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.

Pharmacokinetic and pharmacodynamic properties of TRU-015, a CD20-directed small modular immunopharmaceutical protein therapeutic, in patients with rheumatoid arthritis: a Phase I, open-label, dose-escalation clinical study.

BACKGROUND: TRU-015 is a small modular immunopharmaceutical protein drug that binds to CD20 and effectively depleted B cells in nonhuman primates. OBJECTIVE: The aim of this clinical study was to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties, immunogenicity, and tolerability of TRU-015 in patients with rheumatoid arthritis (RA). METHODS: This Phase I, open-label, dose-escalation clinical study was conducted at 4 medical centers in the United States. Patients with RA who were receiving stable-dose methotrexate were enrolled in 1 of 8 dose groups and received TRU-015 as a single IV dose of 0.015, 0.05, 0.15, 0.5, 1.5, 5, or 15, or 2 IV doses of 15 mg/kg, administered 7 days apart (30 mg/kg). Patients were enrolled in the next higher dose cohort based on the tolerability observed in the prior cohort. Prior to TRU-015 infusion, patients were premedicated with an antihistamine and acetaminophen and may have received a corticosteroid at the investigator's discretion. Serum samples were collected for analysis of PK properties (serum t((1/2))) and neutralizing antibodies to TRU-015; enzyme-linked immunosorbent assays and a cell-based neutralizing assay were used to evaluate samples from patients. PD response was measured using B-cell (CD19(+)-cell) count using flow cytometry at prespecified time points. Tolerability was assessed during drug infusion and at prespecified time points after infusion using physical examination and laboratory analysis. Patients were followed for >or=4 weeks and until B-cell recovery. RESULTS: Thirty-seven patients were enrolled. Most were female (81%) and white (95%); the mean age was 53 years. Serum t((1/2)) ranged from 12 to 19 days. B-cell depletion generally increased in degree and duration with increasing doses. No neutralizing antibodies to TRU-015 were detected. Mild adverse events (AEs) included back pain, headache, peripheral edema, and upper respiratory infection (5 patients each). Mild urticaria occurred in 1 patient. Grade 3 AEs included hypertension, arthralgia, and urticaria and bronchospasm (1 patient each). No dose-limiting toxicity was found. CONCLUSIONS: In this small population of patients with RA, the C(max) and the AUC appeared to increase in a dose-proportional manner. The mean t((1/2)) ranged from 12 to 19 days. TRU-015 was associated with dose-dependent B-cell depletion and an acceptable tolerability profile.

A randomized, open-label, multicenter trial comparing once-a-day AVINZA (morphine sulfate extended-release capsules) versus twice-a-day OxyContin (oxycodone hydrochloride controlled-release tablets) for the treatment of chronic, moderate to severe low back pain: improved physical functioning in the ACTION trial.

This multicenter trial compared the efficacy, safety, and effect on quality of life and work limitation of once-daily extended-release morphine sulfate capsules (AVINZA, A-MQD) and twice-daily controlled-release oxycodone HCI tablets (OxyContin, O-ER) in subjects with chronic, moderate to severe low back pain. After randomization and a period of opioid dose titration, subjects (n=266) underwent an eight-week evaluation phase and an optionalf our-month extension phase (n=174 in extension phase). Subjects were assessed using the 12-item Short-Form Health Survey (SF-12) and the Work Limitations Questionnaire (WLQ). In both groups, significant improvements were observed in the SF-12 mean scores forp hysicalf unctioning (p < 0.001), role physical (p < 0.0001), bodilyp ain (p < 0.0001), physical summary (p < 0.001), and mental component summary (p < 0.005). At the end of the titration period, greater relative improvements from baseline were seen in the SF-12 section on physical components in the A-MQD group versus the O-ER group, with significant differences observed for physical functioning (p = 0.0374), role physical (p = 0.0341), bodily pain (p = 0.0001), andp hysical summary (p = 0.0022). In both groups, SF-12 mean scores improved significantly for mental health (p < 0.01), role emotional (p < 0.01), socialfunctioning (p < 0.0005), vitality (p < 0.005), and the mental component summary (p < 0.005), but no significant differences were noted between the two groups. Both groups reported improvement from baseline in WLQ physical demands scores, with no significant differences noted between the two groups. At the end of the evaluation phase, fewer subjects were unable to work due to illness or treatment in the A-MQD group than in the O-ER group (8.5 percent versus 19.4 percent, respectively; p = 0.0149). In conclusion, compared to twice-daily OxyContin, once-daily A VINZA resulted in significantly better and earlier improvement ofp hysicalf unction and ability to work.

