Clinical Trial Results:
Long-Term Tolerability and Safety of Immune Globulin Infusion 10% (Human) With Recombinant Human Hyaluronidase (HYQVIA/HyQvia) for the Treatment of Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
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Summary
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EudraCT number |
2016-000374-37 |
Trial protocol |
FR DK CZ GB ES NO GR SK DE PL HR IT |
Global end of trial date |
04 Jul 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
17 Jul 2024
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First version publication date |
17 Jul 2024
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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 |
161505
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02955355 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Takeda
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Sponsor organisation address |
95 Hayden Avenue, Lexington, United States, MA 02421
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Public contact |
Study Director, Takeda, TrialDisclosures@takeda.com
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Scientific contact |
Study Director, Takeda, TrialDisclosures@takeda.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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
04 Jul 2023
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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 |
04 Jul 2023
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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 |
The main purpose of this study is to evaluate the long-term safety, tolerability, and immunogenicity of HYQVIA/HyQvia.
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Protection of trial subjects |
Each participant signed an informed consent form (ICF) before participating in the study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Nov 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
United States: 4
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Country: Number of subjects enrolled |
Argentina: 1
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Country: Number of subjects enrolled |
Brazil: 5
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Country: Number of subjects enrolled |
Canada: 4
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Country: Number of subjects enrolled |
Colombia: 2
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Country: Number of subjects enrolled |
Czechia: 4
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Country: Number of subjects enrolled |
Denmark: 1
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Country: Number of subjects enrolled |
France: 6
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Country: Number of subjects enrolled |
Germany: 1
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Country: Number of subjects enrolled |
Greece: 2
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Country: Number of subjects enrolled |
Italy: 8
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Country: Number of subjects enrolled |
Mexico: 6
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Country: Number of subjects enrolled |
Poland: 9
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Country: Number of subjects enrolled |
Serbia: 18
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Country: Number of subjects enrolled |
Slovakia: 3
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
Türkiye: 6
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Country: Number of subjects enrolled |
United Kingdom: 2
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Worldwide total number of subjects |
85
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EEA total number of subjects |
37
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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) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
65
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From 65 to 84 years |
19
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85 years and over |
1
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Recruitment
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Recruitment details |
Participants took part in the study at 39 investigative sites worldwide from 14 November 2016 to 04 July 2023. | ||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 85 participants with a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who completed Study 161403 (NCT02549170) without CIDP worsening were enrolled in this Extension Study to receive HYQVIA/HyQvia. | ||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall 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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HYQVIA/HyQvia | ||||||||||||||||||||
Arm description |
Participants received HYQVIA/HyQvia (recombinant human hyaluronidase [rHuPH20] at a dose of 80 units per gram (U/g) immunoglobulin G [IgG], followed by subcutaneous [SC] immune globulin infusion [IGI] 10%) at the same monthly equivalent dose as the individual participant’s IgG treatment in Study 161403, every 3 or 4 weeks in this Extension Study for 77.3 months or until relapse. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
HYQVIA/HyQvia
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Investigational medicinal product code |
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Other name |
IGI 10% with rHuPH20, Immune Globulin Infusion 10% (Human) (IGI 10%) with recombinant human hyaluronidase (rHuPH20)
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Participants received rHuPH20 SC at a dose of 80 U/g IgG, followed by SC IGI 10% at the same monthly equivalent dose as the individual participant’s IgG treatment in Study 161403.
