Joel M. Kremer

Integrated safety in tocilizumab clinical trials

IntroductionThe efficacy and safety of tocilizumab in patients with rheumatoid arthritis have been evaluated in a comprehensive phase 3 program. Patients from these randomized trials could receive tocilizumab treatment in open-label extension trials. Here, the long-term safety profile of tocilizumab, using pooled data from all of these trials, is reported.MethodsCumulative safety data (as of February 6, 2009) from five core phase 3 trials, two ongoing extension trials, and one clinical pharmacology study were analyzed. Two patient populations were evaluated: an all-control population (n = 4,199), which included all patients randomly assigned in the placebo-controlled portions of the five core studies, and an all-exposed population (n = 4,009), which included patients from any of the eight studies who received at least one dose of tocilizumab.ResultsTotal exposure to tocilizumab was 8,580 patient years (PY), and total duration of observation was 9,414 PY. Overall adverse event (AE) and serious AE (SAE) rates were 278.2/100 PY and 14.4/100 PY, respectively. These events included serious infections (4.7/100 PY), opportunistic infections (0.23/100 PY), gastrointestinal perforations (0.28/100 PY), malignancy (1.1/100 PY), myocardial infarction (0.25/100 PY), and stroke (0.19/100 PY). The rates of SAEs and serious infections were stable over time; no increase with prolonged exposure was noted.ConclusionsThe longer-term safety profile of tocilizumab (mean treatment duration, 2.4 years) is consistent with that observed in the phase 3 studies (duration up to 1 year).

Longterm Safety and Efficacy of Tocilizumab in Patients with Rheumatoid Arthritis: A Cumulative Analysis of Up to 4.6 Years of Exposure

Objective. To assess the longterm safety and efficacy of tocilizumab (TCZ) in patients with moderate to severe rheumatoid arthritis (RA). Methods. Patient data were from 5 randomized controlled TCZ trials (n = 4211), their open-label extension phases (n = 3512), and a drug interaction study (n = 23). All randomly assigned patients, regardless of previous RA treatment, were analyzed. Measures of safety included number of adverse events (AE), serious AE (SAE), AE leading to treatment discontinuation, laboratory tests, and deaths. Efficacy measures included American College of Rheumatology (ACR) 20/50/70 responses, tender joint count (TJC), swollen joint count (SJC), ACR core set components, and low disease activity (LDA) or Disease Activity Score in 28 joints (DAS28) remission. ACR/European League Against Rheumatism (EULAR) disease remission was a posthoc exploratory analysis. Results. Total duration of observation was 12,293 patient-years (PY). No new safety signals were identified; infections were the most common AE and SAE. The rate of serious infections was 4.5/100 PY. Improvements from baseline in clinical efficacy, measured as ACR20/50/70 responses, TJC, SJC, ACR core set components, and LDA and DAS28 remission, were generally sustained through at least 216 weeks of followup. ACR/EULAR disease remission was attained by 16.5% (Boolean) and 22.7% (index) of patients at Week 216. Conclusion. TCZ has to date been studied for up to 4.6 years (240 weeks) of treatment in patients with RA. Our analysis reveals a longer-term safety profile consistent with previous observations, no new safety signals, and durable efficacy of TCZ in a large clinical trial program.

Evaluation of composite measures of treatment response without acute-phase reactants in patients with rheumatoid arthritis

OBJECTIVES To evaluate composite measures of response without acute-phase reactants in RA patients. Specifically, Clinical Disease Activity Index (CDAI)-derived response criteria were compared with the European League Against Rheumatism (EULAR) response criteria, and the modified ACR (mACR) response criteria were compared to the ACR response criteria. METHODS Data from 10 108 RA patients enrolled in the Consortium of Rheumatology Researchers of North America registry were examined, including 649 patients initiating DMARD therapy. CDAI cut-off points for disease activity levels and responses were derived using receiver operating characteristic curves with the DAS28 and EULAR response criteria as gold standards. The kappa-statistics were applied to assess agreement between CDAI-derived and EULAR-defined responses, as well as ACR20 and ACR50 with mACR20- and mACR50-defined responses, respectively. RESULTS For the components of the EULAR response, the derived CDAI cut-off points for DAS28 levels of 3.2 and 5.1 were 7.6 and 19.6, respectively. The derived CDAI cut-off points were 4.3 and 10.0 for DAS28 changes of 0.6 and 1.2, respectively. There were moderate to substantial agreements between CDAI-derived and EULAR responses (kappa = 0.57-0.71). Agreement of ACR20 and ACR50 with mACR20 and mACR50 responses, respectively, was excellent (kappa = 0.88-0.95). CONCLUSIONS Agreement between composite measures of response without acute-phase reactants and standard measures ranged from moderate to excellent. The mACR20 and mACR50 criteria as well as CDAI-derived response criteria, can serve as composite measures of response in clinical practice and research settings without access to acute-phase reactants.

