Rheumatoid Arthritis: Kivitz AJ

Burge DJ, Bookbinder SA, Kivitz AJ, Fleischmann RM, Shu C, Bannink J. · Trubion Pharmaceuticals Inc., Seattle, Washington, USA. · Clin Ther. · Pubmed #19014836 No free full text.

Abstract: 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.

Kaine JL, Kivitz AJ, Birbara C, Luo AY. · Sarasota Arthritis Research Center, Sarasota, Florida 34239, USA. · J Rheumatol. · Pubmed #17304653 No free full text.

Abstract: OBJECTIVE: This study compared the immunogenicity of influenza and pneumococcal vaccines in adult patients with rheumatoid arthritis (RA) receiving adalimumab or placebo. METHODS: In this double-blind, randomized, multicenter study, patients received adalimumab or placebo on Days 1, 15, and 29. Pneumococcal and influenza vaccines were administered on Day 8 (vaccine baseline). Vaccine response (> or = 2-fold titer increase from baseline in > or = 3 of 5 pneumococcal antigens and > or = 4-fold titer increase from baseline in > or = 2 of 3 influenza antigens) and protective antibody titers (> or = 1.6 microg/ml pneumococcal antibody concentration to > or = 3 of 5 antigens and > or = 1:40 influenza antibody titer to > or = 2 of 3 antigens) were analyzed 4 weeks' postvaccination. RESULTS: Following pneumococcal vaccination, percentages of patients achieving a vaccine response were similar in the adalimumab and placebo groups [37.4% and 40.4%, respectively; 95% CI (confidence interval) -16.2%, 10.3%]. Percentages of patients with protective antibody titers were similar in both treatment groups (adalimumab: 85.9%, placebo: 81.7%). Following influenza vaccination, percentages of patients achieving a vaccine response were lower with adalimumab than placebo (51.5% and 63.3%, respectively; 95% CI -25.2%, 1.6%)--a result explained by the subgroup of patients with preexisting protective antibody titers at baseline. For patients without protective antibody titers at baseline, response rates were similar in the 2 groups (adalimumab: 73.3%, placebo: 73.9%). Percentages of patients with protective antibody titers were similar in both treatment groups (adalimumab: 98%, placebo: 94.5%). CONCLUSION: Patients with RA treated with adalimumab can be effectively and safely immunized with pneumococcal and influenza vaccines.

Bradley JD, Dmitrienko AA, Kivitz AJ, Gluck OS, Weaver AL, Wiesenhutter C, Myers SL, Sides GD. · Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. · J Rheumatol. · Pubmed #15742431 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy and safety of a selective inhibitor of secretory phospholipase (sPLA2), LY333013, in the treatment of rheumatoid arthritis (RA). METHODS: Two hundred and fifty-one patients with active RA despite treatment with one or more disease modifying antirheumatic drugs (DMARD) received oral doses of LY333013 (50, 250, and 1000 mg) or placebo once daily for 12 weeks. Concomitant low-dose glucocorticoids (< or = 10 mg/day prednisone equivalent) were allowed. Clinical improvement was assessed using the response criteria of the American College of Rheumatology (ACR20), and safety was evaluated with respect to adverse events and laboratory test abnormalities. RESULTS: The demographic characteristics of the treatment groups were similar. Dose-response relationships were found for ACR20 responses (p = 0.058) and reductions in C-reactive protein (p = 0.058) at week 1. The proportions of patients with an ACR20 response subsequently increased in all study groups including the placebo group at weeks 4 and 8, and the initial treatment benefit was lost. Adverse events were generally mild in severity and not associated with treatment. CONCLUSION: Treatment with LY333013 for 12 weeks was well tolerated but ineffective as an adjunct to DMARD treatment of active RA.

van Holten J, Pavelka K, Vencovsky J, Stahl H, Rozman B, Genovese M, Kivitz AJ, Alvaro J, Nuki G, Furst DE, Herrero-Beaumont G, McInnes IB, Musikic P, Tak PP. · Academic Medical Centre, University of Amsterdam, Netherlands. · Ann Rheum Dis. · Pubmed #15242865 links to  free full text

