John H. Coombs

The Safety and Efficacy of a JAK Inhibitor in Patients With Active Rheumatoid Arthritis Results of a Double-Blind, Placebo-Controlled Phase IIa Trial of Three Dosage Levels of CP-690,550 Versus Placebo

OBJECTIVE To determine the efficacy, safety, and tolerability of 3 different dosages of CP-690,550, a potent, orally active JAK inhibitor, in patients with active rheumatoid arthritis (RA) in whom methotrexate, etanercept, infliximab, or adalimumab caused an inadequate or toxic response. METHODS Patients (n = 264) were randomized equally to receive placebo, 5 mg of CP-690,550, 15 mg of CP-690,550, or 30 mg of CP-690,550 twice daily for 6 weeks, and were followed up for an additional 6 weeks after treatment. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at 6 weeks. RESULTS By week 6, the ACR20 response rates were 70.5%, 81.2%, and 76.8% in the 5 mg, 15 mg, and 30 mg twice daily groups, respectively, compared with 29.2% in the placebo group (P < 0.001). Improvements in disease activity in CP-690,550-treated patients compared with placebo were seen in all treatment groups as early as week 1. ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4. The most common adverse events reported were headache and nausea. The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4% (versus 26.2% in the placebo group). No opportunistic infections or deaths occurred. Increases in mean low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels, and increases in mean serum creatinine level (0.04-0.06 mg/dl) were seen in all CP-690,550 treatment arms. CONCLUSION Our findings indicate that CP-690,550 is efficacious in the treatment of RA, resulting in rapid, statistically significant, and clinically meaningful reductions in the signs and symptoms of RA. Further studies of CP-690,550 in RA are warranted.

Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomised, double-blind, placebo-controlled trial

Objectives: To determine the efficacy of CP-690,550 in improving pain, function and health status in patients with moderate to severe active rheumatoid arthritis (RA) and an inadequate response to methotrexate or a tumour necrosis factor α inhibitor. Methods: Patients were randomised equally to placebo, CP-690,550 5, 15 or 30 mg twice daily for 6 weeks, with 6 weeks’ follow-up. The patient’s assessment of arthritis pain (pain), patient’s assessment of disease activity, Health Assessment Questionnaire-Disability Index (HAQ-DI) and Short Form-36 (SF-36) were recorded. Results: At week 6, significantly more patients in the CP-690,550 5, 15 and 30 mg twice-daily groups experienced a 50% improvement in pain compared with placebo (44%, 66%, 78% and 14%, respectively), clinically meaningful reductions in HAQ-DI (⩾0.3 units) (57%, 75%, 76% and 36%, respectively) and clinically meaningful improvements in SF-36 domains and physical and mental components. Conclusions: CP-690,550 was efficacious in improving the pain, function and health status of patients with RA, from week 1 to week 6.

Stated Preferences of Patients with Cancer for Health-related Quality-of-life (HRQOL) Domains During Treatment

Objectives: It is postulated that patients with different cancer diagnoses, stages of disease and treatments will exhibit different individual preferences for health-related quality-of-life (HRQOL) functional domains and symptoms. Methods: A stated-preference (SP) instrument incorporating all functional domains and symptoms of the EORTC Quality of Life Questionnaire (QLQ-C30) was administered to 400 patients with either breast (n=150); colorectal (n=150) or non-small cell lung cancer (n=100) who had previously experienced chemotherapy. The SP survey asked patients to make choices between a series of hypothetical functional/symptom pairs defined by combinations of HRQOL attributes, and depicted by levels of functioning and symptomatology. Results: In the 400 patients, considered as one group, role, cognitive, and social functioning, fatigue, nausea/vomiting, pain, appetite loss, diarrhea and financial difficulties were most important, whereas physical and emotional functioning, dyspnea, constipation and insomnia were less important. The four effects that patients with breast cancer most wished to avoid were nausea and vomiting, pain, and decreases in emotional and role functioning. Patients with colorectal cancer listed diarrhea as the second most important effect to avoid (after nausea/vomiting, but before pain and role functioning), whereas those with non-small cell lung cancer listed dyspnea as the fourth most important effect to avoid. Conclusion: These results provide more precise information regarding patient treatment concerns than that provided by the usual measurement of HRQOL. This information can be used by clinical trial investigators to design more precise interventions to improve HRQOL in the domains of greatest importance to patients and by all health care professionals to improve counseling of patients.

Are Chemotherapy Patients' HRQoL Importance Weights Consistent with Linear Scoring Rules? A Stated-choice Approach

AbstractObjective: To compare a linear scoring rule with the subjective importance of different domain and symptom levels of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) among patients undergoing chemotherapy. Methods: Using a stated-choice or choice-format conjoint analysis survey instrument, we elicited patient preferences for varying levels of physical, role, social, emotional, and cognitive function along with chemotherapy-related side effects and financial difficulties. A total of 375 patients completed the questionnaire: 159 breast cancer, 117 colorectal cancer, 99 non-small-cell lung cancer; and 21 with unknown tumor type. Constrained maximum likelihood estimates were used to estimate relative importance weights for each level of each domain and symptom. Results: Summary HRQoL measures generally presume that differences among Likert categories are equally important to patients within and across outcomes. Our results indicate strong non-linearities both within and across domain and symptom categories. Improvements from severe pain to mild pain, severe fatigue to no fatigue, and severe social limitations to moderate social limitations are all about twice as important as no work to limited work in the Role domain. Conclusions: Our results indicate large differences in the impact of individual domains and symptoms on patient perceptions of well-being. Most cancer patients are likely to be less concerned about specific symptoms than the impact of those symptoms on their ability to function physically, socially, and in their daily roles.

Patient preferences for reducing toxicities of treatments for gastrointestinal stromal tumor (GIST)

Purpose: To quantify gastrointestinal stromal tumor (GIST) patients’ preferences for reducing treatment toxicities and the likely effect of toxicities on patients’ stated adherence. Methods: English-speaking members of the Life Raft Group, a GIST patient advocacy and research organization, aged 18 years and older, completed a web-enabled survey including a series of treatment-choice questions, each presenting a pair of hypothetical GIST medication toxicity profiles. Each profile was defined by common or concerning toxicities verified via pretest interviews including: severity of edema, diarrhea, nausea, fatigue, rash, hand-foot syndrome, and heart failure; and risk of serious infection. Each subject answered 13 choice-format questions based on a predetermined experimental design with known statistical properties. Subjects were asked to rate the likelihood that they would miss or skip doses of medications with different toxicity profiles. Random-parameters logit was used to estimate a relative preference weight for each level of toxicity. Results: 173 subjects completed the survey. Over the ranges of toxicity levels included in the study, heart failure was the most important toxicity. Edema was the least important. For all toxicities, reducing severity from severe to moderate was more important to subjects than reducing severity from moderate to mild. Reducing heart failure from moderate to mild and diarrhea from severe to moderate had the largest effects on subjects’ evaluation of adherence. Conclusions: All toxicities included in the study are important to patients. Treating or reducing severe toxicities is much more important to patients than treating or reducing moderate toxicities. Focused reductions of certain toxicities may improve treatment adherence.