Phase 1 Dose Escalation Study of Intra-Articular Administration of tgAAC94 - Full Text View

Sponsored by:	Targeted Genetics Corporation
Information provided by:	Targeted Genetics Corporation
ClinicalTrials.gov Identifier:	NCT00617032

Purpose

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.

Condition	Intervention	Phase
Rheumatoid Arthritis	Genetic: tgAAC94 gene therapy vector Genetic: tgAAC94 placebo	Phase I

MedlinePlus related topics: Edema Rheumatoid Arthritis

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety Study
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

Further study details as provided by Targeted Genetics Corporation:

Primary Outcome Measures:

Serious adverse events [ Time Frame: From study drug administration through final study visit ] [ Designated as safety issue: Yes ]
Severe or very severe adverse events [ Time Frame: From study drug administration through final study visit ] [ Designated as safety issue: Yes ]
Study drug-related adverse events [ Time Frame: From study drug administration through final study visit ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Change in tenderness and swelling of injected joint [ Time Frame: Days 3 and 7 and Weeks 2, 4, 8, and 12 ] [ Designated as safety issue: No ]
Change in tenderness and swelling of non-injected joints [ Time Frame: Weeks 2, 4, and 12 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
Joint fluid measures (cell count and differential, total protein and TNFR:Fc protein) [ Time Frame: Weeks 4 and 12 ] [ Designated as safety issue: No ]
TNFR:Fc protein levels in serum [ Time Frame: Day 7 and Weeks 2, 4, 8, and 12 ] [ Designated as safety issue: No ]
Serum neutralizing antibodies to AAV2 [ Time Frame: Weeks 4 and 12 ] [ Designated as safety issue: Yes ]
Presence of tgAAC94 in peripheral blood mononuclear cells (PBMCs) [ Time Frame: Day 3 and Weeks 2 and 8 ] [ Designated as safety issue: Yes ]

Enrollment:	15
Study Start Date:	February 2004
Study Completion Date:	November 2005
Primary Completion Date:	November 2005 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Active Comparator 1x10^10 DRP/mL tgAAC94	Genetic: tgAAC94 gene therapy vector Single Dose 1x10^10 DNase resistant particles (DRP) / mL joint volume
2: Active Comparator 1x10^11 DRP/mL tgAAC94	Genetic: tgAAC94 gene therapy vector Single dose 1x10^11 DNase resistant particles (DRP) / mL joint volume
3: Placebo Comparator Single dose tgAAC94 placebo	Genetic: tgAAC94 placebo Single dose

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00617032

Locations

United States, California
UCLA Division of Rheumatology
Los Angeles, California, United States
United States, Colorado
Denver Arthritis Research Center
Denver, Colorado, United States
United States, Washington
Swedish Rheumoatology Research
Seattle, Washington, United States
Canada, British Columbia
Arthritis Research Centre of Canada
Vancouver, British Columbia, Canada
Canada, Manitoba
Arthritis Centre Clinical Research Unit UofManitoba
Winnipeg, Manitoba, Canada
Canada, Ontario
Mt Sinai Hospital
Toronto, Ontario, Canada
Toronto Western Hospital
Toronto, Ontario, Canada

Sponsors and Collaborators

Targeted Genetics Corporation

Investigators

Study Director:

Alison Heald, MD

Targeted Genetics Corporation

More Information

Responsible Party:	Targeted Genetics Corporation ( Rae Saltzstein, Senior Director Quality and Regulatory Affairs )
Study ID Numbers:	13E04, RAC Protocol # 0307-588, HPB 0088676
Study First Received:	February 5, 2008
Last Updated:	February 5, 2008
ClinicalTrials.gov Identifier:	NCT00617032
Health Authority:	United States: Food and Drug Administration; Canada: Health Canada

Study placed in the following topic categories:

Autoimmune Diseases
Musculoskeletal Diseases
Joint Diseases
Arthritis

Connective Tissue Diseases
Arthritis, Rheumatoid
Rheumatic Diseases

Additional relevant MeSH terms:

Immune System Diseases

ClinicalTrials.gov processed this record on January 14, 2009