Dose Confirmation Trial of AAV5-hFIXco-Padua

• Sponsor: CSL Behring (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03489291
• Collaborator: (none)
• Enrollment: 3
• Locations: 4
• Arm: 1
• Anticipated Duration (Months): 61.9
• Patients Per Site: 0.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is an open-label, single-dose, single-arm, multi-center trial, with a screening, a treatment + post-treatment follow-up phase, and a long-term follow-up phase.

The IMP AMT-061 is a recombinant adeno-associated viral vector of serotype 5 (AAV5) containing the Padua variant of a codon-optimized human FIX complementary deoxyribonucleic acid (cDNA) under the control of a liver-specific promoter. The IMP is identified as AAV5-hFIXco-Padua (AMT- 061). The pharmaceutical form of AMT-061 is a solution for intravenous infusion.

The administered dose of AMT-061 will be 2 x 10^13 gc/kg.

Condition or Disease	Intervention/Treatment	Phase
Hemophilia B	Genetic: AAV5-hFIXco-Padua (AMT-061)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: open-label, single-dose, single-arm, multi-center trialopen-label, single-dose, single-arm, multi-center trial
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase IIb, Open-label, Single-dose, Single-arm, Multi-center Trial to Confirm the Factor IX Activity Level of the Serotype 5 Adeno-associated Viral Vector Containing the Padua Variant of a Codon-optimized Human Factor IX Gene (AAV5-hFIXco-Padua, AMT-061) Administered to Adult Subjects With Severe or Moderately Severe Hemophilia B
• Actual Study Start Date: Jul 24, 2018
• Actual Primary Completion Date: Oct 30, 2018
• Anticipated Study Completion Date: Sep 20, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single infusion of AMT-061 Subjects will receive a single infusion of AAV5-hFIXco-Padua (AMT- 061) at baseline. After IMP administration (post IMP), subjects will be monitored for tolerance to the IMP and detection of potential immediate AEs at the clinical trial site for 24 hours (overnight stay).	Genetic: AAV5-hFIXco-Padua (AMT-061); Single intravenous infusion of AAV5-hFIXco-Padua (AMT-061)

Outcome Measures

Primary Outcome Measures

1. FIX Activity Levels [6 weeks post-dose]

   To confirm that a single dose of 2x10^13 gc/kg AMT-061 will result in FIX activity levels of ≥5% at 6 weeks after dosing measured by the one-stage (aPTT-based) assay.

Secondary Outcome Measures

1. Annualized Exogenous Factor IX Usage [30 months post-dose]

   Annualized use was calculated as the normalized amount of therapy administered per baseline weight, extrapolated where necessary from any time period less or greater than 1 year. Therapy administered included the total dosage of FIX given as prophylaxis and on-demand. Use for invasive procedures was not included.

2. Annualized Bleeding Rate (ABR) [30 months post-dose]

   ABR was calculated as the ratio of the number of bleeds to the number of days in the time interval multiplied by 365.25.

3. FIX Activity Levels [52 weeks post-dose]

   Measured by the one-stage (aPTT-based) assay.

4. Annualized Exogenous Factor IX Usage Post-Continuous Prophylaxis [30 months post-dose]

   The Post-Continuous-Prophylaxis period began on the day after the end of continuous (routine) prophylaxis.

5. Safety Endpoints [5 years post-dose]

   AEs Hematology and serum chemistry parameters ALT/AST levels and corticosteroid use for ALT/AST elevations Parameters on antibody formation to AAV5 and human factor IX AAV5 capsid-specific T cell response Inflammatory markers Vector DNA in semen and blood AFP

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male

2. Age ≥18 years

3. Subjects with congenital hemophilia B classified as severe or moderately severe

4. 20 previous exposure days of treatment with FIX protein

Exclusion Criteria:

