Clinical Trial Results:
A Multicenter Study of the Efficacy, Tolerability, Safety, and Pharmacokinetics of Immune Globulin Subcutaneous (Human) IgPro20 in Subjects with Primary Immunodeficiency
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Summary
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EudraCT number |
2006-006745-13 |
Trial protocol |
DE GB FR ES SE IT PL |
Global end of trial date |
31 Aug 2009
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Jul 2016
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First version publication date |
06 Aug 2015
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ZLB06_001CR
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00542997 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
CSL Behring AG
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Sponsor organisation address |
Wankdorfstrasse 10, Bern 22, Switzerland, 3000
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Public contact |
Trial Registration Co-ordinator, CSL Behring, clinicaltrials@cslbehring.com
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Scientific contact |
Trial Registration Co-ordinator, CSL Behring, clinicaltrials@cslbehring.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Oct 2009
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Aug 2009
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the efficacy, tolerability, safety, and pharmacokinetics (PK) of IgPro20 in subjects with primary immunodeficiency (PID). As the primary objective, the IgPro20 dose should result in sustained immunoglobulin G (IgG) trough levels (Ctrough) comparable to the previous IgG treatment.
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Protection of trial subjects |
This study was conducted in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and standard operating procedures for clinical research and development at CSL Behring and the Clinical Research Organisations (CROs) involved. Compliance with these requirements also constitutes conformity with the ethical principles of the Declaration of Helsinki (version of 1996). The study was conducted under a protocol reviewed and approved by an IEC/IRB; the study was conducted by scientifically and medically qualified persons; the benefits of the study were in proportion to the risks; the rights and welfare of the subjects were respected; the physicians conducting the study did not find the hazards to outweigh the potential benefits; the results reported are accurate; and each subject or subject’s parent or legal guardian gave his or her written informed consent before any protocol driven tests or evaluations were performed.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
28 Sep 2007
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Romania: 10
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Country: Number of subjects enrolled |
Switzerland: 2
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Country: Number of subjects enrolled |
Poland: 8
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Country: Number of subjects enrolled |
Spain: 10
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Country: Number of subjects enrolled |
Sweden: 1
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Country: Number of subjects enrolled |
United Kingdom: 4
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Country: Number of subjects enrolled |
France: 2
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Country: Number of subjects enrolled |
Germany: 14
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Worldwide total number of subjects |
51
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EEA total number of subjects |
49
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
18
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Adolescents (12-17 years) |
7
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Adults (18-64 years) |
26
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
This multinational study enrolled subjects at 15 of the participating study centers in Europe. | ||||||||||||
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Pre-assignment
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Screening details |
Screening took place 1 to 4 weeks prior to the first IgPro20 infusion. | ||||||||||||
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Period 1
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Period 1 title |
Wash in / Wash out Period
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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IgPro20 | ||||||||||||
Arm description |
IgPro20 administered as a subcutaneous infusion at weekly intervals by the subject/parent/guardian. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
IgPro20
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Investigational medicinal product code |
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Other name |
Human Normal Immunoglobulin for Subcutaneous Administration (IGSC), Hizentra, SCIG
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
IgPro20 is a liquid formulation of normal human IgG at a concentration of 20% administered as a SC infusion at weekly intervals. The initial weekly dose was determined based on subjects' previous treatment. Dose adjustments could be performed during the wash-in/wash-out period at the discretion of the investigator.
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Period 2
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Period 2 title |
Efficacy Period
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Is this the baseline period? |
No | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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IgPro20 | ||||||||||||
Arm description |
IgPro20 administered as a subcutaneous infusion at weekly intervals by the subject/parent/guardian. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
IgPro20
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Investigational medicinal product code |
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Other name |
Human Normal Immunoglobulin for Subcutaneous Administration (IGSC), Hizentra, SCIG
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
IgPro20 is a liquid formulation of normal human IgG at a concentration of 20% administered as a SC infusion at weekly intervals. The initial weekly dose was determined based on subjects' previous treatment. Dose adjustments could be performed during the wash-in/wash-out period at the discretion of the investigator.
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Baseline characteristics reporting groups
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Reporting group title |
IgPro20
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Reporting group description |
IgPro20 administered as a subcutaneous infusion at weekly intervals by the subject/parent/guardian. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
IgPro20
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Reporting group description |
IgPro20 administered as a subcutaneous infusion at weekly intervals by the subject/parent/guardian. | ||
Reporting group title |
IgPro20
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Reporting group description |
IgPro20 administered as a subcutaneous infusion at weekly intervals by the subject/parent/guardian. | ||
Subject analysis set title |
IgPro20 (PK Substudy)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects enrolled and treated with subcutaneous infusion of IgPro20 participating in the pharmacokinetic sub-study.
