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

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

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).

Study Overview

• Status: Completed
• Conditions: Arthritis, Rheumatoid; Arthritis, Psoriatic; Ankylosing Spondylitis
• Intervention / Treatment: Genetic: tgAAC94 gene therapy vector; Genetic: tgAAC94 gene therapy vector; Genetic: tgAAC94 gene therapy vector; Genetic: tgAAC94 gene therapy vector; Genetic: tgAAC94 gene therapy vector; Genetic: tgAAC94 gene therapy vector; Genetic: tgAAC94 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.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Glendale, Arizona, United States, 85308
      • Sun Valley Arthritis Center
    • Tuscon, Arizona, United States, 85704
      • Catalina Pointe Clinical Research, Inc
  • California
    • Palm Desert, California, United States, 92260
      • Desert Medical Advances
    • Upland, California, United States, 91786
      • Boling Clinical Trials
  • Colorado
    • Denver, Colorado, United States, 80230
      • Denver Arthritis Research Center
  • Florida
    • Boca Raton, Florida, United States, 33486
      • RASF-Clinical Research Center
    • Ocala, Florida, United States, 34474
      • Ocala Rheumatology Research Center
    • Stuart, Florida, United States, 34996
      • Radiant Research Stuart
  • Idaho
    • Coeur d'Alene, Idaho, United States, 83814
      • Coeur D'Alene Arthritis Clinic
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Center for Clinical Research
    • Springfield, Illinois, United States, 62704
      • The Arthritis Center
  • Maryland
    • Frederick, Maryland, United States, 21702
      • Arthritis and Osteoporosis Center of Maryland
  • Nevada
    • Reno, Nevada, United States, 89502
      • Arthritis Center of Reno
  • New York
    • Johnson City, New York, United States, 13790
      • United Medical Associates
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73103
      • Bone and Joint Hospital Research Dept.
  • Pennsylvania
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Center for Clinical Research
    • Willow Grove, Pennsylvania, United States, 19090
      • Rheumatic Disease Associates
  • Texas
    • Austin, Texas, United States, 78705
      • Austin Rheumatology Research
    • Dallas, Texas, United States, 75235
      • Metroplex Clinical Research Center
    • Dallas, Texas, United States, 75231
      • Arthritis Consultation Center
    • San Antonio, Texas, United States, 78217
      • Radiant Research San Antonio Northeast
  • Washington
    • Seattle, Washington, United States, 98104
      • Seattle Rheumatology Associates, PLLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: 4	Genetic: tgAAC94 placebo; placebo
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.; 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.; 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.
ACTIVE_COMPARATOR: 2; 1x10^12 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.; 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.; 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.
ACTIVE_COMPARATOR: 3; 1x10^13 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.; 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.; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Serious adverse events	From time of study drug administration through final study visit
Severe or very severe adverse events	From time of study drug administration through final study visit
Study-drug related adverse events	From time of study drug administration through final study visit

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in tenderness and swelling of target joint	All scheduled study visits
Time to qualifying for second injection of study drug	Week A12 or 18 or 24
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	Day A0, Weeks A4, 8, 12, 18, 24, Day B0, Weeks B4, B8, B12, B18, B24, B30, withdrawal
Human tumor necrosis factor receptor (TNFR)-immunoglobulin (IgG1) Fc fusion (TNFR:Fc) protein levels in synovial fluid and serum	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
Serum anti-adeno-associated virus serotype 2 (AAV2) capsid neutralizing antibodies	Day A0, Weeks A4, 12, 24, Day B0, Weeks B4, 12,24, 30, withdrawal
Joint inflammation and damage on MRI scan	Day A0, Weeks A4, 12, 24

Collaborators and Investigators

• Sponsor: Targeted Genetics Corporation
• Investigators: Study Director: Alison Heald, MD, Targeted Genetics Corporation

Publications and helpful links

General Publications

• Heald AE, Fudman EJ, Anklesaria P, Mease PJ; 13G01 Study Team. Single-joint outcome measures: preliminary validation of patient-reported outcomes and physical examination. J Rheumatol. 2010 May;37(5):1042-8. doi: 10.3899/jrheum.090827. Epub 2010 Mar 15.
• Frank KM, Hogarth DK, Miller JL, Mandal S, Mease PJ, Samulski RJ, Weisgerber GA, Hart J. Investigation of the cause of death in a gene-therapy trial. N Engl J Med. 2009 Jul 9;361(2):161-9. doi: 10.1056/NEJMoa0801066.

Helpful Links

• Sponsor Home Page

Study record dates

Study Major Dates

• Study Start: August 1, 2005
• Primary Completion (ACTUAL): October 1, 2008
• Study Completion (ACTUAL): May 1, 2009

Study Registration Dates

• First Submitted: August 2, 2005
• First Submitted That Met QC Criteria: August 2, 2005
• First Posted (ESTIMATE): August 4, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): July 29, 2009
• Last Update Submitted That Met QC Criteria: July 27, 2009
• Last Verified: July 1, 2009

More Information

Terms related to this study

• Keywords: Arthritis; Rheumatoid arthritis; AAV; Gene therapy; Inflammatory arthritis; tgAAC94
• Additional Relevant MeSH Terms: Skin Diseases; Infections; Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin Diseases, Papulosquamous; Spinal Diseases; Bone Diseases; Spondylarthropathies; Spondylarthritis; Psoriasis; Bone Diseases, Infectious; Ankylosis; Arthritis; Arthritis, Rheumatoid; Arthritis, Psoriatic; Spondylitis; Spondylitis, Ankylosing
• Other Study ID Numbers: 13G01; NIH Protocol Number: 0504-705