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Baseline characteristics reporting groups
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Reporting group title |
HYQVIA/HyQvia
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Reporting group description |
Participants received HYQVIA/HyQvia (recombinant human hyaluronidase [rHuPH20] at a dose of 80 units per gram (U/g) immunoglobulin G [IgG], followed by subcutaneous [SC] immune globulin infusion [IGI] 10%) at the same monthly equivalent dose as the individual participant’s IgG treatment in Study 161403, every 3 or 4 weeks in this Extension Study for 77.3 months or until relapse. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
HYQVIA/HyQvia
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Reporting group description |
Participants received HYQVIA/HyQvia (recombinant human hyaluronidase [rHuPH20] at a dose of 80 units per gram (U/g) immunoglobulin G [IgG], followed by subcutaneous [SC] immune globulin infusion [IGI] 10%) at the same monthly equivalent dose as the individual participant’s IgG treatment in Study 161403, every 3 or 4 weeks in this Extension Study for 77.3 months or until relapse. | ||
Subject analysis set title |
Placebo Then HYQVIA/HyQvia
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Participants received placebo in the study 161403 and received HYQVIA/HyQvia (rHuPH20 at a dose of 80 U/g IgG, followed by SC IGI 10%) at the same monthly equivalent dose as the individual participant’s IgG treatment in Study 161403, every 3 or 4 weeks in this Extension Study for 77.3 months or until relapse.
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Subject analysis set title |
HYQVIA/HyQvia Then HYQVIA/HyQvia
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Participants received HYQVIA/HyQvia in the study 161403 and received HYQVIA/HyQvia (rHuPH20 at a dose of 80 U/g IgG, followed by SC IGI 10%) at the same monthly equivalent dose as the individual participant’s IgG treatment in Study 161403, every 3 or 4 weeks in this Extension Study for 77.3 months or until relapse.
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End point title |
Number of Participants With any Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), Regardless of Causality [1] | ||||||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered an investigational product (IP) that did not necessarily have a causal relationship with the treatment. An SAE was defined as an untoward medical occurrence that at any dose met one or more of the following criteria: outcome was fatal/resulted in death, was life-threatening, required inpatient hospitalisation or resulted in prolongation of an existing hospitalisation, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. Treatment emergent adverse events (TEAEs) were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
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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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Participants With Causally Related Treatment-emergent SAEs and AEs [2] | ||||||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered an IP that did not necessarily have a causal relationship with the treatment. An SAE was defined as an untoward medical occurrence that at any dose met one or more of the following criteria: outcome was fatal/resulted in death, was life-threatening, required inpatient hospitalisation or resulted in prolongation of an existing hospitalisation, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. Causality was used to determine whether there was a reasonable possibility that the IP was etiologically related to/associated with the AE. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
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| Notes [2] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Participants With Adverse Reactions (ARs) or Suspected Adverse Reactions (SARs) Categorised as Serious and Non-serious [3] | ||||||||||
End point description |
An AR plus SAR is any AE that meets any of the following criteria: an AE considered by either the investigator and/or the sponsor to be possibly or probably related to IP administration, or that begins during infusion of IP or within 72 hours following the end of IP infusion, or AE for which causality assessment is missing or indeterminate. Serious AR/SAR=any AR/SAR that is an untoward medical occurrence which at any dose meets one or more of following criteria: outcome is fatal/results in death, is life-threatening, requires inpatient hospitalisation or results in prolongation of existing hospitalisation, results in persistent or significant disability/incapacity,is a congenital anomaly/birth defect,is a medically important event,thromboembolic events,hemolytic anemia. Nonserious AR/SAR=AR/SAR that does not meet the criteria. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
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| Notes [3] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Causally Related Treatment-Emergent SAEs and AEs Associated With Infusions [4] | ||||||||||||
End point description |
An AE=any untoward medical occurrence in participant administered IP that did not necessarily have causal relationship with treatment. An SAE=an untoward medical occurrence that at any dose met one/more of following criteria: outcome was fatal/resulted in death, was life-threatening, required inpatient hospitalisation/resulted in prolongation of existing hospitalisation, resulted in persistent/significant disability/incapacity, was congenital anomaly/birth defect, was medically important event. TEAEs=AEs that occurred during or after administration of the first dose of IP in this Extension Study. AEs associated with an infusion are defined as AEs occurring after administration of IP (or any TEAE). Causality was used to determine whether there was a reasonable possibility that the IP was etiologically related to/associated with the AE. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