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End point title |
Total Serum IgG Trough Levels [1] | ||||||||||||
End point description |
Total IgG trough levels for IgPro20 treatment at steady state were compared with documented trough level data for IgG treatment received prior to enrolling in the study (pre-study data are from enrolled subjects with at least 3 documented IgG trough values ≥ 5 g/L during up to 6 months of intravenous (IGIV) or subcutaneous (IGSC) replacement therapy prior to receiving IgPro20 study treatment). For this purpose, 6 consecutive IgPro20 trough values (obtained prior to infusions 12 to 17) per subject were aggregated to the subject’s median value and then median values across subjects were summarised using descriptive statistics. The same procedure was applied to pre-study treatment using the 3 most recent IgG trough values ≥ 5 g/L obtained prior to the first IgPro20 infusion.
The intention-to-treat (ITT) population included all subjects treated with IgPro20 during the efficacy period (starting with Week 12); pre-study treatment IgG trough levels were not available for 2 subjects.
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End point type |
Primary
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End point timeframe |
Up to 6 months prior to first IgPro20 treatment (Pre-study treatment) and Week 12 to 17 (Infusions 12 to 17)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Variables were summarized using descriptive statistics. |
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| Notes [2] - Intention-to-treat (ITT) population. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Annual Rate of Clinically Documented Serious Bacterial Infections (ITT Population) | ||||||
End point description |
Serious bacterial infections (SBIs) included bacterial pneumonia, bacteraemia/septicaemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess. Diagnosis of the SBIs was based on the presence of predefined clinical signs and symptoms as well as on laboratory parameters.
The annual rate was calculated based on the total number of SBIs and the total number of study days during the efficacy period for all subjects in the ITT population and adjusted to 365 days.
Intention-to-treat (ITT) population analysis. The ITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with Week 12).
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End point type |
Secondary
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End point timeframe |
Efficacy period: week 12 to week 40 after study start or to the completion visit
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| Notes [3] - ITT population. Number of Subject Days Analyzed: 8745 |
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| No statistical analyses for this end point | |||||||
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End point title |
Annual Rate of Clinically Documented Serious Bacterial Infections (PPE Population) | ||||||
End point description |
Serious bacterial infections (SBIs) included bacterial pneumonia, bacteraemia/septicaemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess. Diagnosis of the SBIs was based on the presence of predefined clinical signs and symptoms as well as on laboratory parameters.
The annual rate was calculated based on the total number of SBIs and the total number of study days during the efficacy period for all subjects in the PPE population and adjusted to 365 days.
Per Protocol Efficacy (PPE) population analysis. The PPE population included all subjects who completed the 28-week efficacy period according to protocol.
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End point type |
Secondary
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End point timeframe |
Efficacy period: week 12 to week 40 after study start or to the completion visit
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| Notes [4] - PPE population Number of Subject Days Analyzed: 6729 |
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| No statistical analyses for this end point | |||||||
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End point title |
Annual Rate of Infection Episodes | ||||||||
End point description |
The annual rate of episodes was calculated based on the total number of any infection type and the total number of study days during the efficacy period for all subjects in the ITT population and adjusted to 365 days.
Intention-to-treat (ITT) population analysis. The ITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with Week 12).
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End point type |
Secondary
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End point timeframe |
Efficacy period: week 12 to week 40 after study start or to the completion visit
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| Notes [5] - ITT population Number of Subject Days Analyzed: 8745 |
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| No statistical analyses for this end point | |||||||||
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End point title |
Annual Rate of Days Out of Work / School / Kindergarten / Day Care or Unable to Perform Normal Activities Due to Infections | ||||||||
End point description |
The annual rate was calculated based on the total number of days out of work/school/kindergarten/day care or unable to perform normal activities due to infections in the efficacy period divided by the total number of days in the efficacy period for all subjects and adjusted to 365 days.
Intention-to-treat (ITT) population analysis. The ITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with Week 12).
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End point type |
Secondary
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End point timeframe |
Efficacy period: week 12 to week 40 after study start or to the completion visit
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| Notes [6] - ITT population Number of Subject Days Analyzed: 9033 |
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| No statistical analyses for this end point | |||||||||
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End point title |
Annual Rate of the Number of Days of Hospitalization Due to Infections | ||||||||
End point description |
The annual rate was calculated based on the total number of days of hospitalization due to infections in the efficacy period divided by the total number of days in the efficacy period for all subjects and adjusted to 365 days.
Intention-to-treat (ITT) population analysis. The ITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with Week 12).
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End point type |
Secondary
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End point timeframe |
Efficacy period: week 12 to week 40 after study start or to the completion visit
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| Notes [7] - ITT population Number of Subject Days Analyzed: 9033 |
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| No statistical analyses for this end point | |||||||||
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End point title |
Annual Rate of Antibiotic Use for Infection Prophylaxis and Treatment | ||||||||
End point description |
The annual rate was calculated based on the total number of days of antibiotic use in the efficacy period divided by the total number of days in the efficacy period for all subjects and adjusted to 365 days.
