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Phase 1 Dose Escalation Study of Intra-Articular Administration of tgAAC94

Primary Purpose

Rheumatoid Arthritis

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

tgAAC94 gene therapy vector

tgAAC94 placebo

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis

Eligibility Criteria

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

Inclusion Criteria:

Rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis, diagnosed according to published criteria
Persistent moderate (grade 2) or sever (grade 3) swelling due to inflammatory arthritis in at least one peripheral joint eligible for injection
For subjects with rheumatoid arthritis, an adequate trial of at least one disease-modifying antirheumatic drug (DMARD) prior to screening
For subjects currently on DMARD(s), a stable regimen for inflammatory arthritis for the previous three months, with no changes in doses in the four weeks prior to screening
Age greater than 18 years
Be willing to practice effective birth control measures during the study, if of reproductive ability
Able to give written informed consent

Exclusion Criteria:

Current use of a TNF-alpha antagonist
Disease severe enough to warrant use of a systemic TNF-alpha antagonist in the next three months
Discontinuation of TNF-alpha antagonists in the past because of safety concerns
Current use of anakinra
Poor functional status, defined as being bed-bound or wheelchair-bound
Corticosteriod therapy at doses higher than the equivalent of 10 mg prednisone per day
Any of the following laboratory values: Hemoglobin <8.5 gm/dL, white blood cell count <3500 per mm^3, platelet <100 K/microL, creatinine >2 mg/dL, bilirubin >2 mg/dL, AST or ALT >2 times the upper limit of normal, or abnormal coagulation profiles
Known HIV infection, known hepatitis C infection, or known positive serologic test for hepatitis B surface antigen
Positive PPD, unless previously treated with appropriate prophylaxis
Pregnancy or lactation, either at the time of screening or planned in the next six months
Inflammatory bowel disease, such as Crohn's disease or ulcerative colitis
Serious medical disease, such as sever liver or kidney disease, uncompensated congestive heart failure, myocardial infarction within six months, unstable angina, uncontrolled hypertension, severe pulmonary disease or active asthma, demyelinating neurological disease, history of cancer (other than cutaneous basal and squamous cell carcinoma) with less than five years documentation of a disease free state, insulin-dependent diabetes, recurrent opportunistic infections or other concurrent medical condition that, in the opinion of the investigator, would make the subject unsuitable for the study
Unlikely to comply with the protocol

Sites / Locations

UCLA Division of Rheumatology
Denver Arthritis Research Center
Swedish Rheumoatology Research
Arthritis Research Centre of Canada
Arthritis Centre Clinical Research Unit UofManitoba
Mt Sinai Hospital
Toronto Western Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Arm Description

1x10^10 DRP/mL tgAAC94

1x10^11 DRP/mL tgAAC94

Single dose tgAAC94 placebo

Outcomes

Primary Outcome Measures

Serious adverse events

Severe or very severe adverse events

Study drug-related adverse events

Secondary Outcome Measures

Change in tenderness and swelling of injected joint

Change in tenderness and swelling of non-injected joints

Reduction in disease activity, as measured by American College of Rheumatology (ACR) criteria and Disease Activity Score (DAS)

Joint fluid measures (cell count and differential, total protein and TNFR:Fc protein)

TNFR:Fc protein levels in serum

Serum neutralizing antibodies to AAV2

Presence of tgAAC94 in peripheral blood mononuclear cells (PBMCs)

Full Information

NCT ID

NCT00617032

First Posted

February 5, 2008

Last Updated

February 5, 2008

Sponsor

Targeted Genetics Corporation

1. Study Identification

Unique Protocol Identification Number

NCT00617032

Brief Title

Phase 1 Dose Escalation Study of Intra-Articular Administration of tgAAC94

Official Title

A Phase 1 Dose Escalation Study of Intra-Articular Administration of tgAAC94, a Recombinant Adeno-Associated Vector Containing the TNFR:Fc Fusion Gene, in Inflammatory Arthritis

