Clinical Trial Results:
A Multicenter Phase 2 Open-Label, Single-Arm, Prospective, Interventional Study of Plasma-Derived Factor VIIII/VWF (Alphanate®)
in Immune Tolerance Induction Therapy in Subjects with Congenital Hemophilia A
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Summary
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EudraCT number |
2015-005524-26 |
Trial protocol |
ES IT |
Global end of trial date |
18 Sep 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Oct 2021
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First version publication date |
02 Oct 2021
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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 |
GBI1406
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03095287 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
IND/CTA Number: 016703 | ||
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Sponsors
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Sponsor organisation name |
Grifols Biologicals LLC
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Sponsor organisation address |
5555 Valley Boulevard, Los Angeles, United States, CA 90032
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Public contact |
Rhonda Griffin, Grifols Therapeutics LLC, +1 919 316 6693, Rhonda.griffin@grifols.com
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Scientific contact |
Rhonda Griffin, Grifols Therapeutics LLC, +1 919 316 6693, Rhonda.griffin@grifols.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 |
18 Sep 2020
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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 |
18 Sep 2020
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The purpose of the study is to assess the percentage of subjects who achieve complete immune tolerance within 33 months of initiating Alphanate for immune tolerance induction (ITI) and to assess the safety of Alphanate treatment for ITI.
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Protection of trial subjects |
All study subjects were required to read and sign an Informed Consent Form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Jan 2018
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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 |
India: 2
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Worldwide total number of subjects |
2
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EEA total number of subjects |
0
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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) |
2
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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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 |
Subjects took part in the study at two sites in India from 03 January 2018 (first subject enrolled to receive the study drug) to 18 September 2020 (last subject completed). | ||||||||||||
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Pre-assignment
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Screening details |
Male subjects with diagnosis of Congenital Hemophilia A were enrolled in a single arm to receive alphanate. The study was to be conducted in 2 phases: Immune Tolerance Induction Phase followed by Prophylactic Phase. However, due to the limited enrollment, the study was terminated prior to the start of Prophylactic Phase. | ||||||||||||
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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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Alphanate | ||||||||||||
Arm description |
Subjects entered the immune tolerance induction (ITI) phase and received alphanate IV at a starting dose of 100 IU/kg/day. Dose could be uptitrated to 200 IU/kg/day based on investigator’s discretion. The maximum duration of treatment was 32 months and 2 weeks. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Alphanate
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Investigational medicinal product code |
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Other name |
Plasma Derived Factor VIII/von Willebrand Factor
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received Alphanate IV daily until complete immune tolerance was achieved or for 33 months if complete immune tolerance was not achieved. Alphanate was administered 100 International units (IU)/kg/day for at least 90 days during ITI phase. After the first 90 days, dose could be increased to 200 IU/kg/day if there was <20% decrease in inhibitor titer or an increase in the rate of bleeding events relative to the rate of bleeding events experienced during the first 90 days of treatment, or if the inhibitor increased to >500 Bethesda Units (BU), after initiation of Alphanate ITI treatment.
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Baseline characteristics reporting groups
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Reporting group title |
Alphanate
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Reporting group description |
Subjects entered the immune tolerance induction (ITI) phase and received alphanate IV at a starting dose of 100 IU/kg/day. Dose could be uptitrated to 200 IU/kg/day based on investigator’s discretion. The maximum duration of treatment was 32 months and 2 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Alphanate
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Reporting group description |
Subjects entered the immune tolerance induction (ITI) phase and received alphanate IV at a starting dose of 100 IU/kg/day. Dose could be uptitrated to 200 IU/kg/day based on investigator’s discretion. The maximum duration of treatment was 32 months and 2 weeks. | ||
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End point title |
Percentage of Subjects who Achieved Complete Immune Tolerance Within 33 Months of Initiation of Immune Tolerance Induction (ITI) Treatment Phase [1] | ||||||||
End point description |
Complete immune tolerance was defined as the participants achieving 2 consecutive undetectable inhibitor titers (<0.6 BU) performed within 2 weeks of each other, Factor VIII activity (FVIII:C) in vivo plasma recovery ≥66% of the predicted normal value and FVIII:C half-life ≥6 hours after a 72-hour FVIII treatment-free period.