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| Notes [4] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Treatment-Emergent SAEs and AEs Associated With Infusions, Regardless of Causality [5] | ||||||||||||
End point description |
An AE=any untoward medical occurrence in a participant administered an IP that did not necessarily have a causal relationship with the treatment. An SAE was defined as an untoward medical occurrence that at any dose met one or more of the following criteria: outcome was fatal/resulted in death, was life-threatening, required inpatient hospitalisation or resulted in prolongation of an existing hospitalisation, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. AEs associated with an infusion are defined as AEs occurring after administration of IP (or any TEAE). Participants can have more than one TEAE associated with infusion. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
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| Notes [5] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Participants With Treatment-Emergent Adverse Events That May be a Result of Immune-Mediated Responses [6] | ||||||||
End point description |
Percentage of participants with TEAEs that may be a result of immune-mediated response to either immunoglobulin, rHuPH20, or other factors such as allergic reactions, immune complex-mediated reactions: local, complex-mediated reactions: systemic, thrombotic and embolic events were assessed. TEAEs were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. The percentage was rounded off to the nearest decimal. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
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| Notes [6] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Infusions Associated With One or More Systemic TEAEs [7] | ||||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered an IP that did not necessarily have a causal relationship with the treatment. TEAEs were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. Systemic TEAEs were defined as AEs that were not included in the Medical Dictionary for Regulatory Activities (MedDRA) Higher Level Group Term "administration site reactions" and did not contain the phrase "injection site". Infusions associated with one or more AEs are defined as follows: if an AE occurs after an infusion but prior to the next infusion that infusion is associated with that AE. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
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| Notes [7] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Serious and Non-Serious ARs or SARs Associated with Infusions [8] | ||||||||||||
End point description |
AR/SAR=AE that meets any of following criteria:AE considered by investigator/sponsor to be possibly/probably related to IP administration,begins during/within 72 hours following end of IP infusion/AE for which causality assessment is missing/indeterminate. ARs/SARs associated with infusion=AEs considered by investigator to be occurring after IP administration.Serious AR/SAR=AR/SAR that is untoward medical occurrence which at any dose meets any of following criteria:outcome is fatal,life-threatening,requires inpatient hospitalisation/prolongation of existing hospitalisation,results in persistent/significant disability/incapacity,is a congenital anomaly/birth defect,is a medically important event,thromboembolic events,hemolytic anemia.Nonserious AR/SAR=AR/SAR that does not meet criteria. Participants can have >1 AR/SAR associated with infusion. Safety Analysis Set included all participants who were enrolled in this Extension Study & who received at least 1 dose of study medication.
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End point type |
Primary
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End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
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| Notes [8] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Infusions for Which the Infusion Rate Was Reduced and/or the Infusion was Interrupted or Stopped due to Intolerability and/or TEAEs [9] | ||||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered an IP that did not necessarily have a causal relationship with the treatment. TEAEs were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
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| Notes [9] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Infusions Associated with One or More Local TEAEs [10] | ||||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered an IP that did not necessarily have a causal relationship with the treatment. TEAEs were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. Local TEAEs were defined as AEs that were included in the MedDRA Higher Level Group Term "administration site reactions" or contained the phrase "injection site" or "infection site". Infusions associated with one or more AEs are defined as follows: if an AE occurs after an infusion but prior to the next infusion that infusion is associated with that AE. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
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| Notes [10] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of TEAEs Temporally Associated With Infusions [11] | ||||||||
End point description |
TEAEs that occurred during infusion or within 72 hours post-infusion were considered to be temporally associated with infusions. TEAEs were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. Participants can have more than one TEAE temporally associated with infusion. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
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| Notes [11] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Rate of TEAEs Categorised as Systemic and Local Regardless of Causality, Expressed as Number of Events Per Participant [12] | ||||||||||||
End point description |