Study Type

Interventional

2. Study Status

Record Verification Date

February 2008

Overall Recruitment Status

Completed

Study Start Date

February 2004 (undefined)

Primary Completion Date

November 2005 (Actual)

Study Completion Date

November 2005 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor

Targeted Genetics Corporation

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Study 1304 is a Phase I dose escalation study conducted in adults with persistent moderate (grade 2) or severe (grade 3) swelling due to inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis) in at least one peripheral joint eligible for injection. Disease must not be severe enough to warrant use of a TNF-alpha antagonist in the next three months. Current use of TNF-alpha antagonists is not permitted. Subjects with rheumatoid arthritis must have had an adequate trial of at least one disease-modifying antirheumatic drug (DMARD) prior to screening. The primary objective is to evaluate the safety of intra-articular administration of tgAAC94.

Detailed Description

tgAAC94 is a recombinant adeno-associated virus serotype 2 (AAV2) vector genetically engineered to contain the cDNA for a human tumor necrosis factor receptor (TNFR)-immunoglobulin (IgG1) Fc fusion (TNFR:Fc) gene. The DNA sequence of TNFR:Fc in tgAAC94 codes for a protein sequence identical to etanercept (Enbrel). TNF-alpha has been strongly implicated as a major participant in the inflammatory cascade that leads to joint damage and destruction in diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Intra-articular delivery of the TNFR:Fc gene (tgAAC94) should result in expression of the secreted protein in the joint space and provide local high concentrations of soluble TNFR:Fc for an extended period of time without requiring frequent administration. Thus, this proposed therapy would be useful in those inflammatory arthritis patients who have a persistently problematic joint despite the use of systemic TNF-alpha blockade or who have a limited number of arthritic joints. Extensive preclinical studies using rAAV2 containing several different transgenes in a variety of animal models have shown efficient and persistent gene transfer and expression with minimal toxicity. The parent virus (wild-type AAV2) is a naturally occurring, non-replicating virus that depends on a helper virus, such as adenovirus, for replication. The recombinant AAV2 vector is unable to replicate in target host cells because it lacks the AAV genes, whose protein products are also required in trans, for replication and packaging of progeny virus. Extensive epidemiological studies have found AAV2 to be non-pathogenic. Although there is no cure for inflammatory arthritis, treatment has been revolutionized by the advent of anti-TNF-alpha therapies. These include etanercept (Enbrel), infliximab (Remicade) and adalimumab (Humira), which consist of soluble TNF receptors, chimeric human-mouse anti-TNF-alpha monoclonal antibodies and fully human anti-TNF-alpha monoclonal antibodies, respectively. Clinical studies have shown these products to improve the signs and symptoms, inhibit the structural damage, and impact functional outcomes in patients with inflammatory arthritis.

6. Conditions and Keywords

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

Rheumatoid Arthritis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

15 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Active Comparator

Arm Description

1x10^10 DRP/mL tgAAC94

Arm Title

Arm Type

Active Comparator

Arm Description

1x10^11 DRP/mL tgAAC94

Arm Title

Arm Type

Placebo Comparator

Arm Description

Single dose tgAAC94 placebo

Intervention Type

Genetic

Intervention Name(s)

tgAAC94 gene therapy vector

Intervention Description

Single Dose 1x10^10 DNase resistant particles (DRP) / mL joint volume

Intervention Type

Genetic

Intervention Name(s)

tgAAC94 gene therapy vector

Intervention Description

Single dose 1x10^11 DNase resistant particles (DRP) / mL joint volume

Intervention Type

Genetic

Intervention Name(s)

tgAAC94 placebo

Intervention Description

Single dose

Primary Outcome Measure Information:

Title

Serious adverse events

Time Frame

From study drug administration through final study visit

Title

Severe or very severe adverse events

Time Frame

From study drug administration through final study visit

Title

Study drug-related adverse events

Time Frame

From study drug administration through final study visit

Secondary Outcome Measure Information:

