Safety Dose Finding Study of ADVM-043 Gene Therapy to Treat Alpha-1 Antitrypsin (A1AT) Deficiency (ADVANCE)

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ClinicalTrials.gov Identifier: NCT02168686

Recruitment Status : Completed

First Posted : June 20, 2014

Results First Posted : August 8, 2022

Last Update Posted : October 5, 2023

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Sponsor:

Information provided by (Responsible Party):

Adverum Biotechnologies, Inc.

Study Type	Interventional
Study Design	Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Alpha 1-Antitrypsin Deficiency
Intervention	Genetic: ADVM-043
Enrollment	6

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Part A: Dose 1	Part A: Dose 2	Part A: Dose 3
Arm/Group Description	Single IV infusion of ADVM-043 at 8...	Single IV infusion of ADVM-043 at 4...	Single IV infusion of ADVM-043 at 1...
Arm/Group Description	Single IV infusion of ADVM-043 at 8E13 total vg	Single IV infusion of ADVM-043 at 4E14 total vg	Single IV infusion of ADVM-043 at 1.2E15 total vg
Period Title: Overall Study
Started	2	2	2
Completed	2	2	2
Not Completed	0	0	0

Baseline Characteristics

Arm/Group Title		Part A: Dose 1	Part A: Dose 2	Part A: Dose 3	Total
Arm/Group Description		Single IV infusion of ADVM-043 at 8...	Single IV infusion of ADVM-043 at 4...	Single IV infusion of ADVM-043 at 1...	Total of all reporting groups
Arm/Group Description		Single IV infusion of ADVM-043 at 8E13 total vg	Single IV infusion of ADVM-043 at 4E14 total vg	Single IV infusion of ADVM-043 at 1.2E15 total vg	Total of all reporting groups
Overall Number of Baseline Participants		2	2	2	6
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2 participants	2 participants	2 participants	6 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	2 100.0%	2 100.0%	1 50.0%	5 83.3%
	>=65 years	0 0.0%	0 0.0%	1 50.0%	1 16.7%
Age, Continuous Mean (Full Range) Unit of measure: Years
	Number Analyzed	2 participants	2 participants	2 participants	6 participants
		40.5 (25 to 56)	53.5 (52 to 55)	61.0 (53 to 69)	51.7 (25 to 69)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2 participants	2 participants	2 participants	6 participants
	Female	0 0.0%	1 50.0%	2 100.0%	3 50.0%
	Male	2 100.0%	1 50.0%	0 0.0%	3 50.0%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2 participants	2 participants	2 participants	6 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	White	2 100.0%	2 100.0%	2 100.0%	6 100.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment Measure Type: Number Unit of measure: Participants
United States	Number Analyzed	2 participants	2 participants	2 participants	6 participants
United States		2	2	2	6

Outcome Measures

1.Primary Outcome


Title	Treatment-emergent Adverse Events Related to ADVM-043
Description	Number and proportion of subjects experiencing treatment-related adver...
Description	Number and proportion of subjects experiencing treatment-related adverse events related to ADVM-043
Time Frame	From ADVM-043 infusion through End-of-Study visit at 52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Part A: Dose 1	Part A: Dose 2	Part A: Dose 3
Arm/Group Description:	Single IV infusion of ADVM-043 at 8...	Single IV infusion of ADVM-043 at 4...	Single IV infusion of ADVM-043 at 1...
Arm/Group Description:	Single IV infusion of ADVM-043 at 8E13 total vg	Single IV infusion of ADVM-043 at 4E14 total vg	Single IV infusion of ADVM-043 at 1.2E15 total vg
Overall Number of Participants Analyzed	2	2	2
Measure Type: Count of Participants Unit of Measure: Participants
	0 0.0%	1 50.0%	2 100.0%

