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Safety and Dose Finding Study of DTX101 (AAVrh10FIX) in Adults With Moderate/Severe to Severe Hemophilia B

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ClinicalTrials.gov Identifier: NCT02618915
Recruitment Status : Terminated (Sponsor decision; not due to any safety concerns related to DTX101.)
First Posted : December 2, 2015
Results First Posted : November 14, 2018
Last Update Posted : November 14, 2018
Sponsor:
Information provided by (Responsible Party):
Ultragenyx Pharmaceutical Inc

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hemophilia B
Intervention Genetic: DTX101
Enrollment 6
Recruitment Details  
Pre-assignment Details  
Arm/Group Title DTX101, Cohort 1 DTX101, Cohort 2
Hide Arm/Group Description a single peripheral intravenous (IV) infusion of 1.6 x 10^12 genome copies (GC)/kg DTX101 a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101
Period Title: Overall Study
Started 3 3
Completed 3 3
Not Completed 0 0
Arm/Group Title DTX101, Cohort 1 DTX101, Cohort 2 Total
Hide Arm/Group Description a single peripheral IV infusion of 1.6 x 10^12 GC/kg DTX101 a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101 Total of all reporting groups
Overall Number of Baseline Participants 3 3 6
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 6 participants
18-49 years 0 3 3
50-84 years 3 0 3
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 6 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
Male
3
 100.0%
3
 100.0%
6
 100.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 6 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
Not Hispanic or Latino
3
 100.0%
3
 100.0%
6
 100.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Factor IX (FIX) Activity   [1] 
Mean (Standard Deviation)
Unit of measure:  IU/dL
Number Analyzed 3 participants 3 participants 6 participants
1.67  (0.577) 0.87  (0.709) 1.27  (0.566)
[1]
Measure Description: The documented history or measurement before the Day 0 visit following the appropriate washout was used for the baseline values of FIX activity.
1.Primary Outcome
Title Number of Participants With Adverse Events (AEs), Treatment-Related Adverse Events (TEAEs), and Serious AEs (SAEs)
Hide Description An AE was defined as any untoward medical occurrence in a participant enrolled into this study (from the time the participant 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.
Time Frame up to 52 weeks after dosing (Cohort 1) or 44 weeks after dosing (Cohort 2)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Set: all participants who received DTX101 including participants who received a partial dose or failed infusion.
Arm/Group Title DTX101, Cohort 1 DTX101, Cohort 2
Hide Arm/Group Description:
a single peripheral IV infusion of 1.6 x 10^12 GC/kg DTX101
a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101
Overall Number of Participants Analyzed 3 3
Measure Type: Count of Participants
Unit of Measure: Participants
All TEAEs
3
 100.0%
3
 100.0%
All Serious TEAEs
1
  33.3%
0
   0.0%
2.Primary Outcome
Title Change From Baseline in FIX Activity at Week 6
Hide Description Peak plasma level of FIX after IV administration as determined by the activated partial thromboplastin time (aPTT) clot-based assay. Change from baseline: postbaseline value - baseline value. For the change from baseline, only participants with a value at both baseline visit and the specific postbaseline visit were included.
Time Frame Baseline, Week 6
Hide Outcome Measure Data
Hide Analysis Population Description
As Treated Set: all participants who received any amount of DTX101.
Arm/Group Title DTX101, Cohort 1 DTX101, Cohort 2
Hide Arm/Group Description:
a single peripheral IV infusion of 1.6 x 10^12 GC/kg DTX101
a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101
Overall Number of Participants Analyzed 3 3
Mean (Standard Deviation)
Unit of Measure: IU/dL
5.00  (1.732) 9.80  (4.687)
3.Secondary Outcome
Title Annualized Bleeding Rate
Hide Description The number of bleeding episodes per participant was recorded, and the annualized number of bleeding episodes was calculated.
Time Frame Week 0 to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
As Treated Set: all participants who received any amount of DTX101.
