Clinical Trial Results:
A Multicenter Extension Study of the Efficacy, Tolerability, and Safety of Immune Globulin Subcutaneous (Human) IgPro20 in Subjects With Primary Immunodeficiency (PID)
|
Summary
|
|
EudraCT number |
2014-003605-15 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
16 Jun 2010
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
13 Jul 2016
|
First version publication date |
06 Aug 2015
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
IgPro20_3001
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT00719680 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
CSL Behring AG
|
||
Sponsor organisation address |
Wankdorfstrasse 10, Bern 22, Switzerland, 3000
|
||
Public contact |
Trial Registration Co-ordinator, CSL Behring, clinicaltrials@cslbehring.com
|
||
Scientific contact |
Trial Registration Co-ordinator, CSL Behring, clinicaltrials@cslbehring.com
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
12 May 2011
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
16 Jun 2010
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The purpose of this study was to determine whether a long-term use of a new human immunoglobulin G with proline (IgPro) is safe and effective in the treatment of primary immunodeficiency.
|
||
Protection of trial subjects |
This study was conducted in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, the Declaration of Helsinki (version of 1996), and standard operating procedures for clinical research and development at CSL Behring and the Clinical Research Organizations (CROs) involved. Compliance with these requirements also constitutes conformity with the ethical principles of the Declaration of Helsinki. The study was conducted under a protocol reviewed and approved by an 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.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
04 Jun 2008
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
United States: 21
|
||
Worldwide total number of subjects |
21
|
||
EEA total number of subjects |
0
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
1
|
||
Adolescents (12-17 years) |
1
|
||
Adults (18-64 years) |
16
|
||
From 65 to 84 years |
3
|
||
85 years and over |
0
|
||
|
|||||||||||||||
|
Recruitment
|
|||||||||||||||
Recruitment details |
- | ||||||||||||||
|
Pre-assignment
|
|||||||||||||||
Screening details |
This multicenter study was conducted at 4 sites in the US. The number of subjects treated at each site ranged from 2 to 9. | ||||||||||||||
|
Period 1
|
|||||||||||||||
Period 1 title |
Overall trial (overall period)
|
||||||||||||||
Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
|
||||||||||||||
Blinding used |
Not blinded | ||||||||||||||
|
Arms
|
|||||||||||||||
|
Arm title
|
IgPro20 | ||||||||||||||
Arm description |
A liquid formulation of normal human IgG at a concentration of 20%. IgPro20 was administered as a subcutaneous infusion weekly or twice weekly, depending on the investigator's judgment and the subject’s preference. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
IgPro20
|
||||||||||||||
Investigational medicinal product code |
|||||||||||||||
Other name |
Human Normal Immunoglobulin for Subcutaneous Administration (IGSC), Hizentra, IgG with Proline
|
||||||||||||||
Pharmaceutical forms |
Solution for injection
|
||||||||||||||
Routes of administration |
Subcutaneous use
|
||||||||||||||
Dosage and administration details |
The IgPro20 dose is the same as in the previous pivotal study ZLB04_009CR (EudraCT Number: 2014-003607-30, NCT00419341) infused subcutaneously weekly or twice a week (in the latter case, half of a weekly dose will be used)
|
||||||||||||||
|
|||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
IgPro20
|
|||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
A liquid formulation of normal human IgG at a concentration of 20%. IgPro20 was administered as a subcutaneous infusion weekly or twice weekly, depending on the investigator's judgment and the subject’s preference. | |||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
IgPro20
|
||
Reporting group description |
A liquid formulation of normal human IgG at a concentration of 20%. IgPro20 was administered as a subcutaneous infusion weekly or twice weekly, depending on the investigator's judgment and the subject’s preference. | ||
Subject analysis set title |
IgPro20 - ITT
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The Intention-to-Treat (ITT) population comprised all subjects treated with study medication during any study period.
|
||
Subject analysis set title |
IgPro20 - PPE
|
||
Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The Per-Protocol Efficacy (PPE) population comprised all subjects who completed at least 48 weeks of the efficacy period that started with the first IgPro20 dose in this study.
|
||
Subject analysis set title |
IgPro20 - AT
|
||
Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The all-treated (AT) safety population comprised all subjects treated with the study medication during any study period.
|
||
|
|||||||||
End point title |
Annualized Rate of Serious Bacterial Infection (Intention-to-Treat Population) [1] | ||||||||
End point description |
The annualized rate was based on the total number of infections and the total number of subject study days for all subjects in the specified analysis population and adjusted to 365 days.
