Evaluating hybrid controls methodology in early-phase oncology trials: A simulation study based on the MORPHEUS-UC trial.

Phase Ib/II oncology trials, despite their small sample sizes, aim to provide information for optimal internal company decision-making concerning novel drug development. Hybrid controls (a combination of the current control arm and controls from one or more sources of historical trial data [HTD]) can be used to increase statistical precision. Here we assess combining two sources of Roche HTD to construct a hybrid control in targeted therapy for decision-making via an extensive simulation study. Our simulations are based on the real data of one of the experimental arms and the control arm of the MORPHEUS-UC Phase Ib/II study and two Roche HTD for atezolizumab monotherapy. We consider potential complications such as model misspecification, unmeasured confounding, different sample sizes of current treatment groups, and heterogeneity among the three trials. We evaluate two frequentist methods (with both Cox and Weibull accelerated failure time [AFT] models) and three different commensurate priors in Bayesian dynamic borrowing (with a Weibull AFT model), and modifications within each of those, when estimating the effect of treatment on survival outcomes and measures of effect such as marginal hazard ratios. We assess the performance of these methods in different settings and the potential of generalizations to supplement decisions in early-phase oncology trials. The results show that the proposed joint frequentist methods and noninformative priors within Bayesian dynamic borrowing with no adjustment on covariates are preferred, especially when treatment effects across the three trials are heterogeneous. For generalization of hybrid control methods in such settings, we recommend more simulation studies.

The burden of symptomatic skeletal events in castrate-resistant prostate cancer patients with bone metastases at three Canadian uro-oncology centres.

INTRODUCTION: Metastatic bone disease in castrate-resistant prostate cancer risks significant morbidity, including symptomatic skeletal events. We estimated the healthcare resource costs of managing skeletal events. METHODS: A retrospective chart review was conducted for patients who died from or were treated palliatively for metastatic castrate-resistant prostate cancer from 2006-2013 at Centre Hospitalier de l'Université de Montréal (Montreal), Princess Margaret Cancer Centre (Toronto), or Vancouver General Hospital (Vancouver). RESULTS: Of 393 patients, 275 (70%) experienced 833 events (85 per 100 patient-years), with a median (95% confidence interval) time (months) to first event of 17.6 (15.3, 21.7). The mean metastatic bone disease-related healthcare resource use cost (2014 Canadian dollars) estimate for patients without symptomatic skeletal events was $9550 and between $22 101 (observed) and $34 615 (adjusted) for patients with at least one event. Fewer patients in Montreal (55%) experienced events compared to Toronto (79%) or Vancouver (76%). Median time (months) to first event was longer in Montreal (25.0 [18.5, 32.6]) than in Toronto (14.6 [9.7, 16.8] or Vancouver (17.3 [14.8, 24.0]). More patients received bone-targeted therapy in Montreal (64%) and Toronto (60%) than in Vancouver (24%). Bone-targeted therapy was mostly administered every 3-4 weeks in Montréal and every 3-4 months in Toronto. CONCLUSIONS: Metastatic bone disease-related healthcare resource use costs for Canadian castrate-resistant prostate cancer patients are high. Symptomatic skeletal events occurred frequently, with the incremental cost of one or more events estimated between $12 641 and $25 120. Symptomatic skeletal event incidence and bone-targeted therapy use varied considerably between three Canadian uro-oncology centres. An important limitation is that only patients who died from prostate cancer were included, potentially overestimating costs.

OBSERVE-5: Comparison of Etanercept-Treated Psoriasis Patients From Canada and the United States.

