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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Arthritis, Rheumatoid, Arthritis, Psoriatic, Ankylosing Spondylitis

Intervention / Treatment
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* Genetic: tgAAC94 gene therapy vector
* Genetic: tgAAC94 gene therapy vector
* Genetic: tgAAC94 placebo
* Genetic: tgAAC94 gene therapy vector
* Genetic: tgAAC94 gene therapy vector
* Genetic: tgAAC94 gene therapy vector
* Genetic: tgAAC94 gene therapy vector


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>1x10^11 DRP/mL tgAAC94 | Genetic: tgAAC94 gene therapy vector<br>* Single Dose 1x10^11 DRP/mL<br>Genetic: tgAAC94 gene therapy vector<br>* 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.<br>|
| Active Comparator: 2<br>1x10^12 DRP/mL tgAAC94 | Genetic: tgAAC94 gene therapy vector<br>* Single Dose 1x10^12 DRP/mL tgAAC94<br>Genetic: tgAAC94 gene therapy vector<br>* 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.<br>|
| Active Comparator: 3<br>1x10^13 DRP/mL tgAAC94 | Genetic: tgAAC94 gene therapy vector<br>* Single Dose 1x10^13 DRP/mL tgAAC94<br>Genetic: tgAAC94 gene therapy vector<br>* 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.<br>|
| Placebo Comparator: 4<br> | Genetic: tgAAC94 placebo<br>* placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AAV, tgAAC94, Rheumatoid arthritis, Inflammatory arthritis, Arthritis, Gene therapy