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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


Phase 1/Phase 2
18 Years
75 Years
Not Enrolling
Both
Arthritis, Rheumatoid, Arthritis, Psoriatic, Ankylosing Spondylitis

Thank you

Trial Information

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


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.


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.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Serious adverse events

Outcome Time Frame:

From time of study drug administration through final study visit

Safety Issue:

Yes

Principal Investigator

Alison Heald, MD

Investigator Role:

Study Director

Investigator Affiliation:

Targeted Genetics Corporation

Authority:

United States: Food and Drug Administration

Study ID:

13G01

NCT ID:

NCT00126724

Start Date:

August 2005

Completion Date:

May 2009

Related Keywords:

  • Arthritis, Rheumatoid
  • Arthritis, Psoriatic
  • Ankylosing Spondylitis
  • tgAAC94
  • Rheumatoid arthritis
  • Inflammatory arthritis
  • Arthritis
  • Gene therapy
  • AAV
  • Arthritis
  • Arthritis, Psoriatic
  • Arthritis, Rheumatoid
  • Spondylitis
  • Spondylitis, Ankylosing

Name

Location

Northwestern Center for Clinical ResearchChicago, Illinois  60611
Altoona Center for Clinical ResearchDuncansville, Pennsylvania  16635
Ocala Rheumatology Research CenterOcala, Florida  34474
Arthritis Center of RenoReno, Nevada  89502
Sun Valley Arthritis CenterGlendale, Arizona  85308
Catalina Pointe Clinical Research, IncTuscon, Arizona  85704
Desert Medical AdvancesPalm Desert, California  92260
Boling Clinical TrialsUpland, California  91786
Denver Arthritis Research CenterDenver, Colorado  80230
RASF-Clinical Research CenterBoca Raton, Florida  33486
Radiant Research StuartStuart, Florida  34996
Coeur d'Alene Arthritis ClinicCoeur d'Alene, Idaho  83814
The Arthritis CenterSpringfield, Illinois  62704
Arthritis and Osteoporosis Center of MarylandFrederick, Maryland  21702
United Medical AssociatesJohnson City, New York  13790
Bone and Joint Hospital Research Dept.Oklahoma City, Oklahoma  73103
Rheumatic Disease AssociatesWillow Grove, Pennsylvania  19090
Austin Rheumatology ResearchAustin, Texas  78705
Arthritis Consultation CenterDallas, Texas  75231
Metroplex Clinical Research CenterDallas, Texas  75235
Radiant Research San Antonio NortheastSan Antonio, Texas  78217
Seattle Rheumatology Associates, PLLCSeattle, Washington  98104