BACKGROUND: OBSERVE-5 surveillance registry results evaluating etanercept safety and effectiveness in patients with moderate to severe psoriasis from Canada and the United States have been reported from data collected between May 2006 and December 2012. Although both countries have an identical indicated starting dose, the maintenance dose can differ and thus affect management strategies and outcomes. OBJECTIVE: To compare the long-term safety and effectiveness outcomes of etanercept in the Canadian and US cohorts. METHODS: Primary end points included exposure-adjusted event incidence rates of serious adverse events and serious infectious events. Secondary end points included exposure-adjusted event incidence rates of events of medical interest and efficacy outcomes. RESULTS: Over 5 years, Canadian patients received a higher maintenance dose of etanercept (50 mg twice/week) more frequently than those from the United States. Safety outcome comparisons revealed that Canadian patients had a significantly lower occurrence of serious adverse events than patients from the United States, with an overall exposure-adjusted event incidence rate per 100 patient-years of 4.46 (95% confidence interval [CI], 3.05-6.29) vs 7.76 (95% CI 7.04-8.54), respectively. Serious infectious event rates were not significantly different between the 2 countries. Secondary outcomes of events of medical interest and effectiveness also did not reveal significant differences between the 2 cohorts. CONCLUSION: After 5 years of etanercept use, safety and effectiveness outcomes were similar between patients from Canada and the United States, with the exception of a significantly lower rate of serious adverse events in the Canadian population.

Single-Arm Study of Etanercept in Adult Patients with Moderate to Severe Rheumatoid Arthritis Who Failed Adalimumab Treatment.

INTRODUCTION: To evaluate the efficacy and safety of etanercept treatment in adult patients with moderate to severe rheumatoid arthritis (RA) who failed to respond (primary failure) or lost a satisfactory response (secondary failure) to adalimumab. METHODS: All patients discontinued prior adalimumab treatment and continued methotrexate with etanercept 50 mg once weekly for 24 weeks. The primary study endpoint was American College of Rheumatology 20% improvement criteria (ACR20) at week 12. RESULTS: Eighty-five patients (mean age 56.6 years; female 80.0%) were evaluated for safety and 84 for efficacy. Thirty (35.7%) patients achieved ACR20 at week 12; the lower bound of the 95% confidence interval (CI; 25.6, 46.9) was greater than the prespecified goal of 24% based on previous research. Improvements from baseline in clinical outcomes and patient-reported outcomes were observed at each study visit. In planned subgroup analyses, patients with anti-adalimumab antibodies and secondary adalimumab failure had the highest ACR20 response to etanercept at week 12 (11/17 patients; 64.7%). Among the patients with secondary adalimumab failure, those with anti-adalimumab antibodies were fivefold more likely to have an ACR20 response to etanercept than those without anti-adalimumab antibodies (odds ratio 5.2; 95% CI 2.0, 13.5; P < 0.001). Adverse events were reported for 62 (72.9%) patients and were consistent with previous studies of etanercept. Most adverse events were mild or moderate in severity. CONCLUSION: Switching to etanercept is a therapeutic option in patients with RA who fail adalimumab treatment. The presence of anti-adalimumab antibodies may provide additional support for switching to etanercept, particularly in patients with secondary adalimumab failure. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01927757.

Predictors of Topical Use in Psoriasis Patients in the REFINE Study.

BACKGROUND: The factors influencing the use of topical agents in combination with biologic therapies for the treatment of plaque psoriasis (PsO) are not well understood. OBJECTIVE: To examine potential predictors of topical use in patients with moderate to severe plaque PsO receiving etanercept (ETN). METHODS: Post hoc descriptive analyses and a multinomial regression of the REFINE study data were used to examine associations between topical agent potency and covariates, including Psoriasis Area and Severity Index (PASI) score, study site, and province. RESULTS: Not achieving PASI 90 at week 12 predicted topical use, with a lower PASI 90 rate in patients who used high-potency topical agents post randomization (P = .003). Additionally, statistically significant differences were found in patterns of topical use among Canadian provinces (P = .007), with the use of high-potency topical agents being greater in Ontario and Quebec than the rest of Canada. CONCLUSION: This analysis revealed that region and PASI 90 status at week 12 predict topical use.

Long-term Management of Moderate to Severe Plaque Psoriasis Patients With Etanercept: A Case Series.