2.Primary Outcome


Title	Abnormal Changes in Clinical Laboratory Parameters
Description	Number of participants with ≥1 abnormal shift from Baseline in n...
Description	Number of participants with ≥1 abnormal shift from Baseline in neutrophil count, hemoglobin, important serum chemistry parameters
Time Frame	From ADVM-043 infusion through End-of-Study visit at 52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Part A: Dose 1	Part A: Dose 2	Part A: Dose 3	Total
Arm/Group Description:	Single IV infusion of ADVM-043 at 8...	Single IV infusion of ADVM-043 at 4...	Single IV infusion of ADVM-043 at 1...	All Participants
Arm/Group Description:	Single IV infusion of ADVM-043 at 8E13 total vg	Single IV infusion of ADVM-043 at 4E14 total vg	Single IV infusion of ADVM-043 at 1.2E15 total vg	All Participants
Overall Number of Participants Analyzed	2	2	2	6
Measure Type: Number Unit of Measure: participants
Neutrophil Count Shifts to High	2	1	2	5
Neutrophil Count Shifts to Low	0	0	0	0
Hemoglobin Shifts to High	0	1	1	2
Hemoglobin Shifts to Low	0	0	0	0
Alanine Transaminase Shifts to High (max >1.0 to ≤2.0×upper limit of normal)	1	1	1	3
Alanine Transaminase Shifts to High (max >2.0 to ≤3.0×upper limit of normal	0	1	1	2
Alanine Transaminase Shifts to High (max >3.0×upper limit of normal)	0	0	0	0
Aspartate Transaminase Shifts to High (max >1.0 to ≤2.0×upper limit of normal)	0	1	1	2
Aspartate Transaminase Shifts to High (max >2.0 to ≤3.0×upper limit of normal)	0	0	1	1
Aspartate Transaminase Shifts to High (max >3.0×upper limit of normal)	0	0	0	0
Alkaline Phosphatase Shifts to High	0	0	1	1
Creatinine Shifts to High	0	0	0	0
Creatinine Shifts to Low	0	0	1	1
Creatine Kinase Shifts to High	1	0	1	2
Creatine Kinase Shifts to Low	1	0	0	1
Albumin Shifts to High	0	0	0	0
Albumin Shifts to Low	0	0	0	0
Direct Bilirubin Shifts to High	0	0	0	0
Direct Bilirubin Shifts to Low	0	0	0	0
Serum Glucose Shifts to High	2	1	1	4
Serum Glucose Shifts to Low	1	0	2	3

3.Secondary Outcome


Title	Change in Plasma Concentrations of M-specific A1AT up to 52 Weeks
Description	Change from baseline at Week 52 of plasma concentration of M-specific ...
Description	Change from baseline at Week 52 of plasma concentration of M-specific A1AT for subjects who did not receive PAT post-dose Note: Two subjects in Dose 1 Arm/Group, had results available at Week 52; the remaining 4 subjects in Dose 2 Arm/Group and Dose 3 Arm/Group had resumed PAT therapy after Week 24, and their results were censored from the Week 52 timepoint. While data on the Total Plasma Concentrations of A1AT up to 52 Weeks were collected for 1 study participant in Part A: Dose 3, no data were collected on the Change in Plasma Concentrations of M-specific A1AT due to the initiation of PAT after 24 weeks in Part A: Dose 3 subjects.
Time Frame	At Week 52

Outcome Measure Data

Analysis Population Description

Not analyzed per the statistical analysis plan because participants initiated PAT therapy


Arm/Group Title	Part A: Dose 1	Part A: Dose 2	Part A: Dose 3	Total: All Participants
Arm/Group Description:	Single IV infusion at 8E13 total vg	Single IV infusion at 4E14 total vg	Single IV infusion at 1.2E15 total ...	All subjects who received ADVM-043
Arm/Group Description:	Single IV infusion at 8E13 total vg	Single IV infusion at 4E14 total vg	Single IV infusion at 1.2E15 total vg	All subjects who received ADVM-043
Overall Number of Participants Analyzed	2	0	0	2
Mean (Standard Deviation) Unit of Measure: uM
	88.050 (19.955)			88.050 (19.955)

