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

Arthritis, Rheumatoid Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00126724
• Other study ID #: 13G01
• Secondary ID: NIH Protocol Num
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: August 2, 2005
• Last updated: July 27, 2009
• Start date: August 2005
• Est. completion date: May 2009

Study information

• Verified date: July 2009
• Source: Targeted Genetics Corporation
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: May 2009
• Est. primary completion date: October 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Ankylosing Spondylitis
• Arthritis
• Arthritis, Psoriatic
• Arthritis, Rheumatoid
• Spondylitis
• Spondylitis, Ankylosing

Intervention

Genetic:
• tgAAC94 gene therapy vector
Single Dose 1x10^11 DRP/mL
• 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.
• tgAAC94 placebo
placebo
• tgAAC94 gene therapy vector
Single Dose 1x10^12 DRP/mL tgAAC94
• 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.
• tgAAC94 gene therapy vector
Single Dose 1x10^13 DRP/mL tgAAC94
• 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.

Locations

Country	Name	City	State
United States	Austin Rheumatology Research	Austin	Texas
United States	RASF-Clinical Research Center	Boca Raton	Florida
United States	Northwestern Center for Clinical Research	Chicago	Illinois
United States	Coeur d'Alene Arthritis Clinic	Coeur d'Alene	Idaho
United States	Arthritis Consultation Center	Dallas	Texas
United States	Metroplex Clinical Research Center	Dallas	Texas
United States	Denver Arthritis Research Center	Denver	Colorado
United States	Altoona Center for Clinical Research	Duncansville	Pennsylvania
United States	Arthritis and Osteoporosis Center of Maryland	Frederick	Maryland
United States	Sun Valley Arthritis Center	Glendale	Arizona
United States	United Medical Associates	Johnson City	New York
United States	Ocala Rheumatology Research Center	Ocala	Florida
United States	Bone and Joint Hospital Research Dept.	Oklahoma City	Oklahoma
United States	Desert Medical Advances	Palm Desert	California
United States	Arthritis Center of Reno	Reno	Nevada
United States	Radiant Research San Antonio Northeast	San Antonio	Texas
United States	Seattle Rheumatology Associates, PLLC	Seattle	Washington
United States	The Arthritis Center	Springfield	Illinois
United States	Radiant Research Stuart	Stuart	Florida
United States	Catalina Pointe Clinical Research, Inc	Tuscon	Arizona
United States	Boling Clinical Trials	Upland	California
United States	Rheumatic Disease Associates	Willow Grove	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Targeted Genetics Corporation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serious adverse events		From time of study drug administration through final study visit	Yes
Primary	Severe or very severe adverse events		From time of study drug administration through final study visit	Yes
Primary	Study-drug related adverse events		From time of study drug administration through final study visit	Yes
Secondary	Change in tenderness and swelling of target joint		All scheduled study visits	No
Secondary	Time to qualifying for second injection of study drug		Week A12 or 18 or 24	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	Yes
Secondary	Joint inflammation and damage on MRI scan		Day A0, Weeks A4, 12, 24	No

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