BACKGROUND: Currently, etanercept (ETN) safety and efficacy in patients with moderate to severe plaque psoriasis (PsO) has been reported up to 5 years. OBJECTIVE: To present a case series of PsO patients receiving continuous ETN therapy for 7 or more years. METHODS: Physicians collected data retrospectively from 52 patient charts from 5 centres across Canada. RESULTS: Patients in this case series had PsO an average of 31.5 years. Nearly half of patients also had psoriatic arthritis (24/52). All patients demonstrated sustained improvement in Psoriasis Area and Severity Index (PASI) and percentage of affected body surface area (BSA) following ETN treatment. Of the 52 patients, 33 have been receiving ETN for 10 years or more. CONCLUSION: The clinical experience described in this case series report suggests maintenance of ETN efficacy in PsO patients who receive therapy for 7 years or more and indicates that patients can be successfully managed with long-term ETN therapy.

The Canadian methotrexate and etanercept outcome study: a randomised trial of discontinuing versus continuing methotrexate after 6 months of etanercept and methotrexate therapy in rheumatoid arthritis.

OBJECTIVE: To determine if withdrawing methotrexate (MTX) after 6 months of combination etanercept (ETN)+MTX, in MTX-inadequate responders with active rheumatoid arthritis (RA), is non-inferior to continuing ETN+MTX. METHODS: Tumour necrosis factor-inhibitor naïve RA patients with disease activity score 28 (DAS28)≥3.2, swollen joint count≥3, despite stable MTX, were treated with ETN+MTX for 6 months, followed by randomisation to either continue ETN+MTX or switch to ETN monotherapy for an additional 18 months. The primary endpoint was change in DAS28 from 6-month randomisation to 12 months. The non-inferiority margin of change in DAS28 was 0.6, with prespecified analyses (DAS28<3.2 vs DAS28≥3.2). RESULTS: 205 patients were randomised. DAS28 was stable in patients on ETN+MTX and increased slightly in patients on ETN monotherapy from 6 to 12 months. Non-inferiority was not achieved, with an adjusted difference of 0.4 (0.1 to 0.7) between the ETN and the ETN+MTX groups, for the month 6-12 change in DAS28. However, patients who achieved low disease activity (LDA; DAS28<3.2) at 6 months had a similar disease activity at 12 months, whether on monotherapy or combination therapy (DAS28 change 0.7 ETN vs 0.57 ETN+MTX, p=0.8148). Conversely, for patients who did not reach LDA at 6 months, those on ETN monotherapy had increased disease activity at 12 months, while disease activity continued to decrease for patients on combination therapy, at 12 months (DAS28 change 0.4 ETN vs -0.4 ETN+MTX, p=0.0023). CONCLUSIONS: Non-inferiority was not achieved. Withdrawing MTX after 6 months of continuation ETN+MTX in MTX inadequate responders did not yield the same degree of improvement between 6 and 12 months compared with continuing ETN+MTX. TRIAL REGISTRATION: ClinicalTrials.gov-NCT00654368.

An analysis of the treatment effect of panitumumab on overall survival from a phase 3, randomized, controlled, multicenter trial (20020408) in patients with chemotherapy refractory metastatic colorectal cancer.

Panitumumab is a fully human monoclonal antibody that targets the epidermal growth factor receptor. Results from the primary analysis of a phase 3, randomized, controlled study showed a statistically significant improvement in progression-free survival for patients receiving panitumumab; however, overall survival was confounded by best supportive care (BSC) patients that crossed over to panitumumab therapy after disease progression. Three post hoc analyses are presented that approximate the panitumumab overall survival treatment effect in both the all-randomized and wild-type (WT) KRAS populations by using the BSC patients with mutant (MT) KRAS as the comparator group to discount the effect of crossover from BSC to panitumumab. The primary post hoc analysis showed a median overall survival of 6.4 months for all KRAS-evaluable patients randomized to panitumumab versus 4.4 months for patients with MT KRAS tumors randomized to BSC, yielding an adjusted hazard ratio (95 % CI) of 0.764 (0.598-0.977). Similar results were observed for the two secondary post hoc analyses. These analyses suggest a positive treatment effect of panitumumab in both the overall and WT KRAS patient populations consistent with an improvement in overall survival relative to BSC.

