Clinical Trial Results:
A Long-Term Follow-up Study to Evaluate the Safety, Tolerability, and Efficacy of Adeno-Associated Virus (AAV) rh10-Mediated Gene Transfer of Human Factor IX in Adults With Moderate/Severe to Severe Hemophilia B
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Summary
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EudraCT number |
2016-003430-25 |
Trial protocol |
GB |
Global end of trial date |
06 Dec 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
16 Dec 2022
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First version publication date |
16 Dec 2022
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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 |
101HEMB02
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02971969 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
IND Number: 16543 | ||
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Sponsors
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Sponsor organisation name |
Ultragenyx Pharmaceutical Inc.
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Sponsor organisation address |
60 Leveroni Court, Novato, California , United States, 94949
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Public contact |
Patient Advocacy, Ultragenyx Pharmaceutical, Inc., +1 415 756-8657, Trialrecruitment@ultragenyx.com
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Scientific contact |
Medical Information, Ultragenyx Pharmaceutical, Inc., +1 888 756-8657, Medinfo@ultragenyx.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 |
06 Dec 2021
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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 |
06 Dec 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To determine the long-term safety and efficacy of DTX101 following a single IV infusion in adults with moderate/severe to severe hemophilia B.
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Protection of trial subjects |
The trial was designed, conducted, recorded, and reported in accordance with the principles established by the 18th World Medical Association General Assembly (Helsinki, 1964) and subsequent amendments and clarifications adopted by the General Assemblies. The investigators made every effort to ensure that the study was conducted in full conformance with Helsinki principles, International Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines, current Food and Drug Administration (FDA) regulations, EU Clinical Trial Directive 2001/20/EC, and local ethical and regulatory requirements. Each investigator was thoroughly familiar with the appropriate administration and potential risks of administration of the study drug, as described in the protocol and Investigator’s Brochure, prior to the initiation of the study. The method of obtaining and documenting informed consent and the contents of the informed consent form (ICF) complied with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of Human Subjects,” the Health Insurance Portability and Accountability Act regulations, and all other applicable regulatory requirements. Investigators were responsible for preparing the ICF and submitting it to the Sponsor for approval prior to submission to the Institutional Review Board (IRB). All ICFs were written in regional language and contained the minimum elements for consent as mandated by the ICH guidelines. An IRB-approved ICF was provided by the Sponsor prior to initiation of the study. Investigators obtained signed written informed consent from each potential study subject prior to the conduct of any study procedures and after the methods, objectives, requirements, and potential risks of the study were fully explained to each potential subject. Consent for participation could be withdrawn at any time for any reason by the subject.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
16 Jan 2017
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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 |
United Kingdom: 2
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Country: Number of subjects enrolled |
United States: 4
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Worldwide total number of subjects |
6
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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) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
5
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects enrolled in Study 101HEMB02 after completing Study 101HEMB01 (EudraCT number 2015-001486-67), defined as completing visits through Week 52 (Cohort 1) or Week 44 (Cohort 2). Subjects were followed in Study 101HEMB02 for at least 4 years, for a total of at least 5 years from the time of DTX101 administration. | |||||||||
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Pre-assignment
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Screening details |
After providing informed consent, the subject completed Day 0 assessments and the Investigator determined the subject’s eligibility to participate in the study. The Day 0 Visit could coincide with the Study 101HEMB01 Week 52 Visit for subjects in Cohort 1 or the Study 101HEMB01 Week 44 Visit for subjects in Cohort 2. | |||||||||
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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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Are arms mutually exclusive |
Yes
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Arm title
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Cohort 1 | |||||||||
Arm description |
Subjects enrolled in Study 101HEMB02 who received a single intravenous (IV) infusion of DTX101 during Study 101HEMB01 at a dose level of 1.6 × 10^12 GC/kg . No DTX101 was administered during Study 101HEMB02. | |||||||||
Arm type |
No Intervention | |||||||||
Investigational medicinal product name |
DTX101
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Investigational medicinal product code |
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Other name |
non-replicating recombinant AAVrh10 encoding human FIX (hFIX), AAVrh10FIX
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
No DTX101 was administered during Study 101HEMB02.
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Arm title
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Cohort 2 | |||||||||
Arm description |
Subjects enrolled in Study 101HEMB02 who received a single IV infusion of DTX101 during Study 101HEMB01 at a dose level of 5.0 × 10^12 GC/kg. No DTX101 was administered during Study 101HEMB02. | |||||||||
Arm type |
No Intervention | |||||||||
Investigational medicinal product name |
DTX101
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Investigational medicinal product code |
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Other name |
non-replicating recombinant AAVrh10 encoding human FIX (hFIX), AAVrh10FIX
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
No DTX101 was administered during Study 101HEMB02.