Acute serious bacterial infections included pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess.
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
For the duration of the study, up to approximately 104 weeks
|
||||||||
| 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: End point data analysis consisted of the estimation of the annualized rate and 99% upper confidence interval limit as per protocol; no statistical hypothesis was planned or conducted (in accordance with the US Food and Drug Administration Guidance for Industry on “Safety, efficacy, and pharmacokinetic studies to support marketing of immune globulin intravenous (human) as replacement therapy for primary humoral immunodeficiency” [June 2008]). |
|||||||||
|
|||||||||
| Notes [2] - Subject study days analyzed: 11950 |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Annualized Rate of Serious Bacterial Infection (Per-Protocol Efficacy Population) | ||||||||
End point description |
The annualized rate was based on the total number of infections and the total number of subject study days for all subjects in the specified analysis population and adjusted to 365 days.
Acute serious bacterial infections included pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
For the duration of the study, up to approximately 104 weeks
|
||||||||
|
|||||||||
| Notes [3] - Subject study days analyzed: 11037 |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Annualized Rate of Any Infection | ||||||||
End point description |
The annualized rate was based on the total number of infections and the total number of subject study days for all subjects in the specified analysis population and adjusted to 365 days.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
For the duration of the study, up to approximately 104 weeks
|
||||||||
|
|||||||||
| Notes [4] - Subject study days analyzed: 11950 |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Trough Levels of Total Immunoglobulin G (IgG) Serum Concentrations | ||||||||
End point description |
Mean of individual median total IgG trough concentration.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Before infusion at Weeks 1, 24, 48, 72, and 96
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Number of Days Out of Work / School / Kindergarten / Day Care or Inability to Perform Normal Activities Due to Infection | ||||||||
End point description |
|||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
For the duration of the study, up to approximately 104 weeks
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Annualized Rate of Days Out of Work / School / Kindergarten / Day Care or Inability to Perform Normal Activities Due to Infection | ||||||||
End point description |
The annualized rate was based on the total number of days out of work / school / kindergarten / day care or inability to perform normal activities due to infection, and the total number of subject study days for all subjects in the specified analysis population and adjusted to 365 days.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
For the duration of the study, up to approximately 104 weeks
|
||||||||
|
|||||||||
| Notes [5] - Subject study days analyzed: 11950 |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Number of Days of Hospitalization Due to Infection | ||||||||
End point description |
|||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
For the duration of the study, up to approximately 104 weeks
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Annualized Rate of Hospitalization Due to Infection | ||||||||
End point description |
The annualized rate was based on the total number of days of hospitalization due to infection and the total number of subject study days for all subjects in the specified analysis population and adjusted to 365 days.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
For the duration of the study, up to approximately 104 weeks
|
||||||||
|
|||||||||
| Notes [6] - Subject study days analyzed: 11950 |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Use of Antibiotics for Infection Prophylaxis and Treatment | ||||||||
End point description |
Annualized rate of days with antibiotics for infection prophylaxis and treatment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
For the duration of the study, up to approximately 104 weeks
|
||||||||
|
|||||||||
| Notes [7] - Subject exposure days analyzed: 11950 |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||
End point title |
Rate of All AEs by Relatedness and Severity | ||||||||||||||||||||
End point description |
The rate of AEs was the number of AEs over the number of infusions administered.
At least possibly related AEs included possibly related AEs, probably related AEs, and related AEs.
Mild AE: Did not interfere with routine activities; Moderate AE: Interfered somewhat with routine activities; Severe AE: Impossible to perform routine activities.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
For the duration of the study, up to approximately 104 weeks
|
||||||||||||||||||||
|
|||||||||||||||||||||
| Notes [8] - Infusions analyzed: 1735 |
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Relatedness and Severity of All AEs (Percentage of Total AEs) | ||||||||||||||||||
End point description |
At least possibly related AEs included possibly related AEs, probably related AEs, and related AEs.