4.Secondary Outcome


Title	Changes in Total Plasma Concentrations of A1AT up to 52 Weeks
Description	Change from baseline at Week 24 and Week 52 of total A1At plasma conce...
Description	Change from baseline at Week 24 and Week 52 of total A1At plasma concentration for subjects who did not receive PAT post -dose
Time Frame	At Week 52

Outcome Measure Data

Analysis Population Description

Not analyzed per the statistical analysis plan because participant initiated PAT therapy


Arm/Group Title		Part A: Dose 1	Part A: Dose 2	Part A: Dose 3	Total: All Participants
Arm/Group Description:		Single IV infusion of ADVM-043 8E13...	Single IV infusion of ADVM-043 4E14...	Single IV infusion of ADVM-043 1.2E...	All participant who received ADVM-0...
Arm/Group Description:		Single IV infusion of ADVM-043 8E13 total vg	Single IV infusion of ADVM-043 4E14 total vg	Single IV infusion of ADVM-043 1.2E15 total vg	All participant who received ADVM-043
Overall Number of Participants Analyzed		2	2	2	6
Mean (Full Range) Unit of Measure: uM
Mean change from Baseline at Week 24 serum Total Protein	Number Analyzed	2 participants	2 participants	2 participants	6 participants
Mean change from Baseline at Week 24 serum Total Protein		1.230 (-0.08 to 2.54)	1.870 (0.14 to 3.60)	1.145 (0.20 to 2.09)	1.415 (-0.08 to 3.60)
Mean change from Baseline at Week 52 serum Total Protein	Number Analyzed	2 participants	0 participants	1 participants	3 participants
Mean change from Baseline at Week 52 serum Total Protein		1.220 (-0.44 to 2.88)		0.640 (0.640 to 0.640)	1.027 (-0.44 to 2.88)

Adverse Events

Time Frame	From ADVM-043 infusion through End-of-Study visit at 52 weeks
Adverse Event Reporting Description	Subject incidence of treatment-emergent serious adverse events