One-year, multicenter, open-label, single-arm study evaluating the safety and effectiveness of etanercept for the treatment of moderate-to-severe plaque psoriasis in a Canadian population.

BACKGROUND: Although etanercept is well tolerated and effective in moderate-to-severe plaque psoriasis, data are limited in Canadian practice settings. OBJECTIVE: To assess the effectiveness and safety of etanercept in Canadian patients with moderate-to-severe plaque psoriasis (Physician Global Assessment [PGA] ≥ 3) in routine practice. METHODS: A 1-year, multicenter, open-label trial of 246 patients enrolled from March 2006 to July 2009 was conducted. Patients received etanercept 50 mg subcutaneously twice weekly for 3 months and then 50 mg once weekly for 9 months. The primary end point was the proportion of patients achieving a PGA score ≤ 2 at month 12. Secondary end points included the proportion of patients achieving PGA score ≤ 2 at months 3, 6, and 9 and change from baseline at month 12 for Patient Global Assessment (PtGA), body surface area, and Dermatology Life Quality Index (DLQI). Adverse events were reported. RESULTS: At month 12, 73.5% (95% CI 67.2-79.1) achieved a PGA score ≤ 2. The response was similar regardless of the previous response to systemic or phototherapy. The proportion of patients achieving this score improved from 2.2% (95% CI 0.3-4.2) at baseline to 73.5% (95% CI 67.2-79.1) at 12 months. At 12 months, patients with a DLQI score of 0 or ≥ 5-point improvement was 28.8% (95% CI 22.9-34.7) and 47.3% (95% CI 40.8-53.9), respectively. No new safety signals were reported. CONCLUSION: The majority of this Canadian population demonstrated a meaningful improvement in PGA and DLQI scores over 1 year.

Etanercept improves quality of life outcomes and treatment satisfaction in patients with moderate to severe plaque psoriasis in clinical practice.

BACKGROUND: Etanercept is well tolerated and effective in moderate to severe psoriasis; however, data on patient-reported outcomes (PROs) in Canadian patients remain limited. OBJECTIVE: To assess PROs in Canadian patients with moderate to severe psoriasis receiving etanercept in an open-label trial more representative of general clinical practice than traditional research studies. METHODS: This 1-year, multicenter, single-arm study enrolled 246 patients. Patients received etanercept 50 mg subcutaneously twice weekly for 3 months and then 50 mg once weekly for 9 months. Primary and safety end points were reported previously. Change from baseline to month 12 for the Dermatology Life Quality Index (DLQI), EuroQoL-5D, and Treatment Satisfaction Questionnaire for Medication (TSQM) are secondary outcomes reported here. Post hoc analyses of PROs are also reported. RESULTS: Mean ± standard deviation (SD) DLQI total score improved from 13.7 ± 6.1 at baseline to 3.9 ± 5.6 at month 12. By month 12, 75% of patients achieved a clinically meaningful improvement in the DLQI (≥ 5-point improvement or a score of 0). Fifty-three to 86% of patients reported improvement or complete improvement in the six DLQI subscales. The mean ± SD EuroQoL-5D total score improved from baseline (0.67 ± 0.25) to month 12 (0.83 ± 0.25). The TSQM scores showed improvement in global satisfaction, effectiveness, and convenience after 3 months. CONCLUSIONS: Etanercept was associated with improved PROs and increased treatment satisfaction over 1 year.

Work productivity and healthcare resource utilization outcomes for patients on etanercept for moderate-to-severe plaque psoriasis: results from a 1-year, multicentre, open-label, single-arm study in a clinical setting.