The ACTION study: a randomized, open-label, multicenter trial comparing once-a-day extended-release morphine sulfate capsules (AVINZA) to twice-a-day controlled-release oxycodone hydrochloride tablets (OxyContin) for the treatment of chronic, moderate to severe low back pain.

This large, open-label, randomized, parallel-group, multicenter study compared two oral sustained-release opioids (SROs)--AVINZA (A-MQD), morphine sulfate extended-release capsules given once a day, and OxyContin (O-ER), oxycodone modified-release tablets given twice a day--in SRO-naive subjects ages 30 to 70 with chronic, moderate to severe low back pain. Of the 392 subjects enrolled and randomized, 266 (132 in the A-MQD group and 134 in the O-ER group) completed the opioid dose titration phase and entered an eight-week evaluation phase. During the evaluation phase, A-MQD achieved significantly better pain control than O-ER, as demonstrated by a greater decrease from baseline in pain scores obtained four times daily during weeks one, four, and eight (p = 0.002). The number of breakthrough-pain rescue medication doses adjusted for the number of patient days was significantly lower in the A-MQD group (p < 0.0001). Better pain control with A-MQD was achieved with a significantly lower daily opioid dose than with O-ER (mean 69.9 mg and 91 mg morphine equivalents, respectively; p = 0.0125). Quality of sleep was significantly better with A-MQD for the entire evaluation phase (p = 0.0026). The incidence and severity of elicited opioid side effects were similar in the two groups. This trial demonstrated that once-daily A-MQD provides consistent around-the-clock pain relief in patients with low back pain. In patients who completed opioid dose titration, A-MQD was significantly better than O-ER for reducing pain and improving sleep, while requiring a lower daily opioid dose.

A randomized, open-label study of once-a-day AVINZA (morphine sulfate extended-release capsules) versus twice-a-day OxyContin (oxycodone hydrochloride controlled-release tablets) for chronic low back pain: the extension phase of the ACTION trial.

STUDY DESIGN AND OBJECTIVE: The ACTION trial, an open-label, randomized, multicenter, two-part study, compared the efficacy and safety of two sustained-release opioids (SROs), A VINZA (A-MQD), morphine sulfate extended-release capsules given once a day, and OxyContin (O-ER), oxycodone modified-release tablets given twice a day, in subjects with chronic, moderate to severe low back pain. The first part of the study, the evaluation phase, was followed by an optional four-month extension phase aimed at evaluating the long-term stability of pain control, SRO dose, and quality of sleep. RESULTS: Three hundred and ninety-two subjects were enrolled in the study; 220 completed the evaluation phase, and 174 entered the extensionphase. During the latterphase, subjects in the A-MQD group (n=79) continued to report lower pain scores, better quality of sleep, lower daily morphine-equivalent doses (means of 86 mg versus 119 mg), and a comparable usage of ibuprofen compared to subjects in the O-ER group (n=95). The incidence and severity of elicited opioid side effects were similar between the two groups. CONCLUSIONS: Both study drugs resulted in significant pain relief and improved sleep in SRO-naive patients with chronic low back pain, and this outcome was attained with a stable daily SRO dose. In patients who completed opioid dose titration, A VINZA performed significantly better than OxyContin in reducing pain scores and improving sleep-with a lower morphine-equivalent daily dose-during both the evaluation and extension phases.