Arm/Group Title DTX101, Dose 1 DTX101, Dose 3
Hide Arm/Group Description:
1.6 x 10^12 genome copies (GC)/kg DTX101
5.0 x 10^12 GC/kg DTX101
Overall Number of Participants Analyzed 3 3
Mean (Standard Deviation)
Unit of Measure: bleeding episodes/year
8.7  (5.53) 5.0  (1.00)
4.Secondary Outcome
Title Change From Baseline in FIX Activity Over Time
Hide Description Peak plasma level of FIX after IV administration as determined by the aPTT clot-based assay. Change from baseline: postbaseline value - baseline value. For the change from baseline, only participants with a value at both baseline visit and the specific postbaseline visit were included. Participants were not required to stop prophylactic treatment with recombinant FIX until after Week 4 and may have been restarted on their prophylactic recombinant FIX treatment after Week 14.
Time Frame Baseline, Weeks 2, 4, 6, 8, 12, 16, 24, 32, 40, End of Study (Week 52 for Cohort 1, Week 44 for Cohort 2)/Early Withdrawal
Hide Outcome Measure Data
Hide Analysis Population Description
As Treated Set: all participants who received any amount of DTX101.
Arm/Group Title DTX101, Cohort 1 DTX101, Cohort 2
Hide Arm/Group Description:
a single peripheral IV infusion of 1.6 x 10^12 GC/kg DTX101
a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101
Overall Number of Participants Analyzed 3 3
Mean (Standard Deviation)
Unit of Measure: IU/dL
Week 2 16.33  (14.503) 10.13  (7.988)
Week 4 8.67  (7.234) 14.47  (10.835)
Week 6 5.00  (1.732) 9.80  (4.687)
Week 8 14.67  (17.786) 11.80  (6.646)
Week 12 11.33  (4.933) 5.80  (2.207)
Week 16 7.67  (3.215) 5.47  (3.066)
Week 24 2.33  (1.528) 2.47  (2.214)
Week 32 9.33  (11.846) 10.13  (2.702)
Week 40 15.33  (23.965) 12.80  (16.008)
End of Study/Early Withdrawal 1.67  (0.577) 22.47  (1.380)
5.Secondary Outcome
Title Annualized FIX Replacement Therapy
Hide Description The use of on-demand FIX replacement therapy was recorded by dose (IU/kg) administered, and the annualized use of FIX replacement therapy was calculated. Participants were not required to stop prophylactic treatment with recombinant FIX until after Week 4 and may have been restarted on their prophylactic recombinant FIX treatment after Week 14.
Time Frame Week 0 to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
As Treated Set: all participants who received any amount of DTX101.
Arm/Group Title DTX101, Cohort 1 DTX101, Cohort 2
Hide Arm/Group Description:
a single peripheral IV infusion of 1.6 x 10^12 GC/kg DTX101
a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101
Overall Number of Participants Analyzed 3 3
Mean (Standard Deviation)
Unit of Measure: IU/kg
350115.2  (522106.19) 64246.5  (805.34)
6.Secondary Outcome
Title Number of Participants With Neutralizing Antibodies to FIX (FIX Inhibitors)
Hide Description The development of neutralizing antibodies to FIX (FIX inhibitors), as determined by a Bethesda assay. A value of < 0.3 inhibitor units was considered to be no neutralizing antibodies.
Time Frame Day 0 (predose), Weeks 6, 8, 16, 32, 40, End of Study (Week 52 for Cohort 1, Week 44 for Cohort 2)/Early Withdrawal
Hide Outcome Measure Data
Hide Analysis Population Description
As Treated Set: all participants who received any amount of DTX101.