Abstract: OBJECTIVE: To assess the efficacy of interferon beta (IFN beta) in combination with methotrexate in treatment of patients with rheumatoid arthritis. METHODS: 209 patients with active rheumatoid arthritis, who had been on methotrexate for at least six months and at a stable dose for four weeks before study entry, were randomised in double blind fashion to receive placebo (0.05 ml or 0.5 ml), IFN beta 2.2 microg (0.05 ml), or IFN beta 44 microg (0.5 ml), given subcutaneously three times weekly for 24 weeks. The primary efficacy measure was a change in radiological scores at week 24. The secondary endpoint was the proportion of patients who met the ACR 20% improvement criteria at the end of the study. Synovial biopsy specimens were obtained before and after treatment from a subset of patients. Immunohistochemistry was used to detect the presence of inflammatory cells and the results were measured by digital image analysis. Collagen crosslinks were measured in urine at different times throughout the study. RESULTS: Analysis of radiological scores and clinical variable showed no changes in any of the groups, and there were no differences between the groups. On microscopic analysis of synovial tissue there was no significant change in the scores for infiltration by inflammatory cells after IFN beta treatment. Urinary levels of collagen crosslinks were unchanged between the treatment groups. CONCLUSIONS: At the doses tested, treatment with IFN beta three times weekly in combination with methotrexate did not have a clinical or radiological effect in patients with rheumatoid arthritis.

Kivitz AJ, Nayiager S, Schimansky T, Gimona A, Thurston HJ, Hawkey C. · Altoona Center for Clinical Research, Duncansville, PA, USA. · Aliment Pharmacol Ther. · Pubmed #15153172 links to  free full text

Abstract: BACKGROUND: Lumiracoxib (Prexige; Novartis Pharma AG, Basel, Switzerland) is a cyclooxygenase-2 selective inhibitor associated with improved gastrointestinal safety compared with nonsteroidal anti-inflammatory drugs, in patients with osteoarthritis. AIM: To compare the gastroduodenal safety of lumiracoxib with ibuprofen and celecoxib in patients with rheumatoid arthritis. METHODS: A total of 893 patients with rheumatoid arthritis were randomized to lumiracoxib 400 mg once daily, lumiracoxib 800 mg once daily, ibuprofen 800 mg three times daily or celecoxib 200 mg twice daily for 13 weeks, in a double-blind randomised controlled clinical trial. The primary endpoint was the cumulative incidence of gastroduodenal ulcers over 13 weeks. RESULTS: The incidence of gastroduodenal ulcers >/=3 mm with lumiracoxib 400 mg once daily (2.8%) or lumiracoxib 800 mg once daily (4.3%) was significantly lower than with ibuprofen (13.6%, all P < 0.01) and not different from celecoxib (1.9%). The incidence of adverse events was similar for lumiracoxib 400, 800 mg and celecoxib (78, 75 and 77%, respectively) and higher with ibuprofen (86%). Discontinuation for adverse events was highest for ibuprofen (12.5% vs. 7.9-8.8% for the other groups). CONCLUSIONS: Lumiracoxib demonstrated gastroduodenal safety superior to ibuprofen and similar to celecoxib in patients with rheumatoid arthritis.

Goldstein JL, Kivitz AJ, Verburg KM, Recker DP, Palmer RC, Kent JD. · University of Illinois at Chicago, Chicago, IL 60612, USA. · Aliment Pharmacol Ther. · Pubmed #12848634 links to  free full text

Abstract: BACKGROUND: In long-term outcomes studies, cyclooxygenase COX-2 specific inhibitors spare COX-1 at supratherapeutic doses and therefore demonstrate improved gastrointestinal safety over nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs). However, in clinical practice, anti-inflammatory drugs are often used for short-term treatment of pain. AIM: To compare the short-term upper gastrointestinal mucosal effects of naproxen with the new COX-2 specific inhibitor, valdecoxib, or placebo, in elderly subjects. METHODS: In this multicentre, double-blind, randomized, study, elderly subjects (65-76 years old), with a normal baseline esophagogastroduodenoscopy (EGD), received oral valdecoxib (a supratherapeutic 40 mg b.d. dosage, n = 62), naproxen (500 mg b.d., n = 62), or placebo (n = 62) for 6.5 days. Upper gastrointestinal mucosal injury was evaluated post-treatment by EGD (day 7). RESULTS: Subjects receiving naproxen (11/60, 18%) had significantly more gastroduodenal ulcers post-treatment than those receiving placebo (2/61, 3%; P < 0.01) or valdecoxib (0/60, 0%; P < 0.001). A similar significant finding was observed for gastric ulcer rates. All treatments had similar adverse event rates and clinical laboratory findings. CONCLUSIONS: Valdecoxib, even at supratherapeutic doses, was associated with an ulcer rate significantly lower than naproxen but similar to placebo in healthy elderly subjects, despite the short duration of therapy (6.5 days). Naproxen and valdecoxib were as well tolerated as placebo.

Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC, Isakson PC, Verburg KM, Yu SS, Zhao WW, Geis GS. · Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass 02215, USA. · JAMA. · Pubmed #10580457 links to  free full text

Abstract: CONTEXT: In vitro studies have shown that celecoxib inhibits cyclooxygenase 2 (COX-2) but not COX-1, suggesting that this drug may have anti-inflammatory and analgesic activity without adverse upper gastrointestinal (GI) tract effects that result from COX-1 inhibition. OBJECTIVE: To test whether celecoxib has efficacy as an anti-inflammatory and analgesic with reduced GI tract mucosal damage compared with conventional nonsteroidal anti-inflammatory drugs in patients with rheumatoid arthritis. DESIGN: Randomized, multicenter, placebo-controlled, double-blind trial lasting 12 weeks, with follow-up at weeks 2, 6, and 12, from September 1996 thorugh February 1998. SETTING: Seventy-nine clinical sites in the United States and Canada. PATIENTS: A total of 1149 patients aged 18 years or older with symptomatic rheumatoid arthritis who met inclusion criteria were randomized; 688 (60%) of these completed the study. INTERVENTIONS: Patients were randomized to receive celecoxib, 100 mg, 200 mg, or 400 mg twice per day (n = 240, 235, and 218, respectively); naproxen, 500 mg twice per day (n = 225); or placebo (n = 231). MAIN OUTCOME MEASURES: Improvement in signs and symptoms of rheumatoid arthritis as assessed using standard measures of efficacy and GI tract safety as assessed by upper GI tract endoscopy before and after treatment, compared among treatment groups. RESULTS: All dosages of celecoxib and naproxen significantly improved the signs and symptoms of arthritis compared with placebo. Maximal anti-inflammatory and analgesic activity was evident within 2 weeks of initiating treatment and was sustained throughout the 12 weeks. The incidence of endoscopically determined gastroduodenal ulcers in placebo-treated patients was 4 (4%) of 99, and the incidences across all dosages of celecoxib were not significantly different (P>.40): 9 (6%) of 148 with 100 mg twice per day, 6 (4%) of 145 with 200 mg twice per day, and 8 (6%) of 130 with 400 mg twice per day. In contrast, the incidence with naproxen was 36 (26%) of 137, significantly greater than either placebo or celecoxib (P<.001). The overall incidences of GI tract adverse effects were 19% for placebo; 28%, 25%, and 26% for celecoxib 100 mg, 200 mg, and 400 mg twice per day, respectively; and 31 % for naproxen. CONCLUSION: In this study, all dosages of celecoxib were efficacious in the treatment of rheumatoid arthritis and did not affect COX-1 activity in the GI tract mucosa as evidenced by less frequent incidence of endoscopic ulcers compared with naproxen.

Weisman MH, Paulus HE, Burch FX, Kivitz AJ, Fierer J, Dunn M, Kerr DR, Tsuji W, Baumgartner SW. · Division of Rheumatology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. · Rheumatology (Oxford). · Pubmed #17470434 links to  free full text

