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.

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.

Two-year radiographic and clinical outcomes from the Canadian Methotrexate and Etanercept Outcome study in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate radiographic and clinical outcomes up to 24 months in patients with RA enrolled in the Canadian Methotrexate and Etanercept Outcome study. METHODS: In this open-label non-inferiority trial, patients with inadequate response to MTX received etanercept plus MTX for 6 months and then were randomized to either etanercept monotherapy or continued etanercept plus MTX until 24 months. Radiographic data were analysed using the modified total Sharp score (mTSS), joint space narrowing and erosion scores. Secondary outcomes included the 28-joint DAS with ESR (DAS28-ESR), Simplified Disease Activity Index, Clinical Disease Activity Index, HAQ Disability Index (HAQ-DI) and safety. RESULTS: Two hundred five of 258 patients enrolled were randomized (98 etanercept, 107 etanercept plus MTX). At month 24, the mean increase from baseline to month 24 for the etanercept and etanercept plus MTX arms, respectively, for the mTSS were 0.4 (s.d. 1.9) and 0.0 (s.d. 1.4); for joint space narrowing, 0.1 (s.d. 0.6) and 0.0 (s.d. 0.7) and for erosion, 0.3 (s.d. 1.5) and 0.0 (s.d. 1.0). At month 24, the mean increase from month 6 mean scores/count increases for DAS28-ESR were 0.56 (s.d. 1.26) and 0.08 (s.d. 1.50); for Simplified Disease Activity Index, 4.7 (s.d. 13.1) and 0.9 (s.d. 12.5); for Clinical Disease Activity Index, 4.1 (s.d. 12.3) and 1.0 (s.d. 12.3) and for HAQ-DI, 0.20 (s.d. 0.45) and 0.02 (s.d. 0.54). Patients with DAS28-ESR low disease activity (LDA)/remission at month 6 had numerically better outcomes at month 24 than patients with moderate to high disease activity at month 6. In patients with LDA/remission at month 6, outcomes were similar at month 24 between etanercept monotherapy and etanercept plus MTX, whereas patients with moderate to high disease activity at month 6 had numerically better outcomes with etanercept plus MTX than etanercept at month 24. There were no new safety signals and serious adverse events were not different between groups. CONCLUSION: These results support the possibility of discontinuing MTX in patients who have tolerability issues with MTX if they achieve LDA/remission. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov/; NCT00654368).

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.

Incomplete data in randomized dermatology trials: consequences and statistical methodology.

Randomized clinical trials can provide the highest level of evidence regarding the effectiveness of therapeutic interventions. When individuals in trials do not complete the planned treatment period it is often not possible to observe the desired outcomes, which results in incomplete data. Here we review various mechanisms which can lead to incomplete data, discuss the impact of these mechanisms, and present strategies for dealing with incomplete data. We discuss these issues in the context of clinical trials in dermatology and provide practical recommendations for planning and drawing conclusions from studies which could involve incomplete data.

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.

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.

Transfusion Management of Incident Dialysis Patients in Canada: A Prospective Observational Study.

BACKGROUND: Several studies have demonstrated harm associated with using erythropoiesis-stimulating agents (ESA) to achieve higher hemoglobin (Hb) levels. Subsequently, more conservative use of ESAs has changed anemia therapy in patients with chronic renal failure. OBJECTIVE: The objectives were to identify transfusion rates in hemodialysis (HD) patients during the first year of therapy, to identify factors associated with the probability of transfusion, describe reasons for the transfusions, and identify the Hb values associated with each transfusion. An exploratory objective was to describe the age of red blood cell transfusions. DESIGN: This was a multicenter prospective observational cohort study. SETTING: There were 12 study sites in 5 Canadian provinces. The study was performed from 2012 to 2014. METHODS: The study patients were adult incident chronic HD patients in these centers. Patients with acute kidney injury, peritoneal dialysis, and planned transfer to satellite units were excluded. Patients had to receive at least 1 month of chronic HD to be eligible. Data for 3 months prior to HD were obtained by retrospective chart review. Prospectively, charts were reviewed monthly for 12 months for data abstraction. RESULTS: There were 314 patients enrolled and 79.9% completed 12 month follow-up. Ninety-four (29.9%) patients received at least 1 unit of blood. During the first 90 days, the transfusion episode rate was 148.4 per 100 patient-years compared with 62.6 per 100 patient-years post 90 days. The most frequent indication was a low Hb value (92%) with gastrointestinal bleeding, surgical blood loss, and fatigue accounting for 9.9%, 8.6%, and 4.5%, respectively. Some patients had >1 indication. The mean Hb values prior to transfusion episodes ranged from 75.3 to 78.6 g/L. Cox regression analysis on time to first transfusion and time to first hospitalization/death both showed an association with inpatient initiation of HD. Some 37.5% initiated HD as an inpatient and differed from those starting as an outpatient. They had less predialysis care and laboratory data suggested more inflammation. The mean and median ages of the blood units transfused were 24.9 (SD = 10.0) and 23 days (interquartile range = 17-33). CONCLUSIONS: This work reported the blood transfusion rate in incident HD patients in Canada during a period associated with conservative ESA prescription. The major indication for transfusion was a low Hb rather than clinical symptoms. Initiation of HD as an inpatient was independently associated with the probability of receiving a blood transfusion. These findings require further investigation.

