Single-joint outcome measures: preliminary validation of patient-reported outcomes and physical examination.

OBJECTIVE: To assess the validity, responsiveness, and reliability of single-joint outcome measures for determining target joint (TJ) response in patients with inflammatory arthritis. METHODS: Patient-reported outcomes (PRO), consisting of responses to single questions about TJ global status on a 100-mm visual analog scale (VAS; TJ global score), function on a 100-mm VAS (TJ function score), and pain on a 5-point Likert scale (TJ pain score) were piloted in 66 inflammatory arthritis subjects in a phase 1/2 clinical study of an intraarticular gene transfer agent and compared to physical examination measures (TJ swelling, TJ tenderness) and validated function questionnaires (Disabilities of the Arm, Shoulder and Hand scale, Rheumatoid Arthritis Outcome Score, and the Health Assessment Questionnaire). Construct validity was assessed by evaluating the correlation between the single-joint outcome measures and validated function questionnaires using Spearman's rank correlation. Responsiveness or sensitivity to change was assessed through calculating effect size and standardized response means (SRM). Reliability of physical examination measures was assessed by determining interobserver agreement. RESULTS: The single-joint PRO were highly correlated with each other and correlated well with validated functional measures. The TJ global score exhibited modest effect size and modest SRM that correlated well with the patient's assessment of response on a 100-mm VAS. Physical examination measures exhibited high interrater reliability, but correlated less well with validated functional measures and the patient's assessment of response. CONCLUSION: Single-joint PRO, particularly the TJ global score, are simple to administer and demonstrate construct validity and responsiveness in patients with inflammatory arthritis. (ClinicalTrials.gov identifier NCT00126724).

Safety, tolerability, and clinical outcomes after intraarticular injection of a recombinant adeno-associated vector containing a tumor necrosis factor antagonist gene: results of a phase 1/2 Study.

OBJECTIVE: To assess safety and clinical outcomes in patients with inflammatory arthritis after intraarticular (IA) injection of rAAV2-TNFR:Fc, a recombinant adeno-associated viral vector containing the human tumor necrosis factor (TNF) receptor-immunoglobulin (IgG1) Fc fusion (TNFR:Fc) gene. METHODS: In this phase 1/2 randomized study, adults with persistent moderate or severe inflammation in a target joint, being treated with or without systemic anti-TNF therapy, received a single IA injection of either rAAV2-TNFR:Fc (1 x 10(11), 1 x 10(12), or 1 x 10(13) DNase-resistant particles/ml joint volume) or placebo, followed by open-label rAAV2-TNFR:Fc 12-30 weeks later, depending on when the target joint met predetermined criteria for reinjection. RESULTS: 127 subjects received the first injection of blinded study drug; 95 subjects received open-label rAAV2-TNFR:Fc. Administration site reactions, consisting of transient mild to moderate increases in tenderness and swelling of the injected joint, occurred after 23/191 (12%) rAAV2-TNFR:Fc injections and were dose-dependent. Rates of other adverse events were not dose-dependent. Notable serious adverse events (SAE) included culture-negative septic arthritis in a subject receiving leflunomide and fatal disseminated histoplasmosis considered unrelated to rAAV2-TNFR:Fc in a subject receiving adalimumab. In the phase 2 portion of the study, a 30% decrease in target joint global visual analog scale was observed in 21/50 (42%) rAAV2-TNFR:Fc subjects and 3/16 (19%) placebo subjects 12 weeks after first injection (p = 0.14). CONCLUSION: IA rAAV2-TNFR:Fc resulted in administration site reactions after 12% of injections. A fatal SAE, disseminated histoplasmosis, was considered not related to study agent. Patient-reported outcome measures of clinical response showed greater improvement in treated patients than placebo patients.