Phase 1 Dose Escalation Study of Intra-Articular Administration of tgAAC94
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|ClinicalTrials.gov Identifier: NCT00617032|
Recruitment Status : Completed
First Posted : February 15, 2008
Last Update Posted : February 15, 2008
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 or disease||Intervention/treatment||Phase|
|Rheumatoid Arthritis||Genetic: tgAAC94 gene therapy vector Genetic: tgAAC94 placebo||Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||15 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|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 Start Date :||February 2004|
|Actual Primary Completion Date :||November 2005|
|Actual Study Completion Date :||November 2005|
Active Comparator: 1
1x10^10 DRP/mL tgAAC94
Genetic: tgAAC94 gene therapy vector
Single Dose 1x10^10 DNase resistant particles (DRP) / mL joint volume
Active Comparator: 2
1x10^11 DRP/mL tgAAC94
Genetic: tgAAC94 gene therapy vector
Single dose 1x10^11 DNase resistant particles (DRP) / mL joint volume
Placebo Comparator: 3
Single dose tgAAC94 placebo
Genetic: tgAAC94 placebo
- Serious adverse events [ Time Frame: From study drug administration through final study visit ]
- Severe or very severe adverse events [ Time Frame: From study drug administration through final study visit ]
- Study drug-related adverse events [ Time Frame: From study drug administration through final study visit ]
- Change in tenderness and swelling of injected joint [ Time Frame: Days 3 and 7 and Weeks 2, 4, 8, and 12 ]
- Change in tenderness and swelling of non-injected joints [ Time Frame: Weeks 2, 4, and 12 ]
- 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 ]
- Joint fluid measures (cell count and differential, total protein and TNFR:Fc protein) [ Time Frame: Weeks 4 and 12 ]
- TNFR:Fc protein levels in serum [ Time Frame: Day 7 and Weeks 2, 4, 8, and 12 ]
- Serum neutralizing antibodies to AAV2 [ Time Frame: Weeks 4 and 12 ]
- Presence of tgAAC94 in peripheral blood mononuclear cells (PBMCs) [ Time Frame: Day 3 and Weeks 2 and 8 ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00617032
|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|
|Arthritis Centre Clinical Research Unit UofManitoba|
|Winnipeg, Manitoba, Canada|
|Mt Sinai Hospital|
|Toronto, Ontario, Canada|
|Toronto Western Hospital|
|Toronto, Ontario, Canada|
|Study Director:||Alison Heald, MD||Targeted Genetics Corporation|