TEAEs were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. Systemic TEAEs were defined as AEs that were not included in the MedDRA Higher Level Group Term "administration site reactions" and did not contain the phrase "injection site". Local TEAEs were defined as AEs that were included in the MedDRA Higher Level Group Term "administration site reactions" or contained the phrase "injection site" or "infection site". Events per participant was calculated by dividing number of events by total number of participants in the Safety Analysis Set. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
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| Notes [12] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Rate of TEAEs Categorised as Systemic and Local Regardless of Causality, Expressed as Number of Events Per Infusion [13] | ||||||||||||
End point description |
TEAEs were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. Systemic TEAEs were defined as AEs that were not included in the MedDRA Higher Level Group Term "administration site reactions" and did not contain the phrase "injection site". Local TEAEs were defined as AEs that were included in the MedDRA Higher Level Group Term "administration site reactions" or contained the phrase "injection site" or "infection site". Events per infusion was calculated by dividing number of events by total number of infusions administered to participants in the Safety Analysis Set. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
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| Notes [13] - 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: Only descriptive analysis was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Rate of TEAEs Categorised as Systemic and Local Regardless of Causality, Expressed as Number of Events Per 1000 Participant-year [14] | ||||||||||||
End point description |
TEAEs were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. Systemic TEAEs were defined as AEs that were not included in the MedDRA Higher Level Group Term "administration site reactions" and did not contain the phrase "injection site". Local TEAEs were defined as AEs that were included in the MedDRA Higher Level Group Term "administration site reactions" or contained the phrase "injection site" or "infection site". Events per participant-years was calculated as follows: 1000 x (number of events / total number of days of exposure, i.e., the sum of duration of treatment for all participants in the Safety Analysis Set, divided by 365.25). Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||||||||
| Notes [14] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Rate of IP-Related TEAEs Categorised as Systemic and Local, Expressed as Number of Events Per 1000 Participant-year [15] | ||||||||||||
End point description |
TEAEs=AEs that occurred during or after administration of the first dose of IP in this Extension Study. Systemic TEAEs were defined as AEs that were not included in the MedDRA Higher Level Group Term "administration site reactions" and did not contain the phrase "injection site". Local TEAEs were defined as AEs that were included in the MedDRA Higher Level Group Term "administration site reactions" or contained the phrase "injection site" or "infection site". An adverse event that was “possibly related” or “probably related” to IP, or for which the relationship was unknown or missing, was considered as a “related AE”. Events per participant-years was calculated as follows: 1000 x (number of events / total number of days of exposure, i.e., the sum of duration of treatment for all participants in the Safety Analysis Set, divided by 365.25). Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||||||||
| Notes [15] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Rate of IP-Related TEAEs Categorised as Systemic and Local, Expressed as Number of Events Per Participant [16] | ||||||||||||
End point description |
TEAEs were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. Systemic TEAEs were defined as AEs that were not included in the MedDRA Higher Level Group Term "administration site reactions" and did not contain the phrase "injection site". Local TEAEs were defined as AEs that were included in the MedDRA Higher Level Group Term "administration site reactions" or contained the phrase "injection site" or "infection site". An adverse event that was “possibly related” or “probably related” to IP, or for which the relationship was unknown or missing, was considered as a “related AE”. Events per participant was calculated by dividing number of events by total number of participants in the Safety Analysis Set. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||||||||
| Notes [16] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Rate of IP-Related TEAEs Categorised as Systemic and Local, Expressed as Number of Events Per Infusion [17] | ||||||||||||
End point description |
TEAEs were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. Systemic TEAEs were defined as AEs that were not included in the MedDRA Higher Level Group Term "administration site reactions" and did not contain the phrase "injection site". Local TEAEs were defined as AEs that were included in the MedDRA Higher Level Group Term "administration site reactions" or contained the phrase "injection site" or "infection site". An adverse event that was “possibly related” or “probably related” to IP, or for which the relationship was unknown or missing, was considered as a “related AE”. Events per infusion was calculated by dividing number of events by total number of infusions administered to participants in the Safety Analysis Set. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||||||||
| Notes [17] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Rate of ARs or SARs Categorised as Local and Systemic, Expressed as Reactions Per Infusion [18] | ||||||||||||
End point description |