Arm/Group Title DTX101, Cohort 1 DTX101, Cohort 2
Hide Arm/Group Description:
a single peripheral IV infusion of 1.6 x 10^12 GC/kg DTX101
a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101
Overall Number of Participants Analyzed 3 3
Measure Type: Count of Participants
Unit of Measure: Participants
Day 0 (predose) 0 0
Week 6 0 0
Week 8 0 0
Week 16 0 0
Week 32 0 0
Week 40 0 0
End of Study/Early Withdrawal 0 0
7.Secondary Outcome
Title Number of Participants With Cell-Mediated Immune Response to FIX
Hide Description The development of a cell-mediated immune response to FIX, as determined by enzyme-linked immunospot assay (ELISPOT).
Time Frame Day 0 (predose), Weeks 6, 8, 12, 16, 32, 40, 48, End of Study (Week 52 for Cohort 1, Week 44 for Cohort 2)/Early Withdrawal
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Set: all participants who received DTX101 including subjects who received a partial dose or failed infusion.
Arm/Group Title DTX101, Cohort 1 DTX101, Cohort 2
Hide Arm/Group Description:
a single peripheral IV infusion of 1.6 x 10^12 GC/kg DTX101
a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101
Overall Number of Participants Analyzed 3 3
Measure Type: Count of Participants
Unit of Measure: Participants
Day 0 (predose) 0 0
Week 6 0 0
Week 8 0 0
Week 12 0 0
Week 16 0 0
Week 32 0 0
Week 40 0 0
Week 48 0 0
End of Study/Early Withdrawal 0 0
8.Secondary Outcome
Title Number of Participants Responding to the EuroQoL-5D-5 Level (EQ-5D-5L) Questionnaire
Hide Description EQ-5D-5L is a standardized, subject-rated instrument for use as a measure of health outcomes. The EQ 5D-5L includes 2 components: the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ-VAS). The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each dimension, the participant is instructed to indicate whether he or she has "no problems" (1), "some problems" (2), or "severe problems" (3).
Time Frame Baseline (Day 0 predose), Weeks 24, 36, 48, End of Study/Early Withdrawal (up to Week 52)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Set: all participants who received DTX101 including participants who received a partial dose or failed infusion.
Arm/Group Title DTX101, Cohort 1 DTX101, Cohort 2
Hide Arm/Group Description:
a single peripheral IV infusion of 1.6 x 10^12 GC/kg DTX101
a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101
Overall Number of Participants Analyzed 3 3
Measure Type: Count of Participants
Unit of Measure: Participants
Day 0
3
 100.0%
3
 100.0%
Week 24
3
 100.0%
3
 100.0%
Week 36
3
 100.0%
2
  66.7%
Week 48
2
  66.7%
1
  33.3%
End of Study/Early Withdrawal
2
  66.7%
0
   0.0%
9.Secondary Outcome
Title Number of Participants Responding to the Haemophilia-Specific Quality of Life Questionnaire
Hide Description The Haemophilia-Specific Quality of Life questionnaire asks subjects about their perceptions of their health and treatment. The questionnaire is divided into the following 10 dimensions: physical health, feelings, view of themselves, sports & leisure, work & school, dealing with hemophilia, treatment, future, family planning, and partnership & sexuality. Questions are based on a 5-point Likert-scale (1=never, 2=rarely, 3=sometimes, 4=often, 5=all the time). If the question does not apply to the subject, the "not applicable" response is allowed in 3 of the domains (sport & leisure, work & school, family planning). Positively worded items need to be re-coded and domains will be transformed ranging from 0 to 100; higher domain and total scores indicating a higher impairment of health-related quality of life.
Time Frame Baseline (Day 0 predose), Weeks 24, 36, 48, End of Study/Early Withdrawal (up to Week 52)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Set: all participants who received DTX101 including participants who received a partial dose or failed infusion.
