS	IgPro20 - PPS
Arm/Group Description	The FAS comprised all subjects receiving at least 1 IgPro20 infusion.	The PPS comprised all subjects with the disease under study who a) received uniformly repeated IgPro20 infusions at weekly intervals and b) who had at least 1 documented total serum IgG trough level.
Measure Participants	23	19
Number [infection episodes]	43	38

8. Secondary Outcome

Title	Number of Days Out of Work/School/Kindergarten/Day Care or Unable to Perform Normal Daily Activities Due to Infections.
Description	Median number of days out of work/school/kindergarten/day care or unable to perform normal daily activities due to infections.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The FAS comprised all subjects receiving at least 1 IgPro20 infusion. The PPS comprised all subjects with the disease under study who a) received uniformly repeated IgPro20 infusions at weekly intervals and b) who had at least 1 documented total serum IgG trough level.

Arm/Group Title	IgPro20 - FAS	IgPro20 - PPS
Arm/Group Description	The FAS comprised all subjects receiving at least 1 IgPro20 infusion.	The PPS comprised all subjects with the disease under study who a) received uniformly repeated IgPro20 infusions at weekly intervals and b) who had at least 1 documented total serum IgG trough level.
Measure Participants	23	19
Median (Full Range) [days]	0	0

9. Secondary Outcome

Title	Number of Days of Hospitalization Due to Infections.
Description	Median number of days of hospitalization due to infections.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The FAS comprised all subjects receiving at least 1 IgPro20 infusion. The PPS comprised all subjects with the disease under study who a) received uniformly repeated IgPro20 infusions at weekly intervals and b) who had at least 1 documented total serum IgG trough level.

Arm/Group Title	IgPro20 - FAS	IgPro20 - PPS
Arm/Group Description	The FAS comprised all subjects receiving at least 1 IgPro20 infusion.	The PPS comprised all subjects with the disease under study who a) received uniformly repeated IgPro20 infusions at weekly intervals and b) who had at least 1 documented total serum IgG trough level.
Measure Participants	23	19
Median (Full Range) [days]	0	0

10. Secondary Outcome

Title	Duration of Use of Antibiotics for Infection Prophylaxis and Treatment
Description	Median number of days of use of antibiotics for infection prophylaxis and/or treatment
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The FAS comprised all subjects receiving at least 1 IgPro20 infusion. The PPS comprised all subjects with the disease under study who a) received uniformly repeated IgPro20 infusions at weekly intervals and b) who had at least 1 documented total serum IgG trough level.

Arm/Group Title	IgPro20 - FAS	IgPro20 - PPS
Arm/Group Description	The FAS comprised all subjects receiving at least 1 IgPro20 infusion.	The PPS comprised all subjects with the disease under study who a) received uniformly repeated IgPro20 infusions at weekly intervals and b) who had at least 1 documented total serum IgG trough level.
Measure Participants	23	19
Median (Full Range) [days]	91.5	154.0

11. Other Pre-specified Outcome

Title	Rate of Infection Episodes (Serious and Non-serious)
Description	The annualized rate of infection episodes (serious and non-serious) was based on the total number of infection episodes and the total number of subject study days for all subjects in the FAS population and the PPS population and adjusted to 365 days.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The FAS comprised all subjects receiving at least 1 IgPro20 infusion. The PPS comprised all subjects with the disease under study who a) received uniformly repeated IgPro20 infusions at weekly intervals and b) who had at least 1 documented total serum IgG trough level.

Arm/Group Title	IgPro20 - FAS	IgPro20 - PPS
Arm/Group Description	The FAS comprised all subjects receiving at least 1 IgPro20 infusion.	The PPS comprised all subjects with the disease under study who a) received uniformly repeated IgPro20 infusions at weekly intervals and b) who had at least 1 documented total serum IgG trough level.
Measure Participants	23	19
Measure Total Study Days	3739	3214
Number [infection episodes per subject year]	4.20	4.32

Adverse Events

Time Frame	For the duration of the study, that is, 24 weeks.
Adverse Event Reporting Description	Only AEs starting at or after the first study drug infusion are included. The AT set comprised all subjects receiving at least 1 IgPro20 infusion. AEs in "General disorders" were collected under the MedDRA SOC General disorders and administration site conditions.
Arm/Group Title	IgPro20
Arm/Group Description	Immune globulin subcutaneous (Human): IgPro20 is a 20% (weight per volume [w/v]) liquid formulation of human immunoglobulin for subcutaneous (SC) use. Subjects will receive weekly infusions of IgPro20 for a total of 24 weeks at a dose based on the subject's IgPro20 dose in the pivotal study ZLB06_002CR (NCT01199705).
All Cause Mortality
	IgPro20
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	IgPro20
	Affected / at Risk (%)	# Events
Total	1/23 (4.3%)
Nervous system disorders
Encephalitis	1/23 (4.3%)	1
Other (Not Including Serious) Adverse Events
	IgPro20
	Affected / at Risk (%)	# Events
Total	20/23 (87%)
Gastrointestinal disorders
Dental caries	4/23 (17.4%)	4
General disorders
Injection site induration	2/23 (8.7%)	2
Injection site pain	5/23 (21.7%)	37
Pyrexia	2/23 (8.7%)	4
Infections and infestations
Bronchitis	2/23 (8.7%)	3
Conjunctivitis infective	2/23 (8.7%)	2
Nasopharyngitis	6/23 (26.1%)	13
Pharyngitis	2/23 (8.7%)	2
Sinusitis	2/23 (8.7%)	2
Upper respiratory tract infection	5/23 (21.7%)	8
Injury, poisoning and procedural complications
Arthropod bite	3/23 (13%)	13
Musculoskeletal and connective tissue disorders
Myalgia	2/23 (8.7%)	2
Pain in extremity	2/23 (8.7%)	2
Nervous system disorders
Headache	3/23 (13%)	8
Skin and subcutaneous tissue disorders
Dermatitis contact	2/23 (8.7%)	2
Eczema	6/23 (26.1%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

CSL agreements and restrictions on publishing may vary with individual investigators; however, CSL will not prohibit any investigator from publishing. CSL supports the publication of results from all centers of a multi-center trial and generally requires that reports based on single-site data not precede the primary publication of the entire clinical trial.