An AR plus SAR is any AE that meets any of the following criteria: an AE considered by either the investigator and/or the sponsor to be possibly or probably related to IP administration, or that begins during infusion of IP or within 72 hours following the end of IP infusion, or AE for which causality assessment is missing or indeterminate. Systemic AEs were defined as AEs that were not included in the MedDRA Higher Level Group Term "administration site reactions" and did not contain the phrase "injection site". Local AEs were defined as AEs that were included in the MedDRA Higher Level Group Term "administration site reactions" or contained the phrase "injection site" or "infection site". Events per infusion was calculated by dividing number of events by total number of infusions administered to participants in the Safety Analysis Set. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||||||||
| Notes [18] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Rate of ARs or SARs Categorised as Local and Systemic, Expressed as Reactions Per 1000 Participant-year [19] | ||||||||||||
End point description |
An AR+SAR is any AE that meets any of following criteria: AE considered by either investigator and/or sponsor to be possibly/probably related to IP administration/that begins during infusion of IP/within 72 hours following end of IP infusion/AE for which causality assessment is missing/indeterminate. Systemic AEs=AEs that were not included in MedDRA Higher Level Group Term "administration site reactions" & did not contain phrase "injection site". Local AEs=AEs that were included in the MedDRA Higher Level Group Term "administration site reactions" or contained the phrase "injection site" or "infection site". Events per participant-years was calculated as follows: 1000 x (number of events / total number of days of exposure, i.e., the sum of duration of treatment for all participants in the Safety Analysis Set, divided by 365.25). Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||||||||
| Notes [19] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Rate of ARs or SARs Categorised as Local and Systemic, Expressed as Reactions Per Participant [20] | ||||||||||||
End point description |
An AR plus SAR is any AE that meets any of the following criteria: an AE considered by either the investigator and/or the sponsor to be possibly or probably related to IP administration, or that begins during infusion of IP or within 72 hours following the end of IP infusion, or AE for which causality assessment is missing or indeterminate. Systemic AEs were defined as AEs that were not included in the MedDRA Higher Level Group Term "administration site reactions" and did not contain the phrase "injection site". Local AEs were defined as AEs that were included in the MedDRA Higher Level Group Term "administration site reactions" or contained the phrase "injection site" or "infection site". Events per participant was calculated by dividing number of events by total number of participants in the Safety Analysis Set. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||||||||
| Notes [20] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||
End point title |
Number of Participants That Experienced Treatment-Emergent Local Infusion Site Reactions [21] | ||||||
End point description |
TEAEs were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. AE=any untoward medical occurrence in participant administered an IP that does not have causal relationship with treatment. Adverse reaction/suspected adverse reaction=AE that is considered by the investigator to be possibly or probably related to IP administration, or for which the causality is indeterminate or missing, or that begins during infusion of IP or within 72 hours following the end of IP infusion. All local infusion site treatment-emergent AEs were reported as adverse reactions. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
|
||||||
End point type |
Primary
|
||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||
| Notes [21] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||
End point title |
Rate of Moderate or Severe TEAEs That May be a Result of Immune-Mediated Responses, Expressed as Number of Events Per 100 Infusions [22] | ||||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered an IP that did not necessarily have a causal relationship with the treatment. TEAEs were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. A moderate or severe AE could be a result of immune-mediated response to either immunoglobulin, rHuPH20, or other concomitant medications. The severity of each AE was assessed by the investigator using clinical expertise. Rate per 100 infusions was calculated by dividing the number of events by the total number of infusions and multiplying that by 100. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||||
| Notes [22] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||
End point title |
Number of Participants With Moderate or Severe TEAEs That may be a Result of Immune-Mediated Responses [23] | ||||||
End point description |
AE=any untoward medical occurrence in participant administered IP that did not necessarily have causal relationship with treatment. TEAEs=AEs that occurred during/after administration of first dose of IP in this Extension Study. Moderate/severe AE could be result of immune-mediated response to either immunoglobulin,rHuPH20/other factors like allergic reactions,immune complex-mediated reactions:local,complex-mediated reactions:systemic, thrombotic&embolic events.Severity of AEs was assessed by investigator using clinical expertise based on following description:moderate=AE produces limited impairment of function,may require therapeutic intervention&produces no sequela;severe=AE results in marked impairment of function&may lead to temporary inability to resume usual life pattern&produces sequela,which require prolonged therapeutic intervention. Safety Analysis Set included all participants who were enrolled in this Extension Study & who received at least 1 dose of study medication.