Arm/Group Title DTX101, Cohort 1 DTX101, Cohort 2
Hide Arm/Group Description:
a single peripheral IV infusion of 1.6 x 10^12 GC/kg DTX101
a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101
Overall Number of Participants Analyzed 3 3
Measure Type: Count of Participants
Unit of Measure: Participants
Day 0
3
 100.0%
3
 100.0%
Week 24
3
 100.0%
3
 100.0%
Week 36
3
 100.0%
2
  66.7%
Week 48
2
  66.7%
1
  33.3%
End of Study/Early Withdrawal
2
  66.7%
0
   0.0%
10.Secondary Outcome
Title Average Weekly Use of FIX Replacement Therapy
Hide Description The use of on-demand FIX replacement therapy was recorded by dose (IU/kg) administered and the average weekly use of FIX replacement therapy was calculated. Participants were not required to stop prophylactic treatment with recombinant FIX until after Week 4 and may have been restarted on their prophylactic recombinant FIX treatment after Week 14.
Time Frame Baseline (Screening), Week 0 through Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
As Treated Set: all participants who received any amount of DTX101, with an assessment at given time point.
Arm/Group Title DTX101, Cohort 1 DTX101, Cohort 2
Hide Arm/Group Description:
a single peripheral IV infusion of 1.6 x 10^12 GC/kg DTX101
a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101
Overall Number of Participants Analyzed 3 3
Mean (Standard Deviation)
Unit of Measure: IU/kg
Baseline Number Analyzed 3 participants 3 participants
9659.1  (12502.19) 5037.2  (3502.95)
Week 0 to 2 Number Analyzed 2 participants 1 participants
12120.0  (11144.00) 5000.0 [1]   (NA)
Week 3 to 4 Number Analyzed 1 participants 1 participants
24000.0 [1]   (NA) 7000.0 [1]   (NA)
Week 5 to 6 Number Analyzed 2 participants 1 participants
9068.5  (10611.55) 3000.0 [1]   (NA)
Week 7 to 8 Number Analyzed 2 participants 0 participants
5120.0  (1244.51)
Week 9 to 10 Number Analyzed 1 participants 0 participants
32000.0 [1]   (NA)
Week 11 to 12 Number Analyzed 3 participants 0 participants
8076.7  (10325.91)
Week 13 to 14 Number Analyzed 1 participants 0 participants
12000.0 [1]   (NA)
Week 15 to 16 Number Analyzed 1 participants 0 participants
16000.0 [1]   (NA)
Week 17 to 18 Number Analyzed 1 participants 2 participants
8000.0 [1]   (NA) 3375.0  (883.88)
Week 19 to 20 Number Analyzed 1 participants 1 participants
12000.0 [1]   (NA) 8000.0 [1]   (NA)
Week 21 to 22 Number Analyzed 3 participants 0 participants
7832.8  (3057.68)
Week 23 to 24 Number Analyzed 2 participants 0 participants
8782.5  (10207.09)
Week 25 to 26 Number Analyzed 2 participants 2 participants
8902.5  (4380.53) 5445.0  (3952.73)
Week 27 to 28 Number Analyzed 2 participants 2 participants
8120.0  (5487.15) 4725.0  (1025.30)
Week 29 to 30 Number Analyzed 2 participants 2 participants
12120.0  (11144.00) 2250.0  (353.55)
Week 31 to 32 Number Analyzed 1 participants 2 participants
28000.0 [1]   (NA) 2750.0  (1767.77)
Week 33 to 34 Number Analyzed 1 participants 3 participants
12000.0 [1]   (NA) 2816.7  (1877.72)
Week 35 to 36 Number Analyzed 1 participants 0 participants
12000.0 [1]   (NA)
Week 37 to 38 Number Analyzed 2 participants 2 participants
4795.0  (4532.55) 3500.0  (2828.43)
Week 39 to 40 Number Analyzed 2 participants 2 participants
26795.0  (35645.25) 2375.0  (883.88)
Week 41 to 42 Number Analyzed 1 participants 1 participants
24000.0 [1]   (NA) 1500.0 [1]   (NA)
Week 43 to 44 Number Analyzed 1 participants 1 participants
20000.0 [1]   (NA) 1750.0 [1]   (NA)
Week 45 to 46 Number Analyzed 1 participants 1 participants
20000.0 [1]   (NA) 5000.0 [1]   (NA)
Week 47 to 48 Number Analyzed 1 participants 1 participants
20000.0 [1]   (NA) 7500.0 [1]   (NA)
Week 49 to 50 Number Analyzed 1 participants 0 participants
24000.0 [1]   (NA)
Week 51 to 52 Number Analyzed 1 participants 0 participants
20000.0 [1]   (NA)
[1]
Only 1 participant analyzed at this time point.
