Back to results

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

Primary Purpose

Hemophilia B

Status

Terminated

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

DTX101

About this trial

This is an interventional treatment trial for Hemophilia B focused on measuring gene therapy, Hemophilia B

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

Male ≥ 18 years of age.
Moderate/severe or severe hemophilia B (baseline FIX activity ≤ 2% of normal or documented history of FIX activity ≤2%).
At least 3 bleeding episodes per year that require on-demand treatment with FIX OR are treated with a prophylactic regimen of FIX.
At least 100 days exposure history to FIX.
No documented history of inhibitors (neutralizing antibodies) to exogenous FIX.
No known allergic reaction to exogenous FIX or any component of DTX101.
Willing to stop prophylactic treatment with recombinant FIX at specified time points during the study.

Exclusion Criteria:

History of significant liver disease (ie, portal hypertension).
Significant hepatic inflammation or cirrhosis.
Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
History of human immunodeficiency virus (HIV) infection AND any of the following: CD4+ cell count < 350 cells/mm^3, change in antiretroviral therapy regimen within 6 months prior to Day 0, or plasma viral load > 200 copies/mL, on 2 separate occasions, as measured by polymerase chain reaction.
Anti-AAVrh10 neutralizing antibody titer > 1:5.
Participation (current or previous) in another gene therapy study.
Participation in another investigational medicine study within 3 months before screening.

NOTE: Other protocol defined inclusion/exclusion criteria may apply.

Sites / Locations

Arkansas Children's Hospital
Orthopaedic Institute for Children
University of Florida
Boston Children's Hospital
University of Michigan Hospital and Health Systems, Michigan Clinical Research Unit
Vanderbilt Hemostasis-Thrombosis Clinic
Specialized Hospital for Active Treatment for Hematological Disease
Basingstoke and North Hampshire Hospital, Haemophilia, Haemostasis and Thrombosis Centre
The Christie NHS Foundation Trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

DTX101, Cohort 1

DTX101, Cohort 2

Arm 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

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events (AEs), Treatment-Related Adverse Events (TEAEs), and Serious AEs (SAEs)

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.

Change From Baseline in FIX Activity at Week 6

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.

Secondary Outcome Measures

Annualized Bleeding Rate

The number of bleeding episodes per participant was recorded, and the annualized number of bleeding episodes was calculated.

Change From Baseline in FIX Activity Over Time

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.

Annualized FIX Replacement Therapy

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.

Number of Participants With Neutralizing Antibodies to FIX (FIX Inhibitors)

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.

Number of Participants With Cell-Mediated Immune Response to FIX

The development of a cell-mediated immune response to FIX, as determined by enzyme-linked immunospot assay (ELISPOT).

Number of Participants Responding to the EuroQoL-5D-5 Level (EQ-5D-5L) Questionnaire

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).

Number of Participants Responding to the Haemophilia-Specific Quality of Life Questionnaire

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.

Average Weekly Use of FIX Replacement Therapy

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.

Full Information

NCT ID

NCT02618915

First Posted

November 23, 2015

Last Updated

October 16, 2018

Sponsor

Ultragenyx Pharmaceutical Inc

1. Study Identification

Unique Protocol Identification Number

NCT02618915

Brief Title

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

Official Title

Phase I/II Open-Label Safety and Dose Finding Study of Adeno-Associated Virus (AAV) rh10-Mediated Gene Transfer of Human Factor IX in Adults With Moderate/Severe to Severe Hemophilia B

Study Type

Interventional

2. Study Status

Record Verification Date

October 2018

Overall Recruitment Status

Terminated

Why Stopped

Sponsor decision; not due to any safety concerns related to DTX101.

Study Start Date

December 16, 2015 (Actual)

Primary Completion Date

October 18, 2017 (Actual)

Study Completion Date

October 18, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Ultragenyx Pharmaceutical Inc

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

A Phase 1/2, open-label, dose-finding safety study of single ascending doses of DTX101 in adult males with moderate/severe to severe hemophilia B.

Detailed Description

Hemophilia B is an X-linked recessive genetic bleeding disorder caused by mutations in the factor IX (FIX) gene. FIX is produced in the liver and is critical for fibrin clot formation. Hemophilia B is characterized by frequent, spontaneous internal bleeding that can lead to chronic arthropathy (joint damage), intracranial hemorrhage, and even death. In patients with moderate/severe to severe hemophilia B, the majority of bleeding episodes occur in the joints and, if not treated, lead to debilitating damage and a decreased quality of life. This study will evaluate the safety and efficacy of the adeno-associated virus (AAV) to deliver human factor IX (hFIX) gene, the healthy gene necessary to make FIX, to the liver where FIX is normally produced. This study will determine if AAVrh10 can produce clinically meaningful FIX levels in patients with moderately/severe or severe hemophilia B. This study was previously posted by Dimension Therapeutics, which has been acquired by Ultragenyx in November 2017.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hemophilia B