CONTEXTE: Plusieurs études ont fait état de lésions associées à l'utilisation d'agents stimulant l'érythropoïèse (ASE) pour hausser le taux d'hémoglobine (Hb). Dès lors, une utilisation plus conservatrice des ASE a modifié le traitement de l'anémie chez les patients atteints d'insuffisance rénale chronique. OBJECTIFS DE L'ÉTUDE: L'étude visait à i) établir les taux de transfusion sanguine chez les patients hémodialysés au cours de la première année de traitement; ii) cerner les facteurs associés à la probabilité de recourir à une transfusion sanguine; iii) connaître les raisons de la transfusion; et iv) caractériser le taux d'hémoglobine au moment de l'intervention. En outre, un objectif exploratoire consistait à déterminer l'âge des érythrocytes transfusés. TYPE D'ÉTUDE: Il s'agit d'une étude de cohorte observationnelle prospective multicentrique. CADRE DE L'ÉTUDE: L'étude s'est tenue entre 2012 et 2014 sur douze sites répartis dans cinq provinces canadiennes. MÉTHODOLOGIE: Les patients adultes hémodialysés des centres participants ont été recrutés pour l'étude. Ont été exclus les patients atteints d'insuffisance rénale aiguë, les patients traités par dialyse péritonéale et les patients à être transférés vers une unité satellite. Pour être admissible, le patient devait recevoir un traitement d'hémodialyse continu pendant au moins un mois. On a rétrospectivement tiré des dossiers médicaux les données des trois mois précédant l'hémodialyse, puis on a extrait les données des dossiers médicaux chaque mois sur un an. RÉSULTATS: Un total de 314 patients a participé à l'étude et 79,9 % d'entre eux ont complété les 12 mois de suivi. Sur cette période, 94 patients (29,9 %) ont reçu au moins une transfusion sanguine. Au cours des 90 premiers jours, le taux d'épisodes transfusionnels était de 148,4 pour 100 années-patients, comparativement à 62,6 pour 100 années-patients pour le reste de l'étude. La raison la plus fréquente de recourir à une transfusion était un faible taux d'Hb (92 % des cas); les cas de saignements gastro-intestinaux, de perte de sang périchirurgicale et de fatigue comptaient quant à eux pour 9,9 %, 8,6 % et 4,5 % respectivement. Certains patients cumulant plus d'une indication. Le taux d'Hb moyen prétransfusion variait de 75,3 à 78,6 g/L. Une analyse de régression de Cox sur le temps écoulé jusqu'à la première transfusion et jusqu'à la première hospitalisation (ou le décès) du patient a montré une corrélation avec l'initiation d'un traitement d'hémodialyse chez les patients hospitalisés. Les sujets qui avaient initié leur traitement d'hémodialyse alors qu'ils étaient hospitalisés (37,5 %) ont reçu moins de soins prédialyse et présentaient davantage d'inflammation que les sujets qui avaient commencé leurs traitements d'hémodialyse en tant que patient externe. Enfin, l'âge moyen et l'âge médian des érythrocytes transfusés étaient de 24,9 jours (ÉT : 10,0) et de 23 jours (EIQ : 17 à 23). CONCLUSION: Notre étude a permis de connaître le taux de transfusions sanguines dans une population de patients hémodialysés canadiens au cours d'une période correspondant à une prescription conservatrice d'ASE. On a observé que la principale raison de transfusion était un faible taux d'Hb et non des symptômes cliniques. Enfin, une hémodialyse amorcée en cours d'hospitalisation a été associée à une probabilité accrue de transfusion sanguine. Nos constatations devraient faire l'objet d'études plus approfondies.

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.

Dose Escalation and Co-therapy Intensification Between Etanercept, Adalimumab, and Infliximab: The CADURA Study.