Mild AE: Did not interfere with routine activities; Moderate AE: Interfered somewhat with routine activities; Severe AE: Impossible to perform routine activities.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
For the duration of the study, up to approximately 104 weeks
|
||||||||||||||||||
|
|||||||||||||||||||
| Notes [9] - AT AEs analyzed: 1147 |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||
End point title |
Number of Subjects With Any Temporally Associated Adverse Event (AE) Within 24 or 72 Hours After an Infusion | ||||||||||
End point description |
AEs were considered temporally associated if they occurred between the start of infusion and within 24 or 72 hours after the end of infusion.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
Within 24 or 72 hours after each infusion
|
||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
|||||||||||||
End point title |
Rate of Temporally Associated AEs Within 24 or 72 Hours of an Infusion | ||||||||||||
End point description |
The rate of AEs was the number of AEs over the number of infusions administered.
AEs were considered temporally associated if they occurred between the start of infusion and within 24 or 72 hours after the end of infusion
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Within 24 or 72 hours after each infusion
|
||||||||||||
|
|||||||||||||
| Notes [10] - Infusions analyzed: 1735 |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||
End point title |
Number of Subjects Reporting Mild, Moderate, or Severe Local AEs | ||||||||||||||
End point description |
In addition to the standard MedDRA System Organ Class (SOC) AE assignments, the category of 'local reactions' was defined to provide the possibility for a combined analysis of local reactions and included AEs of infusion site oedema, infusion site reaction, injection site pain, injection site rash, and injection site reaction.
Mild AE: Did not interfere with routine activities; Moderate AE: Interfered somewhat with routine activities; Severe AE: Impossible to perform routine activities.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
For the duration of the study, up to approximately 104 weeks
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||
End point title |
Number of Subjects With Clinically Significant Changes From Baseline to the Completion Visit in Vital Signs | ||||||
End point description |
Vital signs included blood pressure (systolic and diastolic), heart rate, and body temperature.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
At weeks 1, 12, 24, 36, 48, 60, 72, 84, and 96
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||
End point title |
Number of Subjects With Clinically Significant Changes From Baseline to the Completion Visit in Routine Laboratory Parameters | ||||||
End point description |
Routine laboratory parameters included hematology, blood chemistry, and urinalysis parameters.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
At Week 1, and study completion (approximately 104 weeks)
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||
End point title |
Number of Subjects With Clinically Significant Changes From Baseline to the Completion Visit in Viral Safety Markers | ||||||
End point description |
Viral safety markers included human immunodeficiency virus (HIV)-1, HIV-2, hepatitis A virus (HAV), HBV, HCV, and parvovirus B19.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
At Week 1, and study completion (approximately 104 weeks)
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From the time of informed consent until study completion, up to approximately 121 weeks
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
The AT safety population comprised all subjects treated with the study medication during any study period
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
13.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
IgPro20
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
A liquid formulation of normal human IgG at a concentration of 20%. IgPro20 was administered as a subcutaneous infusion weekly or twice weekly, depending on the investigator's judgment and the subject’s preference. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
25 Jun 2008 |
Additional safety endpoints were specified, including the total number of temporally associated AEs (i.e., AEs that began during infusion or within 24 or 72 hours after infusion) and the number of temporally associated AEs per infusion. The projected number of sites was changed from approximately 10 to approximately 5 and the projected number of subjects was changed from approximately 30 to approximately 20. The transition procedures from the preceding study ZLB04_009CR to this extension study were updated. Additional evaluation procedures in case of hemolytic and/or hepatotoxic events were specified (determination of baseline serum haptoglobin and urine hemosiderin values). This amendment was implemented after 3 subjects had received their first infusion of study medication. |
||
16 Oct 2008 |
The trough level ratio (TLR) that was developed in response to a regulatory authority’s suggestion for checking adequate dosing was introduced, together with rules for dose adjustments that were to be implemented if the TLR differed from the stipulated range (1.29 ± 15% times the latest historic IGIV Ctrough. Furthermore, a specific procedure for reporting AEs associated with infections was introduced (2 new CRF pages for reporting infections and potential SBIs). Additional details on evaluation procedures in case of hemolytic and/or hepatotoxic events were provided (repeat tests for abnormal laboratory results). This amendment was implemented after all subjects had received their first infusion of study medication. |
||
09 Sep 2009 |
The rules for IgPro20 dose adjustments that were to be considered if the TLR differed from the stipulated range were updated. Storage and transport temperature requirements for the study medication were updated. This amendment was implemented after all subjects had received their first infusion of study medication. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
|||
| http://www.ncbi.nlm.nih.gov/pubmed/24412910 |
|||
