Study of Intra-articular Delivery of tgAAC94 in Inflammatory Arthritis Subjects
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Purpose
The 13G01 clinical trial is a Phase I/II dose escalation study designed to be conducted in adults with inflammatory arthritis who have persistent moderate or severe swelling in one or more joints, without a disease severe enough to warrant a change in regimen for the next three months.
The study will permit subjects who are concurrently on anti-tumor necrosis factor (TNF)-alpha antagonists. For subjects on disease modifying antirheumatic drugs (DMARDs), a stable regimen for inflammatory arthritis for the previous three months, with no changes in doses in the four weeks prior to screening will be required.
The primary objectives are:
- to evaluate the safety of intra-articular administration of tgAAC94 in subjects currently taking TNF-alpha antagonists, and
- to evaluate the safety of repeat intra-articular administration of tgAAC94 (gene therapy vector).
| Condition | Intervention | Phase |
|---|---|---|
|
Arthritis, Rheumatoid Arthritis, Psoriatic Ankylosing Spondylitis |
Genetic: tgAAC94 gene therapy vector Genetic: tgAAC94 placebo |
Phase 1 Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment |
| Official Title: | A Phase I/II Study of Repeat Intra-articular Administration of tgAAC94, a Recombinant Adeno-Associated Vector Containing the TNFR:Fc Fusion Gene, in Inflammatory Arthritis Subjects With and Without Concurrent TNF-alpha Antagonists |
- Serious adverse events [ Time Frame: From time of study drug administration through final study visit ] [ Designated as safety issue: Yes ]
- Severe or very severe adverse events [ Time Frame: From time of study drug administration through final study visit ] [ Designated as safety issue: Yes ]
- Study-drug related adverse events [ Time Frame: From time of study drug administration through final study visit ] [ Designated as safety issue: Yes ]
- Change in tenderness and swelling of target joint [ Time Frame: All scheduled study visits ] [ Designated as safety issue: No ]
- Time to qualifying for second injection of study drug [ Time Frame: Week A12 or 18 or 24 ] [ Designated as safety issue: No ]
- Reduction in disease activity, as measured by American College of Rheumatology (ACR) criteria, Disease Activity Score (DAS) or Assessments in Ankylosing Spondylitis (ASAS) criteria, as applicable [ Time Frame: Day A0, Weeks A4, 8, 12, 18, 24, Day B0, Weeks B4, B8, B12, B18, B24, B30, withdrawal ] [ Designated as safety issue: No ]
- Human tumor necrosis factor receptor (TNFR)-immunoglobulin (IgG1) Fc fusion (TNFR:Fc) protein levels in synovial fluid and serum [ Time Frame: Serum: Days A0,7,Weeks A4,12,24, Days B0,7,Weeks 8,12,18,24,30, withdrawal. Synovium: Days A0,4,Weeks A12,24, Day B0,Weeks 4,12,24, withdrawal ] [ Designated as safety issue: Yes ]
- Serum anti-adeno-associated virus serotype 2 (AAV2) capsid neutralizing antibodies [ Time Frame: Day A0, Weeks A4, 12, 24, Day B0, Weeks B4, 12,24, 30, withdrawal ] [ Designated as safety issue: Yes ]
- Joint inflammation and damage on MRI scan [ Time Frame: Day A0, Weeks A4, 12, 24 ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 120 |
| Study Start Date: | August 2005 |
| Study Completion Date: | May 2009 |
| Primary Completion Date: | October 2008 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: 1
1x10^11 DRP/mL tgAAC94
|
Genetic: tgAAC94 gene therapy vector
Single Dose 1x10^11 DRP/mL
Genetic: tgAAC94 gene therapy vector
Second dose of 1x10^11 DRP/mL tgAAC94 administered once target joint reaches predetermined criteria for re-injection (on or after Week 12) at the same concentration as initial dose.
|
|
Active Comparator: 2
1x10^12 DRP/mL tgAAC94
|
Genetic: tgAAC94 gene therapy vector
Single Dose 1x10^12 DRP/mL tgAAC94
Genetic: tgAAC94 gene therapy vector
Second dose of 1x10^12 DRP/mL tgAAC94 administered once target joint reaches predetermined criteria for re-injection (on or after Week 12) at the same concentration as initial dose.
|
|
Active Comparator: 3
1x10^13 DRP/mL tgAAC94
|
Genetic: tgAAC94 gene therapy vector
Single Dose 1x10^13 DRP/mL tgAAC94
Genetic: tgAAC94 gene therapy vector
Second dose of 1x10^13 DRP/mL tgAAC94 administered once target joint reaches predetermined criteria for re-injection (on or after Week 12) at the same concentration as initial dose.
|
| Placebo Comparator: 4 |
Genetic: tgAAC94 placebo
placebo
|
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 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 these inflammatory arthritides.
Eligibility| Ages Eligible for Study: | 18 Years to 75 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) diagnosed according to established criteria.
- Persistent moderate (grade 2) or severe (grade 3) swelling due to inflammatory arthritis in at least one peripheral joint eligible for injection.
- For subjects with RA, an adequate trial of at least one disease-modifying drug (DMARD) prior to screening.