1. History of FIX inhibitors

2. Positive FIX inhibitor test at screening

3. Select screening laboratory values > 2 times upper normal limit:

4. Positive human immunodeficiency virus (HIV) at screening, not controlled with anti-viral therapy

5. Active infection with Hepatitis B or C virus at screening

6. History of Hepatitis B or C exposure, currently controlled by antiviral therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Los Angeles Orthopedic Hospital	Los Angeles	California	United States	90007
2	University of California, Davis	Sacramento	California	United States	95817
3	University of California, San Diego	San Diego	California	United States	92122
4	University of Michigan	Ann Arbor	Michigan	United States	48109

Sponsors and Collaborators

• CSL Behring

Investigators

• Principal Investigator: Steven Pipe, MD, University of Michigan

Study Documents (Full-Text)

• Study Protocol - Feb 8, 2022
• Statistical Analysis Plan - Dec 7, 2021

More Information

Publications

None provided.

• Responsible Party: CSL Behring
• ClinicalTrials.gov Identifier: NCT03489291
• Other Study ID Numbers: CSL222_2001 (CT-AMT-061-01)
• First Posted: Apr 5, 2018
• Last Update Posted: Jun 16, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by CSL Behring: Hemophilia,; Gene Therapy; Bleeding; Factor IX; FIX; viral vector; Padua
• Additional relevant MeSH terms: Hemophilia A; Hemophilia B

Study Results

Participant Flow

Arm/Group Title	AMT-061
Arm/Group Description	AAV5-hFIXco-Padua (AMT-061): Single intravenous infusion of AAV5-hFIXco-Padua (AMT-061)
Period Title: Overall Study
STARTED	3
COMPLETED	3
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	AMT-061
Arm/Group Description	AAV5-hFIXco-Padua (AMT-061): Single intravenous infusion of AAV5-hFIXco-Padua (AMT-061)
Overall Participants	3
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	3 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.7 (3.5)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	3 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	3 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 66.7%
White	1 33.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%

Outcome Measures

1. Primary Outcome

Title	FIX Activity Levels
Description	To confirm that a single dose of 2x10^13 gc/kg AMT-061 will result in FIX activity levels of ≥5% at 6 weeks after dosing measured by the one-stage (aPTT-based) assay.
Time Frame	6 weeks post-dose

Outcome Measure Data

Analysis Population Description

All subjects treated

Arm/Group Title	AMT-061
Arm/Group Description	AAV5-hFIXco-Padua (AMT-061): Single intravenous infusion of AAV5-hFIXco-Padua (AMT-061)
Measure Participants	3
Mean (Standard Deviation) [Factor IX activity (%)]	30.6 (6.97)

2. Secondary Outcome

Title	Annualized Exogenous Factor IX Usage
Description	Annualized use was calculated as the normalized amount of therapy administered per baseline weight, extrapolated where necessary from any time period less or greater than 1 year. Therapy administered included the total dosage of FIX given as prophylaxis and on-demand. Use for invasive procedures was not included.
Time Frame	30 months post-dose

Outcome Measure Data

Analysis Population Description

All subjects treated

Arm/Group Title	AMT-061
Arm/Group Description	AAV5-hFIXco-Padua (AMT-061): Single intravenous infusion of AAV5-hFIXco-Padua (AMT-061)
Measure Participants	3
Mean (Standard Deviation) [IU/year]	1220.4 (1078.8)

3. Secondary Outcome

Title	Annualized Bleeding Rate (ABR)
Description	ABR was calculated as the ratio of the number of bleeds to the number of days in the time interval multiplied by 365.25.
Time Frame	30 months post-dose

Outcome Measure Data

Analysis Population Description

All Subjects Treated. Two subjects did not experience any bleeding episodes post-AMT-061 administration. No subjects experienced joint bleeds.