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End point type |
Primary
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End point timeframe |
Up to 32.5 months
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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: Data for this outcome measure was not collected and analysed, as the study was terminated early by the sponsor due to limited enrollment (non-safety related decision). |
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| Notes [2] - The data was not analysed as the study was terminated by sponsor due to limited enrollment. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects who Achieved Either Complete or Partial Immune Tolerance Within 33 Months of Initiation of ITI Treatment Phase | ||||||||
End point description |
Complete immune tolerance was defined as the participants achieving 2 consecutive undetectable inhibitor titers (<0.6 BU) performed within 2 weeks of each other, Factor VIII activity (FVIII:C) in vivo plasma recovery ≥66% of the predicted normal value and FVIII:C half-life ≥6 hours after a 72-hour FVIII treatment-free period. Partial immune tolerance was defined as participants achieving reduction of inhibitor titer to <5 BU confirmed at 2 consecutive assessments within 2 weeks of each other, FVIII:C in vivo plasma recovery of <66% of the predicted normal value or FVIII:C half-life of <6 hours after a 72-hour FVIII treatment-free period and clinical response to FVIII therapy. Data for this outcome measure was not collected and analysed, as the study was terminated early by the sponsor due to limited enrollment (non-safety related decision).
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End point type |
Secondary
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End point timeframe |
Up to 32.5 months
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| Notes [3] - The data was not analysed as the study was terminated by sponsor due to limited enrollment. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects who Achieved Complete or Partial Immune Tolerance Without Relapse During the Prophylactic Phase | ||||||||
End point description |
Relapse during the prophylactic phase for participants who have achieved complete immune tolerance was defined as a return of FVIII inhibitor titer to detectable levels (≥0.6 BU) or FVIII:C recovery <66% of the predicted normal value or FVIII:C half-life <6 hours, confirmed by repeat assessment within approximately 2 weeks. Relapse for participants who have achieved partial immune tolerance was defined as an increase of FVIII inhibitor titer to ≥5 BU, confirmed by repeat assessment within approximately 2 weeks. Data for this outcome measure was not collected and analysed, as the study was terminated early by the sponsor due to limited enrollment (non-safety related decision).
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End point type |
Secondary
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End point timeframe |
12 months during prophylactic phase
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| Notes [4] - The data was not analysed as the study was terminated by sponsor due to limited enrollment. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Bleeding Events During ITI Treatment Phase and Prophylactic Phase | ||||||||
End point description |
This study was terminated, and the data is not reported for this outcome measure to main participant’s confidentiality.
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End point type |
Secondary
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End point timeframe |
Up to 32.5 months
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| Notes [5] - Study was terminated, the data is not reported for this endpoint to maintain subject confidentiality |
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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 |
Up to 32.5 months
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Adverse event reporting additional description |
Safety population included all subjects who received any amount of Alphanate.
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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 |
17.1
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Reporting groups
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Reporting group title |
Alphanate
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Reporting group description |
Subjects entered the immune tolerance induction (ITI) phase and received alphanate IV at a starting dose of 100 IU/kg/day. Dose could be uptitrated to 200 IU/kg/day based on investigator’s discretion. The maximum duration of treatment was 32 months and 2 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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10 Feb 2016 |
The purpose of the amendment was to add synopsis, visits were changed from every month to Weeks 2, 4, 6, and 8 and monthly thereafter, inclusion criterion was changed to restrict range of inhibitor titer levels to > 0.6 BU and < 10 BU at Screening, exclusion criteria was changed to allow for previous use of treatments prohibited during the study (i.e., immunosuppressive drugs azathioprine, cyclophosphamide, high-dose immunoglobulin, interferon, or protein A column or plasmapheresis) prior to study enrolment, requirement to discontinue subjects who experience an interruption of ITI treatments for > 2 weeks, who receive < 80% of prescribed ITI treatment over a continuous 8-week period, or who experience a relapse during the Prophylactic Phase of the study was removed, assessment was added of FVIII:C in vivo recovery and if FVIII:C in vivo recovery is ≥ 66%, that separate visits will be needed to perform the FVIII:C half-life assessment. |
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20 Dec 2016 |
The purpose of the amendment was to add 2-hour time window at the 12-hour timepoint when sampling for FVIII:C
half-life, immunosuppressive treatment initiated after inhibitor diagnosis will be collected under baseline characteristics was added.
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21 Mar 2019 |
The purpose of the amendment was to increase participating sites from 20 to 30, emicizumab was added as a permitted concomitant medication. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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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 | |||||||