Title

Change in tenderness and swelling of injected joint

Time Frame

Days 3 and 7 and Weeks 2, 4, 8, and 12

Title

Change in tenderness and swelling of non-injected joints

Time Frame

Weeks 2, 4, and 12

Title

Reduction in disease activity, as measured by American College of Rheumatology (ACR) criteria and Disease Activity Score (DAS)

Time Frame

Weeks 2, 4, and 12

Title

Joint fluid measures (cell count and differential, total protein and TNFR:Fc protein)

Time Frame

Weeks 4 and 12

Title

TNFR:Fc protein levels in serum

Time Frame

Day 7 and Weeks 2, 4, 8, and 12

Title

Serum neutralizing antibodies to AAV2

Time Frame

Weeks 4 and 12

Title

Presence of tgAAC94 in peripheral blood mononuclear cells (PBMCs)

Time Frame

Day 3 and Weeks 2 and 8

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis, diagnosed according to published criteria Persistent moderate (grade 2) or sever (grade 3) swelling due to inflammatory arthritis in at least one peripheral joint eligible for injection For subjects with rheumatoid arthritis, an adequate trial of at least one disease-modifying antirheumatic drug (DMARD) prior to screening For subjects currently on DMARD(s), a stable regimen for inflammatory arthritis for the previous three months, with no changes in doses in the four weeks prior to screening Age greater than 18 years Be willing to practice effective birth control measures during the study, if of reproductive ability Able to give written informed consent Exclusion Criteria: Current use of a TNF-alpha antagonist Disease severe enough to warrant use of a systemic TNF-alpha antagonist in the next three months Discontinuation of TNF-alpha antagonists in the past because of safety concerns Current use of anakinra Poor functional status, defined as being bed-bound or wheelchair-bound Corticosteriod therapy at doses higher than the equivalent of 10 mg prednisone per day Any of the following laboratory values: Hemoglobin <8.5 gm/dL, white blood cell count <3500 per mm^3, platelet <100 K/microL, creatinine >2 mg/dL, bilirubin >2 mg/dL, AST or ALT >2 times the upper limit of normal, or abnormal coagulation profiles Known HIV infection, known hepatitis C infection, or known positive serologic test for hepatitis B surface antigen Positive PPD, unless previously treated with appropriate prophylaxis Pregnancy or lactation, either at the time of screening or planned in the next six months Inflammatory bowel disease, such as Crohn's disease or ulcerative colitis Serious medical disease, such as sever liver or kidney disease, uncompensated congestive heart failure, myocardial infarction within six months, unstable angina, uncontrolled hypertension, severe pulmonary disease or active asthma, demyelinating neurological disease, history of cancer (other than cutaneous basal and squamous cell carcinoma) with less than five years documentation of a disease free state, insulin-dependent diabetes, recurrent opportunistic infections or other concurrent medical condition that, in the opinion of the investigator, would make the subject unsuitable for the study Unlikely to comply with the protocol

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Alison Heald, MD

Organizational Affiliation

Targeted Genetics Corporation

Official's Role

Study Director

Facility Information:

Facility Name

UCLA Division of Rheumatology

City

Los Angeles

State/Province

California

Country

United States

Facility Name

Denver Arthritis Research Center

City

Denver

State/Province

Colorado

Country

United States

Facility Name

Swedish Rheumoatology Research

City

Seattle

State/Province

Washington

Country

United States

Facility Name

Arthritis Research Centre of Canada

City

Vancouver

State/Province

British Columbia

Country

Canada

Facility Name

Arthritis Centre Clinical Research Unit UofManitoba

City

Winnipeg

State/Province

Manitoba

Country

Canada

Facility Name

Mt Sinai Hospital

City

Toronto

State/Province

Ontario

Country

Canada

Facility Name

Toronto Western Hospital

City

Toronto

State/Province

Ontario

Country

Canada

12. IPD Sharing Statement

Learn more about this trial

Phase 1 Dose Escalation Study of Intra-Articular Administration of tgAAC94

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