Keywords

gene therapy, Hemophilia B

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

6 (Actual)

8. Arms, Groups, and Interventions

Arm Title

DTX101, Cohort 1

Arm Type

Experimental

Arm Description

a single peripheral intravenous (IV) infusion of 1.6 x 10^12 genome copies (GC)/kg DTX101

Arm Title

DTX101, Cohort 2

Arm Type

Experimental

Arm Description

a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101

Intervention Type

Genetic

Intervention Name(s)

DTX101

Other Intervention Name(s)

non-replicating recombinant AAVrh10 encoding human FIX (hFIX), AAVrh10FIX

Intervention Description

solution for IV infusion

Primary Outcome Measure Information:

Title

Number of Participants With Adverse Events (AEs), Treatment-Related Adverse Events (TEAEs), and Serious AEs (SAEs)

Description

Time Frame

up to 52 weeks after dosing (Cohort 1) or 44 weeks after dosing (Cohort 2)

Title

Change From Baseline in FIX Activity at Week 6

Description

Time Frame

Baseline, Week 6

Secondary Outcome Measure Information:

Title

Annualized Bleeding Rate

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

Title

Change From Baseline in FIX Activity Over Time

Description

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

Title

Annualized FIX Replacement Therapy

Description

Time Frame

Week 0 to Week 52

Title

Number of Participants With Neutralizing Antibodies to FIX (FIX Inhibitors)

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

Title

Number of Participants With Cell-Mediated Immune Response to FIX

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

Title

Number of Participants Responding to the EuroQoL-5D-5 Level (EQ-5D-5L) Questionnaire

Description

Time Frame

Baseline (Day 0 predose), Weeks 24, 36, 48, End of Study/Early Withdrawal (up to Week 52)

Title

Number of Participants Responding to the Haemophilia-Specific Quality of Life Questionnaire

Description

Time Frame

Baseline (Day 0 predose), Weeks 24, 36, 48, End of Study/Early Withdrawal (up to Week 52)

Title

Average Weekly Use of FIX Replacement Therapy

Description

Time Frame

Baseline (Screening), Week 0 through Week 52

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male ≥ 18 years of age. Moderate/severe or severe hemophilia B (baseline FIX activity ≤ 2% of normal or documented history of FIX activity ≤2%). At least 3 bleeding episodes per year that require on-demand treatment with FIX OR are treated with a prophylactic regimen of FIX. At least 100 days exposure history to FIX. No documented history of inhibitors (neutralizing antibodies) to exogenous FIX. No known allergic reaction to exogenous FIX or any component of DTX101. Willing to stop prophylactic treatment with recombinant FIX at specified time points during the study. Exclusion Criteria: History of significant liver disease (ie, portal hypertension). Significant hepatic inflammation or cirrhosis. Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. History of human immunodeficiency virus (HIV) infection AND any of the following: CD4+ cell count < 350 cells/mm^3, change in antiretroviral therapy regimen within 6 months prior to Day 0, or plasma viral load > 200 copies/mL, on 2 separate occasions, as measured by polymerase chain reaction. Anti-AAVrh10 neutralizing antibody titer > 1:5. Participation (current or previous) in another gene therapy study. Participation in another investigational medicine study within 3 months before screening. NOTE: Other protocol defined inclusion/exclusion criteria may apply.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director

Organizational Affiliation

Ultragenyx Pharmaceutical Inc

Official's Role

Study Director

Facility Information:

Facility Name

Arkansas Children's Hospital

City

Little Rock

State/Province

Arkansas

ZIP/Postal Code

72202

Country

United States

Facility Name

Orthopaedic Institute for Children

City

Los Angeles

State/Province

California

ZIP/Postal Code

90007

Country

United States

Facility Name

University of Florida

City

Gainesville

State/Province

Florida

ZIP/Postal Code

32610

Country

United States

Facility Name

Boston Children's Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Facility Name

University of Michigan Hospital and Health Systems, Michigan Clinical Research Unit

City

Ann Arbor

State/Province

Michigan

ZIP/Postal Code

48109

Country

United States

Facility Name

Vanderbilt Hemostasis-Thrombosis Clinic

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

Facility Name

Specialized Hospital for Active Treatment for Hematological Disease

City

Sofia

ZIP/Postal Code

1756

Country

Bulgaria

Facility Name

Basingstoke and North Hampshire Hospital, Haemophilia, Haemostasis and Thrombosis Centre

City

Basingstoke

State/Province

Hampshire

ZIP/Postal Code

RG24 9NA

Country

United Kingdom

Facility Name

The Christie NHS Foundation Trust

City

Manchester

ZIP/Postal Code

M20 4BX

Country

United Kingdom

12. IPD Sharing Statement

Learn more about this trial

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

We'll reach out to this number within 24 hrs