Time Frame From first dose of study drug up to 52 weeks after dosing (Cohort 1) or 44 weeks after dosing (Cohort 2).
Adverse Event Reporting Description TEAEs are presented. 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. Due to concerns related to participant re-identification in this study, events are presented by system organ class only.
 
Arm/Group Title DTX101, Cohort 1 DTX101, Cohort 2
Hide Arm/Group Description a single peripheral IV infusion of 1.6 x 10^12 GC/kg DTX101 a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101
All-Cause Mortality
DTX101, Cohort 1 DTX101, Cohort 2
Affected / at Risk (%) Affected / at Risk (%)
Total   0/3 (0.00%)   0/3 (0.00%) 
Hide Serious Adverse Events
DTX101, Cohort 1 DTX101, Cohort 2
Affected / at Risk (%) Affected / at Risk (%)
Total   1/3 (33.33%)   0/3 (0.00%) 
Musculoskeletal and connective tissue disorders     
Musculoskeletal and connective tissue disorders  1  1/3 (33.33%)  0/3 (0.00%) 
1
Term from vocabulary, MedDRA 18.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
DTX101, Cohort 1 DTX101, Cohort 2
Affected / at Risk (%) Affected / at Risk (%)
Total   3/3 (100.00%)   3/3 (100.00%) 
Eye disorders     
Eye disorders  1  0/3 (0.00%)  1/3 (33.33%) 
Gastrointestinal disorders     
Gastrointestinal disorders  1  1/3 (33.33%)  1/3 (33.33%) 
General disorders     
General disorders and administration site conditions  1  1/3 (33.33%)  1/3 (33.33%) 
Infections and infestations     
Infections and infestations  1  1/3 (33.33%)  2/3 (66.67%) 
Injury, poisoning and procedural complications     
Injury, poisoning and procedural complications  1  2/3 (66.67%)  1/3 (33.33%) 
Investigations     
Investigations  1  1/3 (33.33%)  3/3 (100.00%) 
Musculoskeletal and connective tissue disorders     
Musculoskeletal and connective tissue disorders  1  2/3 (66.67%)  1/3 (33.33%) 
Nervous system disorders     
Nervous system disorders  1  1/3 (33.33%)  1/3 (33.33%) 
Psychiatric disorders     
Psychiatric disorders  1  0/3 (0.00%)  1/3 (33.33%) 
Respiratory, thoracic and mediastinal disorders     
Respiratory, thoracic and mediastinal disorders  1  0/3 (0.00%)  2/3 (66.67%) 
Vascular disorders     
Vascular disorders  1  1/3 (33.33%)  0/3 (0.00%) 
1
Term from vocabulary, MedDRA 18.1
Indicates events were collected by systematic assessment
After review of the DTX101 Phase 1/2 clinical trial data, a decision was made to discontinue the development of DTX101. The discontinuation was not due to any safety concerns related to DTX101.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Information
Organization: Ultragenyx Pharmaceutical Inc
Phone: 1-888-756-8657
EMail: Medinfo@ultragenyx.com
Layout table for additonal information
Responsible Party: Ultragenyx Pharmaceutical Inc
ClinicalTrials.gov Identifier: NCT02618915    
Other Study ID Numbers: 101HEMB01
First Submitted: November 23, 2015
First Posted: December 2, 2015
Results First Submitted: October 16, 2018
Results First Posted: November 14, 2018
Last Update Posted: November 14, 2018