Intention-to-treat (ITT) population analysis. The ITT population included all subjects who were treated with IgPro20 during the efficacy period (starting with Week 12).
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End point type |
Secondary
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End point timeframe |
Efficacy period: week 12 to week 40 after study start or to the completion visit
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| Notes [8] - ITT population Number of Subject Days Analyzed: 8745 |
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| No statistical analyses for this end point | |||||||||
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End point title |
Maximum Concentration (Cmax) of Total Serum IgG | ||||||||
End point description |
Per Protocol Pharmacokinetic (PPK) population analysis. A total of 24 of the 51 enrolled subjects were included in a pharmacokinetic (PK) sub-study. 23 subjects completed the PK sub-study per protocol and were included in the PPK analysis population.
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End point type |
Other pre-specified
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End point timeframe |
Week 28 (±1week)
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| No statistical analyses for this end point | |||||||||
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End point title |
Timepoint of Maximum Concentration (Tmax) of Total Serum IgG | ||||||||
End point description |
Per Protocol Pharmacokinetic (PPK) population analysis. A total of 24 of the 51 enrolled subjects were included in a pharmacokinetic (PK) sub-study. 23 subjects completed the PK sub-study per protocol and were included in the PPK analysis population.
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End point type |
Other pre-specified
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End point timeframe |
Week 28 (±1week)
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Concentration-Time Curve (AUC_last) of Total Serum IgG | ||||||||
End point description |
AUC_last = Area under the concentration-time curve until last measured concentration.
Per Protocol Pharmacokinetic (PPK) population analysis. A total of 24 of the 51 enrolled subjects were included in a pharmacokinetic (PK) sub-study. 23 subjects completed the PK sub-study per protocol and were included in the PPK analysis population.
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End point type |
Other pre-specified
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End point timeframe |
Week 28 (±1week)
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Concentration-Time Curve (AUCτ) of Total Serum IgG | ||||||||
End point description |
AUCτ = Area under the concentration-time curve during regular dosing interval.
Per Protocol Pharmacokinetic (PPK) population analysis. A total of 24 of the 51 enrolled subjects were included in a pharmacokinetic (PK) sub-study. 23 subjects completed the PK sub-study per protocol and were included in the PPK analysis population. 7 subjects were missing data for AUCτ.
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End point type |
Other pre-specified
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End point timeframe |
Week 28 (±1week)
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| Notes [9] - 7 subjects were missing data for AUCτ. |
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
The observation period for adverse events was from the time the subjects had given informed consent until they had the final examination (completion visit up to approximately 40 weeks) or extended when serious adverse events were reported.
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Adverse event reporting additional description |
A total of 1831 infusions of IgPro20 were administered to 51 subjects during the course of the study.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
12.0
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Reporting groups
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Reporting group title |
IgPro20 (All Treated)
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Reporting group description |
All subjects receiving at least 1 infusion of IgPro20 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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11 May 2007 |
A lower limit haemoglobin value of 10 g/dL was defined; subjects with haemoglobin values < 10 g/dL throughout the study were to be discontinued. The secondary objective of changes in viral safety markers was deleted because viral safety markers were only measured at screening. The inclusion criteria were changed to allow subjects with a diagnosis of ARAG to enter the study and minor changes to the schedule of assessments were incorporated. Furthermore, an additional HRQL instrument, the TSQM, was incorporated. This amendment was implemented before any subjects had received the first infusion of IgPro20. |
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31 May 2007 |
The lower age limit of subjects participating in the study was raised to 16 years of age for study sites in the UK to fulfil the requirement of the South West Research Ethics Committee. This amendment was implemented before any subjects had received the first infusion of IgPro20. |
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30 Jan 2009 |
Based on slow recruitment and to ensure sufficient data for children, the number of study sites was changed from approximately 12 study sites to 21 study sites in Europe, the number of subjects was changed from approximately 36 enrolled subjects to 51 enrolled subjects, and the recruitment period was extended from approximately 4 months to 15 months. The number of subgroup analyses as well as the lowest number of subjects in a subgroup was limited to provide meaningful results. Subgroup analyses were only to be done for the primary endpoint and the secondary endpoints number of infections and number of days out of work/school/kindergarten/day care or unable to perform normal activities due to infections. An additional subgroup analysis of treatment-emergent AEs was stipulated. This amendment was implemented after all subjects had received the first infusion of IgPro20 and after 38 subjects had completed the study or had discontinued from the study. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/21705277 http://www.ncbi.nlm.nih.gov/pubmed/21674136 |
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