BACKGROUND: Data investigating the effect of etanercept on work productivity and healthcare resource utilization in Canadian patients in a clinical setting is limited. OBJECTIVE: The aim of the study was to describe work productivity and healthcare resource utilization in patients with psoriasis prescribed etanercept. METHODS: A 12-month, phase IV, non-randomized, multicentre, open-label, single-arm prospective trial of patients with moderate-to-severe plaque psoriasis was conducted between March 2006 and July 2009 in 37 community dermatology practice sites across Canada. A total of 246 patients were enrolled. Major eligibility criteria: ≥18 years of age; diagnosis of moderate-to-severe plaque psoriasis at baseline (Physician Global Assessment [PGA] ≥3, scale 0-5); able to start etanercept therapy as per product monograph. Patients received etanercept (Enbrel(®)) 50 mg subcutaneously twice weekly for 3 months, then 50 mg once weekly for 9 months. Outcomes were measured by average change and average percent change from baseline at months 3, 6, 9 and 12 on the Work Productivity and Activity Impairment (WPAI) and Healthcare Resource Utilization (HRU) questionnaires. RESULTS: The mean degree of impairment while working ± standard deviation (SD) in the total population decreased from 22.7% ± 23.2 at baseline to 6.6% ± 14 after 3 months of treatment (p < 0.0001). From baseline to 3 months, overall work impairment ± SD decreased from 23.7% ± 23.7 to 8.3% ± 16.5 (p < 0.0001) and mean activity impairment outside the workplace decreased from 31.4% ± 26.4 to 12.9% ± 22.4 (p < 0.0001). All these improvements were sustained to month 12. Other variables that decreased on average from baseline to month 3, sustained to month 12, included physician office visits (2.3/month ± 3.5 at baseline to 0.6/month ± 1.0 at month 3; p < 0.0002), hours of assistance required of family and friends to assist with psoriasis (1.1 hours/week ± 2.6 at baseline to 0.3 hours/week ± 1.5 at month 3; p = 0.0002) and amount of time spent on activities to manage psoriasis (5.5 hours/week ± 6.2 at baseline to 1.9 hours/week ± 3.7 at month 3; p < 0.0001). Also, the amount of out-of-pocket expenses to manage psoriasis decreased from $Can94.9/month ± 331.6 at baseline to $Can35.7 ± 69.1 at month 12 (p = 0.0153). CONCLUSIONS: Use of etanercept in Canadian patients in a clinical practice setting correlated with improvement in work productivity and reduced HRU after 3 months of treatment, and improvement was sustained up to 12 months.

Assessment of the long-term safety and effectiveness of etanercept for the treatment of psoriasis in an adult population.

BACKGROUND: Etanercept is well tolerated and effective in moderate to severe plaque psoriasis. However, effectiveness and safety data beyond 2.5 years have not been reported. OBJECTIVE: We sought to assess the effectiveness and safety profile of up to 4 years of etanercept therapy in psoriasis. METHODS: We analyzed prospective data from previous trials and open-label extensions, including 506 patients who initiated etanercept therapy in either of two phase III trials. Patients received etanercept, 25 mg twice weekly, 50 mg weekly, or 50 mg twice weekly, depending on which trial therapy was started. Dosage adjustments were allowed in open-label extensions, but no patients exceeded 50 mg twice weekly. Outcomes included change from baseline for the static Physician Global Assessment and Dermatology Life Quality Index scores. Exposure-adjusted adverse event (AE) rates were calculated. RESULTS: In all, 75.9% (95% confidence interval 67.9-84.0) and 27.8% (95% confidence interval 19.3-36.2) maintained Dermatology Life Quality Index response (≥ 5-point improvement from baseline) and static Physician Global Assessment response (clear or almost clear) at 48 months, respectively. AE and serious AE rates were 243.5 and 7.8 events per 100 patient-years, respectively. No serious AE rates exceeded 1.0 event per 100 patient-years. Overall infection and serious infection rates were 96.9 and 0.9 events per 100 patient-years, respectively. No cases of tuberculosis or lymphoma were reported. LIMITATIONS: Effectiveness data were limited to static Physician Global Assessment and Dermatology Life Quality Index scores. Analysis of AE rates was limited to available comparator databases. CONCLUSION: Etanercept demonstrated sustained effectiveness and a favorable safety profile with no cumulative toxicity for up to 4 years, representing, to our knowledge, the longest published study on etanercept use in psoriasis to date.