Arm/Group Title	Part A: Dose 1		Part A: Dose 2		Part A: Dose 3
Arm/Group Description	Single IV infusion of ADVM-043 at 8...		Single IV infusion of ADVM-043 at 4...		Single IV infusion of ADVM-043 at 1...
Arm/Group Description	Single IV infusion of ADVM-043 at 8E13 total vg		Single IV infusion of ADVM-043 at 4E14 total vg		Single IV infusion of ADVM-043 at 1.2E15 total vg
All-Cause Mortality
	Part A: Dose 1		Part A: Dose 2		Part A: Dose 3
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/2 (0.00%)		0/2 (0.00%)		0/2 (0.00%)
Serious Adverse Events Serious Adverse Events
	Part A: Dose 1		Part A: Dose 2		Part A: Dose 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0.00%)		2/2 (100.00%)		1/2 (50.00%)
Infections and infestations
Clostridium difficile colitis ^† 1	0/2 (0.00%)	0	1/2 (50.00%)	1	0/2 (0.00%)	0
Influenza ^† 1	0/2 (0.00%)	0	0/2 (0.00%)	0	1/2 (50.00%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Meningioma ^† 1	0/2 (0.00%)	0	0/2 (0.00%)	0	1/2 (50.00%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease ^† 1	0/2 (0.00%)	0	0/2 (0.00%)	0	1/2 (50.00%)	2
Pulmonary embolism ^† 1	0/2 (0.00%)	0	1/2 (50.00%)	1	0/2 (0.00%)	0
1 Term from vocabulary, MedDRA (20.1) † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Part A: Dose 1		Part A: Dose 2		Part A: Dose 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100.00%)		2/2 (100.00%)		2/2 (100.00%)
Gastrointestinal disorders
Diarrhea ^† 1	0/2 (0.00%)	0	0/2 (0.00%)	0	1/2 (50.00%)	1
Dysphagia ^† 1	0/2 (0.00%)	0	1/2 (50.00%)	1	0/2 (0.00%)	0
Nausea ^† 1	0/2 (0.00%)	0	0/2 (0.00%)	0	1/2 (50.00%)	1
Toothache ^† 1	0/2 (0.00%)	0	1/2 (50.00%)	1	0/2 (0.00%)	0
General disorders
Face oedema ^† 1	0/2 (0.00%)	0	0/2 (0.00%)	0	1/2 (50.00%)	1
Oedema peripheral ^† 1	0/2 (0.00%)	0	0/2 (0.00%)	0	1/2 (50.00%)	1
Infections and infestations
Bronchitis ^† 1	0/2 (0.00%)	0	1/2 (50.00%)	1	1/2 (50.00%)	1
Pneumonia ^† 1	1/2 (50.00%)	1	1/2 (50.00%)	1	0/2 (0.00%)	0
Chronic sinusitis ^† 1	0/2 (0.00%)	0	1/2 (50.00%)	1	0/2 (0.00%)	0
Tooth abscess ^† 1	0/2 (0.00%)	0	1/2 (50.00%)	1	0/2 (0.00%)	0
Upper respiratory tract infection ^† 1	0/2 (0.00%)	0	0/2 (0.00%)	0	1/2 (50.00%)	1
Viral upper respiratory tract infection ^† 1	1/2 (50.00%)	1	0/2 (0.00%)	0	1/2 (50.00%)	1
Investigations
Transaminases increased ^† 1	0/2 (0.00%)	0	0/2 (0.00%)	0	2/2 (100.00%)	3
Cortisol decreased ^† 1	0/2 (0.00%)	0	0/2 (0.00%)	0	1/2 (50.00%)	1
Crystal urine present ^† 1	0/2 (0.00%)	0	0/2 (0.00%)	0	1/2 (50.00%)	1
Musculoskeletal and connective tissue disorders
Back pain ^† 1	0/2 (0.00%)	0	1/2 (50.00%)	1	0/2 (0.00%)	0
Bursitis ^† 1	0/2 (0.00%)	0	1/2 (50.00%)	1	0/2 (0.00%)	0
Psychiatric disorders
Anxiety disorder ^† 1	1/2 (50.00%)	1	0/2 (0.00%)	0	0/2 (0.00%)	0
Insomnia ^† 1	1/2 (50.00%)	1	0/2 (0.00%)	0	0/2 (0.00%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia ^† 1	0/2 (0.00%)	0	1/2 (50.00%)	1	0/2 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease ^† 1	0/2 (0.00%)	0	1/2 (50.00%)	1	1/2 (50.00%)	1
Vascular disorders
Hypertension ^† 1	1/2 (50.00%)	1	0/2 (0.00%)	0	0/2 (0.00%)	0
1 Term from vocabulary, MedDRA (20.1) † Indicates events were collected by systematic assessment

Limitations and Caveats

Enrollment was stopped after dosing was complete for participants in Cohorts 1, 2, and 3 of Part A. Cohort 4 of Part A and Part B were not enrolled. Only 6 of the up to 25 potentially anticipated participants were enrolled and received study treatment.

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.

Disclosure restrictions on the PIs are that Sponsor can review communications by the PI prior to public release and can embargo communications regarding trial results for varying time periods from the time submitted to the sponsor for review. The Sponsor may require changes to the communication after review and may delay publication upon request by the Sponsor to allow the Sponsor to seek/obtain patent protection.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Chief Development Officer
Organization:	Adverum Biotechnology, Inc.
Phone:	650-649-1413
EMail:	sseyedkazemi@adverum.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Remih K, Amzou S, Strnad P. Alpha1-antitrypsin deficiency: New therapies on the horizon. Curr Opin Pharmacol. 2021 Aug;59:149-156. doi: 10.1016/j.coph.2021.06.001. Epub 2021 Jul 10.

Layout table for additonal information

Responsible Party:	Adverum Biotechnologies, Inc.
ClinicalTrials.gov Identifier:	NCT02168686
Other Study ID Numbers:	ADVM-043-01
First Submitted:	June 10, 2014
First Posted:	June 20, 2014
Results First Submitted:	June 30, 2022
Results First Posted:	August 8, 2022
Last Update Posted:	October 5, 2023

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