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Baseline characteristics reporting groups
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Reporting group title |
Cohort 1
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Reporting group description |
Subjects enrolled in Study 101HEMB02 who received a single intravenous (IV) infusion of DTX101 during Study 101HEMB01 at a dose level of 1.6 × 10^12 GC/kg . No DTX101 was administered during Study 101HEMB02. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort 2
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Reporting group description |
Subjects enrolled in Study 101HEMB02 who received a single IV infusion of DTX101 during Study 101HEMB01 at a dose level of 5.0 × 10^12 GC/kg. No DTX101 was administered during Study 101HEMB02. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cohort 1
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Reporting group description |
Subjects enrolled in Study 101HEMB02 who received a single intravenous (IV) infusion of DTX101 during Study 101HEMB01 at a dose level of 1.6 × 10^12 GC/kg . No DTX101 was administered during Study 101HEMB02. | ||
Reporting group title |
Cohort 2
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Reporting group description |
Subjects enrolled in Study 101HEMB02 who received a single IV infusion of DTX101 during Study 101HEMB01 at a dose level of 5.0 × 10^12 GC/kg. No DTX101 was administered during Study 101HEMB02. | ||
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End point title |
Number of Subjects With Adverse Events (AEs), Treatment-Related Adverse Events (TEAEs), and Serious AEs (SAEs) [1] | |||||||||||||||||||||||||||||||||
End point description |
An AE was defined as any untoward medical occurrence in a subject enrolled into this study (from the time the subject signed the informed consent form until his or her exit from the study), regardless of its causal relationship to study treatment. A TEAE was defined as any event not present before exposure to study product or any event already present that worsened in severity or increased in frequency after exposure to study product. The relationship of TEAE to study product was categorized as “unrelated,” “possibly related,” “probably related,” or “definitely related.” For summaries by relationship, AEs with a missing relationship were considered to be “possibly related.” For summaries by the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 grade (Grades 1 [mild] to 5 [death]), AEs missing a CTCAE grade were considered to be CTCAE Grade 3.
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End point type |
Primary
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End point timeframe |
Follow-up for a median overall duration of 1488.0 days
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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: Descriptive statistics planned per protocol are presented in the data table. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||
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End point title |
Change from Baseline in FIX Activity at Week 208/216 [2] | ||||||||||||
End point description |
As determined by the activated partial thromboplastin time clot-based assay. Change from Baseline = Postbaseline value – Baseline value. For the change from Baseline, only subjects with a value at both the Baseline Visit and the specific postbaseline visit were included.
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End point type |
Primary
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End point timeframe |
Baseline (predose on Day 0 in Study 101HEMB01), Week 208 (Cohort 1)/216 (Cohort 2) ± 14 days
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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: Statistics planned per protocol are presented in the data table. |
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| Notes [3] - 99999=not applicable (1 subject analyzed) |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from Baseline in FIX Activity Over Time | ||||||||||||||||||||||||||||||||||||
End point description |
As determined by the activated partial thromboplastin time clot-based assay. Change from Baseline = Postbaseline value – Baseline value. For the change from Baseline, only subjects with a value at both the Baseline Visit and the specific postbaseline visit were included.
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End point type |
Secondary
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End point timeframe |
Baseline (predose on Day 0 in Study 101HEMB01), Day 0, Weeks 13, 26, 52, 104, 156, 208 (Cohort 1)/216 (Cohort 2) ± 14 days
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| Notes [4] - 99999=not applicable (0 subjects); 999999=not applicable (1 subject) [5] - 99999=not applicable (0 subjects) |
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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 |
Follow-up for a median overall duration of 1488.0 days
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Adverse event reporting additional description |
Events presented below are treatment-emergent adverse events, defined as any event not present before exposure to study product or any event already present that worsened in severity or increased in frequency after exposure to study product.
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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 |
18.1
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Reporting groups
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Reporting group title |
Cohort 1
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Reporting group description |
Subjects enrolled in Study 101HEMB02 who received a single IV infusion of DTX101 during Study 101HEMB01 at a dose level of 1.6 × 10^12 GC/kg . No DTX101 was administered during Study 101HEMB02. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort 2
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Reporting group description |
Subjects enrolled in Study 101HEMB02 who received a single IV infusion of DTX101 during Study 101HEMB01 at a dose level of 5.0 × 10^12 GC/kg. No DTX101 was administered during Study 101HEMB02. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Total
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Reporting group description |
Subjects enrolled in Study 101HEMB02 who received a single IV infusion of DTX101 during Study 101HEMB01 at a dose level of either 1.6 × 10^12 GC/kg or 5.0 × 10^12 GC/kg. No DTX101 was administered during Study 101HEMB02. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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02 Jun 2017 |
• Reduced the number of global study sites from up to 14 to up to 5 and reduced the sample size from approximately 12 to 18 to up to 6 subjects (Section 3.2).
• Added a Week 216 time point (End of Study) for subjects enrolled in Cohort 2 to ensure all subjects are followed for safety for at least 4 years (Section 2, 3.2).
• Increased the visit window for all visits after Day 0 from ±7 days to ±14 days (Table 15-1 and globally).
• Removed the secondary objective and endpoints, which included development of a cell-mediated response to FIX as determined by enzyme-linked immunospot (ELISPOT) assay and the responses to the EuroQol 5D 5-level version™ (EQ-5D-5L) and Haemophilia Specific Quality of Life (Haem-A-QoL) questionnaires. The associated
assessments were also removed (Section 2, 3.2.2, 8.2, 10.2, Table 15-1).
• Removed the exploratory endpoints of the development of a cell-mediated response to AAVrh10 as determined by ELISPOT assay. The associated assessments were also removed (Section 2, 10.3).
• Clarified inclusion criterion #2 to require the completion of Cohort 1/Week 52 or Cohort 2/Week 44 visit in Study 101HEMB01 (Section 4.1).
• Reduced the number of follow-up visits from every 13 weeks to Weeks 26 and 52 for the first year and yearly thereafter for safety and efficacy evaluations. The total follow-up duration was maintained at 4 years (Section 3.2, 3.2.2, Table 15-1).
• Removed electrocardiogram measurements and urinalysis (Section 8.2, 8.2.3, Table 8-1, Table 15-1).
• The recording of on-demand recombinant FIX replacement therapy use was changed from paper or electronic diary to recording as concomitant medications (Section 6.2, 8.1.3).
• The recording of bleeding episodes was changed from paper or electronic diary to as adverse events (Section 8.1.2).
• Interim analyses were changed from annually to on an ad hoc basis (Section 10.4.5). |
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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 | |||