|
||||||
End point type |
Primary
|
||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||
| Notes [23] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||
End point title |
Number of Participants With a TEAE That led to Discontinuation From Study [24] | ||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered an IP that did not necessarily have a causal relationship with the treatment. TEAEs were defined as adverse events that occurred during or after administration of the first dose of IP in this Extension Study. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
|
||||||
End point type |
Primary
|
||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||
| Notes [24] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||
End point title |
Number of Participants Whose Anti-Hyaluronidase Binding Antibody Titers Rose by ≥4-fold From Baseline [25] | ||||||
End point description |
Number of participants whose anti-hyaluronidase antibody titers rose by ≥4 fold from the baseline value at any point during the study was assessed. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
|
||||||
End point type |
Primary
|
||||||
End point timeframe |
Baseline, up to 6.6 years
|
||||||
| Notes [25] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||
End point title |
Number of Participants With Binding Antibodies to rHuPH20 [26] | ||||||
End point description |
Binding antibodies were defined as anti-rHuPH20 titer ≥1:160. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication. Overall number analysed is the number of participants with data available for analyses.
|
||||||
End point type |
Primary
|
||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||
| Notes [26] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
||||||||||
End point title |
Number of Participants With Treatment-Emergent Local Tolerability Events During Ramp-up [27] | |||||||||
End point description |
Participants with local tolerability events=for which infusion rate was reduced and/or infusion was interrupted/stopped due to intolerability and/or AEs.These events were assessed during initial ramp-up for each participant i.e.,during first 8 weeks of open-label extension study 161505[NCT02955355]among participants originally randomised to placebo(as being in placebo arm,they had no ramp-up during the 161403[NCT02549170]study)versus during 8-week ramp-up for participants originally randomised to active HYQVIA in double-blind 161403 study.Thus, data for this endpoint are presented per bifurcation of participants in study 161403. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least 1 dose of study medication. As prespecified in SAP, comparative local tolerability data for ramp-up of 8 weeks from studies 161403 (for participants originally randomised to HYQVIA in double-blind) & 161505 were reported in results of study 161505.
|
|||||||||
End point type |
Primary
|
|||||||||
End point timeframe |
During the ramp-up (8 weeks)
|
|||||||||
| Notes [27] - 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: Only descriptive analysis was planned for this endpoint. |
||||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
|||||||||||||||||||
End point title |
Number of Participants With Local Infusion Reactions, as a Function of Dosing Interval, Infusion Rate per Site, and Infusion Volume per Site [28] | ||||||||||||||||||
End point description |
Local infusion reactions were defined as local (administration site-related) adverse events. Median infusion rate per site was derived as the median value across all participants, per participant’s average infusion rate, by site: actual volume infused / duration in hours of infusion / number of sites. Median infusion volume per site was derived as the median value across all participants, per participant’s average actual volume infused, by site: actual volume infused / number of sites. Number of participants with local infusion reactions as a function of each of these categories are presented below. Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
|
||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||||||||||||||
| Notes [28] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||
End point title |
Number of Participants With Neutralising Antibodies Binding to rHuPH20 [29] | ||||||
End point description |
Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication. Overall number analysed is the number of participants with data available for analyses.
