Study of Intra-articular Delivery of tgAAC94 in Inflammatory Arthritis Subjects

This study has been completed.
Sponsor:
Information provided by:
Targeted Genetics Corporation
ClinicalTrials.gov Identifier:
NCT00126724
First received: August 2, 2005
Last updated: July 27, 2009
Last verified: July 2009
  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:

  1. to evaluate the safety of intra-articular administration of tgAAC94 in subjects currently taking TNF-alpha antagonists, and
  2. 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

Resource links provided by NLM:


Further study details as provided by Targeted Genetics Corporation:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00126724

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
Sponsors and Collaborators
Targeted Genetics Corporation
Investigators
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 July 26, 2014