Malignancy validation in a United States registry of rheumatoid arthritis patients

BackgroundPhysician reporting is commonly used to ascertain adverse events or outcomes measured in epidemiologic studies. However, little is known on the accuracy of physician reported malignancies compared to pertinent medical record review in large cohort studies.MethodsThe Consortium of Rheumatology Researchers of North America (CORRONA) registry gathers physician-completed questionnaires for rheumatoid arthritis (RA) patients, including request for information on incident malignancies, approximately every three months. For incident malignancies reported from October 1st, 2001, through December 31st, 2007, we retrospectively requested completion of a Targeted Adverse Event (TAE) form for additional information as well as primary source documents to adjudicate the malignancy reports. CORRONA has employed a prospective request for source documentation for these events since 2008. We classified each malignancy as definite, probable, possible, or not a malignancy.ResultsFrom 20,837 RA patients enrolled in CORRONA, 461 incident malignancies were initially reported on physician questionnaires. After review of returned source documents with adjudication, 234 were deemed definite, 69 probable, 101 possible, and 57 not an incident malignancy. The positive predictive value (PPV) of initial physician report of a malignancy versus “definite or probable” malignancy based on adjudication was 0.66 (95% CI 0.61 - 0.70). The PPV was 0.68 (95% CI 0.63 – 0.72) when the subsequent TAE form also confirmed the presence of malignancy. When possible malignancies were included, the PPV of physician-reported malignancies without a subsequent TAE form increased to 0.86 (0.83 – 0.89), and with a subsequent TAE form, 0.89 (0.85-0.91).ConclusionTwelve percent of initial physician reports of incident malignancy could not be confirmed with review of source documents. The most common reason for lack of confirmation was inability to obtain documents or insufficient data in source materials. These results suggest that timely collection of relevant medical records and an adjudication process are required to improve the accuracy of cancer reporting in epidemiologic studies.

Comparative effectiveness of nonbiologic versus biologic disease-modifying antirheumatic drugs for rheumatoid arthritis.

Objective. To evaluate the comparative effectiveness of nonbiologic disease-modifying antirheumatic drugs (DMARD) versus biologic DMARD (bDMARD) for treatment of rheumatoid arthritis (RA), using 2 common analytic approaches. Methods. We analyzed change in Clinical Disease Activity Index (CDAI) scores in patients with RA enrolled in a US-based observational registry from 2001 to 2008 using multivariable (MV) regression and propensity score (PS) matching. Among patients who initiated treatment with a nonbiologic DMARD (n = 1729), we compared patients who switched to, or added, another nonbiologic (n = 182) or a bDMARD (n = 342) at 5, 9, and 24 months after treatment change. Results. Both analytic approaches showed that patients switching to or adding another nonbiologic DMARD demonstrated improvement across 9 and 24 months (both p < 0.001). Both approaches also demonstrated greater improvement in CDAI among recipients of bDMARD relative to a second nonbiologic DMARD at 5 months (p < 0.02). The MV regression approach upheld these results at 9 and 24 months (p < 0.03). In contrast, the PS-matching approach did not show a sustained advantage with bDMARD at these later timepoints, possibly because of lower statistical power and/or lower baseline disease activity in the PS-matched cohort. Conclusion. Patients in both treatment groups generally experienced lower CDAI scores across time. Patients switching to bDMARD demonstrated greater improvement than patients switching to nonbiologic DMARD with both analytic approaches at 5 months. Relative advantages with bDMARD were observed at 9 and 24 months only with MV regression. These analyses provide a practical example of how findings in comparative effectiveness research can diverge with different methodological approaches.

Agreement between Rheumatologist and Patient-reported Adherence to Methotrexate in a US Rheumatoid Arthritis Registry

Objective. Rheumatologists have limited tools to assess medication adherence. The extent to which methotrexate (MTX) adherence is overestimated by rheumatologists is unknown. Methods. We deployed an Internet survey to patients with rheumatoid arthritis (RA) participating in a US registry. Patient self-report was the gold standard compared to MTX recorded in the registry. Results. Response rate to the survey was 44%. Of 228 patients whose rheumatologist reported current MTX at the time of the most recent registry visit, 45 (19.7%) had discontinued (n = 19, 8.3%) or missed ≥ 1 dose in the last month (n = 26, 11.4%). For the subgroup whose rheumatologist also confirmed at the next visit that they were still taking MTX (n = 149), only 2.6% reported not taking it, and 10.7% had missed at least 1 dose. Conclusion. MTX use was misclassified for 13%–20% of patients, mainly because of 1 or more missed doses rather than overt discontinuation. Clinicians should be aware of suboptimal adherence when assessing MTX response.

Gout Prophylaxis Evaluated According to the 2012 American College of Rheumatology Guidelines: Analysis from the CORRONA Gout Registry

Objective. To analyze prophylaxis using the CORRONA (COnsortium of Rheumatology Researchers Of North America) Gout Registry according to the American College of Rheumatology (ACR) guidelines, and to evaluate whether differences in disease characteristics influenced prophylaxis. Methods. All patients with gout in the CORRONA Gout Registry between November 1, 2012, and November 26, 2013, were included. They were divided into 2 groups: “receiving prophylaxis” versus “not receiving prophylaxis” at the time of enrollment. Patients having a flare at time of visit were excluded. Descriptive statistics and multivariable logistic regression models were performed to evaluate the factors associated with prophylaxis. Results. There were 1049 patients with gout available for analysis. There were 441 patients (42%) receiving prophylaxis and 608 (58%) not receiving prophylaxis. The most common drugs used for prophylaxis were colchicine (78%) and nonsteroidal antiinflammatory drugs (32%). Prophylaxis drug combination was used by 45 patients (10.2%). Patients in the “receiving prophylaxis” group were more likely to have a gout duration of ≤ 1 year (n = 68, p < 0.001), ≥ 1 flare in the year previous to enrollment (p < 0.001), ≥ 1 healthcare uses in the last year [Emergency Department (p = 0.029); outpatient visit to primary care, rheumatologist, or urgent care clinic (p < 0.001)], have tophi (p < 0.001), report pain > 3 (p = 0.001), and have disease activity > 10 (p < 0.001) compared with patients in the “not receiving prophylaxis” group. Conclusion. Forty-two percent of patients with gout in the CORRONA Gout Registry were receiving prophylaxis. Prophylaxis was significantly more common in patients with a higher disease burden and activity, which is in agreement with the ACR guidelines. Our study highlights disease characteristics influencing prophylaxis and furthers our knowledge on current use of flare prophylaxis.