- For subjects currently on DMARD(s), a stable regimen of inflammatory arthritis for the previous three months, with no changes in doses four weeks prior to screening.
- Age greater than 18 years and less than 75 years at the time of screening.
- Willingness to practice effective birth control measures during the study (through week 36), if male or female of reproductive ability.
- Able to give written informed consent.
Exclusion Criteria:
- Disease severe enough to warrant a change in regimen for inflammatory arthritis in the next three months.
- Discontinuation of etanercept in the past because of safety concerns.
- Current use of anakinra (Kineret®)or abatacept (Orencia®).
- Corticosteroid therapy at doses higher than the equivalent of 10 mg prednisone per day.
- Steroid or hyaluronate injection in the target joint or receipt of an investigational agent less than four weeks prior to screening.
- Class IV ACR functional status (Hochberg et al., 1992).
- Any of the following laboratory values: Hemoglobin <8.5 gm/dL, white blood cell count <3500 per mm cube, platelet <100 K/uL, creatinine >2 mg/dL, bilirubin >2 mg/dL, AST or ALT >2 times the upper limit of normal, or abnormal coagulation profiles (>2 seconds beyond upper range of normal PT or PTT).
- 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 18 months.
- Inflammatory bowel disease, such as Crohn's disease or ulcerative colitis.
- Serious medical disease, such as severe liver or kidney disease, uncompensated congestive heart failure, myocardial infarction within six months, unstable angina, uncontrolled hypertension, severe pulmonary disease or uncontrolled 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 protocol.
Contacts and Locations| United States, Arizona | |
| Sun Valley Arthritis Center | |
| Glendale, Arizona, United States, 85308 | |
| Catalina Pointe Clinical Research, Inc | |
| Tuscon, Arizona, United States, 85704 | |
| United States, California | |
| Desert Medical Advances | |
| Palm Desert, California, United States, 92260 | |
| Boling Clinical Trials | |
| Upland, California, United States, 91786 | |
| United States, Colorado | |
| Denver Arthritis Research Center | |
| Denver, Colorado, United States, 80230 | |
| United States, Florida | |
| RASF-Clinical Research Center | |
| Boca Raton, Florida, United States, 33486 | |
| Ocala Rheumatology Research Center | |
| Ocala, Florida, United States, 34474 | |
| Radiant Research Stuart | |
| Stuart, Florida, United States, 34996 | |
| United States, Idaho | |
| Coeur d'Alene Arthritis Clinic | |
| Coeur d'Alene, Idaho, United States, 83814 | |
| United States, Illinois | |
| Northwestern Center for Clinical Research | |
| Chicago, Illinois, United States, 60611 | |
| The Arthritis Center | |
| Springfield, Illinois, United States, 62704 | |
| United States, Maryland | |
| Arthritis and Osteoporosis Center of Maryland | |
| Frederick, Maryland, United States, 21702 | |
| United States, Nevada | |
| Arthritis Center of Reno | |
| Reno, Nevada, United States, 89502 | |
| United States, New York | |
| United Medical Associates | |
| Johnson City, New York, United States, 13790 | |
| United States, Oklahoma | |
| Bone and Joint Hospital Research Dept. | |
| Oklahoma City, Oklahoma, United States, 73103 | |
| United States, Pennsylvania | |
| Altoona Center for Clinical Research | |
| Duncansville, Pennsylvania, United States, 16635 | |
| Rheumatic Disease Associates | |
| Willow Grove, Pennsylvania, United States, 19090 | |
| United States, Texas | |
| Austin Rheumatology Research | |
| Austin, Texas, United States, 78705 | |
| Arthritis Consultation Center | |
| Dallas, Texas, United States, 75231 | |
| Metroplex Clinical Research Center | |
| Dallas, Texas, United States, 75235 | |
| Radiant Research San Antonio Northeast | |
| San Antonio, Texas, United States, 78217 | |
| United States, Washington | |
| Seattle Rheumatology Associates, PLLC | |
| Seattle, Washington, United States, 98104 | |
| Study Director: | Alison Heald, MD | Targeted Genetics Corporation |
More Information
No publications provided by Targeted Genetics Corporation
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Rae Saltzstein, Targeted Genetics Corporation |
| ClinicalTrials.gov Identifier: | NCT00126724 History of Changes |
| Other Study ID Numbers: | 13G01, NIH Protocol Number: 0504-705 |
| Study First Received: | August 2, 2005 |
| Last Updated: | July 27, 2009 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by Targeted Genetics Corporation:
|
tgAAC94 Rheumatoid arthritis Inflammatory arthritis |
Arthritis Gene therapy AAV |
Additional relevant MeSH terms:
|
Arthritis Arthritis, Psoriatic Arthritis, Rheumatoid Spondylitis Spondylitis, Ankylosing Joint Diseases Musculoskeletal Diseases Spondylarthropathies Spondylarthritis Spinal Diseases Bone Diseases |
Psoriasis Skin Diseases, Papulosquamous Skin Diseases Rheumatic Diseases Connective Tissue Diseases Autoimmune Diseases Immune System Diseases Bone Diseases, Infectious Infection Ankylosis |
ClinicalTrials.gov processed this record on May 19, 2013