|
||||||
End point type |
Primary
|
||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||
| Notes [29] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||
End point title |
Number of Participants With a Decline of Anti-rHuPH20 Binding Antibody Titers to the Antibody Titer Level at Baseline in Study 161403 or to <1:160 Antibody Titer Level at the Study Completion or Early Discontinuation [30] | ||||||
End point description |
Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
|
||||||
End point type |
Primary
|
||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||
| Notes [30] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||
End point title |
Number of Participants who Had >1:10,000 Anti-rHuPH20 Binding Antibody Titers With Neutralising Antibodies [31] | ||||||||
End point description |
Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication. Overall number analysed is the number of participants who had >1:10,000 anti-rHuPH20 antibody titers.
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||||
| Notes [31] - 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: Only descriptive analysis was planned for this endpoint. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||
End point title |
Number of Participants Who Had >1:10,000 Anti-rHuPH20 Binding Antibody Titers Showing Cross Reactivity With Hyaluronidase (Hyal)-1,2 and 4 | ||||||
End point description |
Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication. Overall number analysed is the number of participants who had >1:10,000 anti-rHuPH20 antibody titers.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
From the first dose of study drug up to end of study (up to 6.6 years)
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From the first dose of study drug up to end of study (up to 6.6 years)
|
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Adverse event reporting additional description |
Safety Analysis Set included all participants who were enrolled in this Extension Study and who received at least one dose of study medication.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
HYQVIA/HyQvia
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants received HYQVIA/HyQvia (rHuPH20 at a dose of 80 U/g IgG, followed by SC IGI 10%) at the same monthly equivalent dose as the individual participant’s IgG treatment in Study 161403, every 3 or 4 weeks in this Extension Study for 77.3 months or until relapse. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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27 Jun 2016 |
The following changes were made as per Amendment 1: 1) Specified that eligible participants may also be recruited from Study 161601 (NCT02955355). 2) The maximum treatment duration was clarified to extend up to 3 years if mandated by regulations. 3) Text was added to clarify the determination of infusion rate based on participant weight, and to specify the differences for administration with single, bifurcated, or trifurcated SC needle sets. 4) The number of potential participants was increased from 124 to 149. 5) A description of Study 161403 was added. 6) The planned statistical analysis was updated. Subgroup analysis was removed and changed to single group analysis. 7) The maximum infusion volume was defined as 1200 milliliters per day (mL/d). 8) Clarified that each participant should be kept on the same infusion schedule as in the parent study. |
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13 Nov 2018 |
The following changes were made as per Amendment 2: 1) All references to Study 161601 was deleted. 2) Planned duration of participant participation was revised. 3) Revised text for dose and mode of administration of IP. 4) Revised rHuPH20 administration text to clarify that the initial infusion rate is to carry over from Study 161403. 5) Planned final analysis of the study was updated. 6) A new section was added on guidance on reporting and assessing rHuPH20 (hyaluronidase) antibody test results. 7) Text was revised for sample size and power calculations. |
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05 Aug 2019 |
The following changes were made as per Amendment 3: 1) Updated primary outcome measures section to include local infusion site reactions to be reported as AEs. 2) Added that an interim analysis is planned to be performed 6 months after unblinding of Study 161403 (unblinding of Epoch 1). |
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10 Jan 2022 |
The following changes were made as per Amendment 4: 1) Target accrual was updated to 88 throughout the protocol. 2) Changed the description for safety/ tolerability outcome measures. 3) Clarified that analyses will be presented by actual treatment received in Study 161403 Epoch 1 and overall. 4) Updated the planned interim analysis timing. |
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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 | |||