Effectiveness and safety of etanercept in patients with psoriatic arthritis in a Canadian clinical practice setting: the REPArE trial.

OBJECTIVE: To describe the longterm effectiveness and safety of etanercept in Canadian patients with psoriatic arthritis (PsA), treated over 24 months in clinical practice. METHODS: Patients with active PsA (≥ 3 tender and ≥ 3 swollen joints) were recruited from 22 centers. Etanercept was administered at 50 mg/week subcutaneously. In addition to clinical assessment of skin and joint disease, conducted at baseline and at Months 6, 12, 18, and 24, regular patient interviews were conducted by telephone. Patient responses related to health status, disability, and work productivity were scored using the patient global assessment tool, the Health Assessment Questionnaire (HAQ), the Health and Labour Questionnaire (HLQ), and the Fatigue Severity Scale. RESULTS: Out of 110 patients, 71 (65%) maintained etanercept treatment through the end of our study. All clinical measures of disease severity, including joint tenderness/pain, joint swelling, and Psoriasis Area and Severity Index score, improved significantly between baseline and Month 6 of etanercept treatment and remained constant thereafter. By the end of our study, 79% of patients achieved a Psoriatic Arthritis Response Criteria response, and 56% of patients achieved a 0.5-point improvement on HAQ, indicating clinically significant improvement in disability; 14% of patients finished our study free of disability (HAQ = 0). Patients' work productivity and fatigue improved significantly in parallel with these clinical and functional improvements. CONCLUSION: Continuous treatment with etanercept over 2 years in a clinical setting improved clinical symptoms of PsA while reducing fatigue, improving work productivity, and ameliorating or eliminating disability.

Dialysis patients treated with Epoetin alfa show improved anemia symptoms: A new analysis of the Canadian Erythropoietin Study Group trial.

The health-related quality of life (HRQOL) claims in the current Epoetin alfa label are based on the reanalyses of the exercise and physical function data from the Canadian Erythropoietin Study Group trial. The reanalysis was done to comply with the Food and Drug Administration's requirement of using statistical methods that are currently standard in evaluating clinical trial data. Presented here are HRQOL results associated with anemia. The Canadian Erythropoietin Study Group trial was a multicenter, double blind, randomized, placebo-controlled trial evaluating the effects of Epoetin alfa on HRQOL in anemic hemodialysis patients. A total of 118 patients who were 18-75 years old, on hemodialysis for >3 months, who had a hemoglobin <9.0 g/dL, and did not have coronary artery disease or diabetes mellitus, were randomized to either receive placebo (n=40), or receive intravenous Epoetin alfa to achieve a target hemoglobin of 9.5-11.0 g/dL (n=40) or a target of 11.5-13.0 g/dL (n=38). Patients were followed for 6 months. The two Epoetin alfa-treatment groups were combined for all analyses performed. This post hoc analysis was conducted using an intent-to-treat repeated measures mixed model analysis of variance using Bonferroni's multiplicity correction. The Epoetin alfa-treated group showed a statistically significant improvement in the Kidney Disease Questionnaire symptom of fatigue in comparison with placebo. Additionally, the change in hemoglobin at 2 months was correlated with change in fatigue, energy, shortness of breath, and weakness, but had minimal effect on depression. These analyses confirm previously reported results, which indicate that treating hemodialysis patients with an erythropoiesis-stimulating agent improves HRQOL.