Arm/Group Title	AMT-061
Arm/Group Description	AAV5-hFIXco-Padua (AMT-061): Single intravenous infusion of AAV5-hFIXco-Padua (AMT-061)
Measure Participants	3
All bleeds	0.27
Spontaneous bleeds	0.14
Traumatic bleeds	0.14

4. Secondary Outcome

Title	FIX Activity Levels
Description	Measured by the one-stage (aPTT-based) assay.
Time Frame	52 weeks post-dose

Outcome Measure Data

Analysis Population Description

All subjects treated

Arm/Group Title	AMT-061
Arm/Group Description	AAV5-hFIXco-Padua (AMT-061): Single intravenous infusion of AAV5-hFIXco-Padua (AMT-061)
Measure Participants	3
Mean (Standard Deviation) [Factor IX activity (%)]	40.8 (9.45)

5. Secondary Outcome

Title	Annualized Exogenous Factor IX Usage Post-Continuous Prophylaxis
Description	The Post-Continuous-Prophylaxis period began on the day after the end of continuous (routine) prophylaxis.
Time Frame	30 months post-dose

Outcome Measure Data

Analysis Population Description

All subjects treated

Arm/Group Title	AMT-061
Arm/Group Description	AAV5-hFIXco-Padua (AMT-061): Single intravenous infusion of AAV5-hFIXco-Padua (AMT-061)
Measure Participants	3
Overall	689.1 (1193.5)
Year 1	568.3 (984.4)
Year 2	1133.3 (1963.0)

6. Secondary Outcome

Title	Safety Endpoints
Description	AEs Hematology and serum chemistry parameters ALT/AST levels and corticosteroid use for ALT/AST elevations Parameters on antibody formation to AAV5 and human factor IX AAV5 capsid-specific T cell response Inflammatory markers Vector DNA in semen and blood AFP
Time Frame	5 years post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	30 months post-dose
Arm/Group Title	AMT-061
Arm/Group Description	AAV5-hFIXco-Padua (AMT-061): Single intravenous infusion of AAV5-hFIXco-Padua (AMT-061)
All Cause Mortality
	AMT-061
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Serious Adverse Events
	AMT-061
	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)
Musculoskeletal and connective tissue disorders
Osteonecrosis	1/3 (33.3%)	2
Other (Not Including Serious) Adverse Events
	AMT-061
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Cardiac disorders
Tachycardia	1/3 (33.3%)	1
Ear and labyrinth disorders
Vertigo	1/3 (33.3%)	1
Gastrointestinal disorders
Tongue disorder	1/3 (33.3%)	1
General disorders
Pain	1/3 (33.3%)	6
Chest pain	1/3 (33.3%)	3
Asthenia	1/3 (33.3%)	1
Immune system disorders
Hypersensitivity	1/3 (33.3%)	1
Infections and infestations
Upper respiratory tract infection	1/3 (33.3%)	2
Bronchitis	1/3 (33.3%)	1
Coccidioidomycosis	1/3 (33.3%)	1
Influenza	1/3 (33.3%)	1
Pneumonia	1/3 (33.3%)	1
Investigations
Alanine aminotransferase increased	1/3 (33.3%)	2
Aspartate aminotransferase increased	1/3 (33.3%)	1
Blood creatine phosphokinase increased	1/3 (33.3%)	1
Blood potassium decreased	1/3 (33.3%)	1
C-reactive protein increased	1/3 (33.3%)	1
Transaminases increased	1/3 (33.3%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	2/3 (66.7%)	3
Back pain	2/3 (66.7%)	2
Joint range of motion decreased	1/3 (33.3%)	1
Joint swelling	1/3 (33.3%)	1
Nervous system disorders
Headache	2/3 (66.7%)	3
Paraesthesia	1/3 (33.3%)	2
Sinus headache	1/3 (33.3%)	2
Dizziness	1/3 (33.3%)	1
Reproductive system and breast disorders
Erectile dysfunction	1/3 (33.3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/3 (33.3%)	2
Vascular disorders
Hypertension	1/3 (33.3%)	1
Peripheral coldness	1/3 (33.3%)	1

Limitations/Caveats

[Not Specified]

More Information

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.