Abstract: OBJECTIVE: To evaluate the safety of etanercept in patients with rheumatoid arthritis (RA) and concomitant comorbidities. METHODS: The safety of etanercept (25 mg twice weekly) in RA patients with at least one comorbidity (i.e. diabetes mellitus, chronic pulmonary disease, recent pneumonia, recurrent infections) was evaluated in a 16-week placebo-controlled, randomized, double-blinded study. The primary endpoint was the incidence of medically important infections (MIIs; defined as those resulting in hospitalization or treatment with intravenous antibiotics). RESULTS: Data from 535 patients were analysed; the study was terminated early because of slow enrolment and lower than predicted incidence of infections. Serious adverse events (5.9% placebo, 8.6% etanercept) were most commonly observed in the cardiovascular system. Six patients (1 placebo; 5 etanercept) died during the study; four deaths were attributed to cardiovascular events. The numerically higher mortality in the etanercept group was not statistically significant [relative risk (95% CI) = 5.06 (0.59, 42.99)] but remains unexplained. No etanercept-related increase in the incidence of MIIs (3.7% placebo, 3.0% etanercept) or overall infections was observed in the total study population or in subgroups of patients who were > or = 65 yrs of age, had diabetes or had chronic pulmonary disease. CONCLUSIONS: Etanercept was generally well tolerated by RA patients with comorbidities. Serious adverse events and deaths occurred more frequently in the etanercept group but event numbers were small and CIs were broad, preventing reliable conclusions from being drawn. Although the study had limited statistical power, the incidence of MIIs in these patients was not increased by etanercept treatment.

Williams GW, Kivitz AJ, Brown MT, Verburg KM. · Department of Medicine, Scripps Clinic, La Jolla, California 92037, USA. · Clin Ther. · Pubmed #16678642 No free full text.

Abstract: OBJECTIVES: The primary aim of this work was to compare the efficacy of valdecoxib 10, 20, and 40 mg QD with that of placebo and naproxen 500 mg BID in patients with rheumatoid arthritis (RA). The overall safety and tolerability profiles of valdecoxib and naproxen were also compared. METHODS: A 12-week, multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled study was performed in patients with adult-onset RA whose disease was in a flare state after discontinuing NSAIDs or other analgesics. Patients were randomly assigned to valdecoxib 10, 20, or 40 mg QD, naproxen 500 mg BID, or placebo. The primary efficacy measures were the American College of Rheumatology (ACR) 20% responder index (ACR-20), physicians' assessments of tender/painful joint count and swollen joint count, and patients' and physicians' global assessments of disease activity. Adverse events, clinical laboratory data, and vital signs were assessed by the investigator and compared between treatment groups to evaluate overall tolerability and safety. RESULTS: A total of 1093 patients were randomized to receive either valdecoxib 10 mg QD (n=226), valdecoxib 20 mg QD (n=219), valdecoxib 40 mg QD (n=209), naproxen 500 mg BID (n=219), or placebo (n=220). At all time points, the proportion of ACR-20 responders was significantly higher in the valdecoxib groups than the placebo group at weeks 2 (10 mg, P<0.001; 20 mg, P=0.008; 40 mg, P= 0.004), 6 (all, P<0.001), and 12 (10 mg, P=0.006; 20 mg, P=0.004; 40 mg, P<0.001). Similarly, at all time points, the proportion of ACR-20 responders was significantly higher in the naproxen 500-mg group than the placebo group (all time points, P<0.001). In addition, mean changes in the number of tender/painful joint counts were significantly greater in the valdecoxib groups than the placebo group at weeks 2 (all, P<0.001), 6 (10 mg, P=0.002; 20 and 40 mg, P<0.001), and 12 (10 mg, P=0.004; 20 mg, P= 0.012; 40 mg, P<0.001). Naproxen treatment was also associated with greater reductions in tender/painful joint count than placebo (all, P<0.001). Mean changes in swollen joint count decreased at all time points in all groups, with significantly greater changes in the valdecoxib and naproxen treatment groups than the placebo group (valdecoxib 20 and 40 mg: week 6, P= 0.014 and P=0.003, respectively; naproxen: week 2, P=0.014; week 6, P=0.015; week 12, P=0.030). Physicians' global assessments of disease activity scores were significantly lower in the valdecoxib (10 mg: weeks 2 and 6, P<0.001; week 12, P=0.001; 20 and 40 mg: all weeks, P<0.001) and naproxen (all time points, P<0.001) treatment groups than the placebo group. Adverse events were reported by 45.5% patients in the placebo group, 51.8% in the valdecoxib 10 mg QD group, 58.0% in the valdecoxib 20 mg QD group, 56.9% in the valdecoxib 40 mg QD group, and 62.6% in the naproxen 500 mg BID treatment group. CONCLUSIONS: Valdecoxib 10, 20, and 40 mg QD were efficacious for treating the signs and symptoms of RA in these patients. The efficacy of valdecoxib 20 and 40 mg QD was not significantly different from that of naproxen 500 mg BID. Valdecoxib was generally well tolerated in this study.