OBJECTIVE: To compare anti-TNF dose escalation, DMARD and/or glucocorticoid intensification, switches to another biologic, and drug and drug-related costs over 12 and 18 months for rheumatoid arthritis (RA) patients initiating etanercept (ETN), adalimumab (ADA), or infliximab (IFX) in routine clinical practice across Canada. METHODS: A retrospective chart review of biologic-naïve adult RA patients newly initiating ADA, ETN, or IFX between January 01, 2006 and December 31, 2012 from 11 practices across Canada. RESULTS: There were 314 patients in the 12-month analysis and 217 in the 18-month analysis. No dose escalation occurred with ETN over 12 and 18 months versus 38% and 32% for IFX (p<0.001) and 2% and 2% for ADA (p=0.199, p=0.218). Over 18 months, dose escalation and/or DMARD and/or glucocorticoid intensification was less frequent among ETN (16%) versus IFX (44%, p=0.005) and ADA (34%, p=0.004). By 18 months, 22% of patients initiating ADA had switched to another biologic compared with 6% of ETN patients (p=0.001).Patients initiating ETN had lower total (drug and drug-related) costs over 12 and 18 months compared to IFX, and no difference compared to ADA when adjusted for potential confounders. Patients with dose escalation had higher costs compared to those with no dose escalation. CONCLUSION: Physicians were more likely to escalate the dose of IFX, but optimize co-therapy with ADA and ETN. ETN patients had no dose escalation and were less likely to have DMARD and/or glucocorticoid intensification than ADA patients. ETN-treated patients had lower costs compared to IFX patients.

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.

Etiology of community-acquired pneumonia treated in an ambulatory setting.

BACKGROUND: Very few studies have addressed the etiology of community-acquired pneumonia (CAP) treated in an ambulatory setting. METHODS: Patients were recruited from physicians' offices and from Emergency Rooms in Canada. Pneumonia was defined as two or more respiratory symptoms and signs and a new opacity on chest radiograph interpreted by a radiologist as pneumonia. Blood and sputum for culture as well as acute and convalescent serum samples for serology were obtained. Antibodies to Mycoplasma pneumoniae and Chlamydia pneumoniae were determined using enzyme-linked immunosorbent assays. RESULTS: Five hundred and seven patients were enrolled in the study; 419 (82%) had blood cultures done, seven (1.4%) of which were positive for Streptococcus pneumoniae; 241 (47.5%) had a sputum processed for culture, 31% of which were positive for a potential respiratory pathogen. 437 (86.2%) had both acute and convalescent serum samples obtained, 148 (33.8%) of which gave a positive result. Overall an etiological diagnosis was made in 48.4% of the patients. M. pneumoniae accounted for 15% of the cases, C. pneumoniae 12%, S. pneumoniae 5.9% and Haemophilus influenzae 4.9%. CONCLUSIONS: Despite considerable effort an etiological diagnosis of CAP treated on an ambulatory basis was made in only half the patients. The most commonly identified pathogens were M. pneumoniae, C. pneumoniae, S. pneumoniae,

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.

Intravenous immune globulin use in Canada.

OBJECTIVES: To determine the amount of intravenous immune globulin (IVIG) used across indications in Canada and which Canadian medical specialties prescribe IVIG. To assess the proportion of IVIG that was used in appropriate off-label and labelled indications versus those deemed to be inappropriate off-label indications. METHODS: In Canada, all IVIG is distributed by the Canadian Blood System to Canadian blood banks within the hospital setting. Hospital blood banks then dispense IVIG to individual patients as it is prescribed and, as such, many institutions maintain a comprehensive database inventory on IVIG use. This study is a retrospective review of IVIG use as obtained from 10 teaching and community hospital blood bank databases in Ontario, Quebec, Alberta and British Columbia. Two of these 10 institutions were pediatric teaching hospitals whereas the remaining eight centres were adult care sites. Product usage was assessed between 1997 and 1999 in adult care sites, and 1997 and 1998 in the pediatric hospitals. The information collected included the number of grams of IVIG dispensed, the indications, the prescribing physician's specialty and the number of patients treated for a given indication, all assessed on an annual basis. A separate analysis was performed to determine the appropriateness of IVIG use where appropriateness was based on the published 1997 and 1999 Canadian Consensus Guidelines for IVIG use. RESULTS: IVIG was prescribed for 90 different indications, six of which are licensed in Canada. When considered as separate populations, adult and pediatric use accounted for 61 and 65 different indications, respectively. Licensed use for all known indications represented approximately 47% and 62% in adult and pediatric settings, respectively. Twenty-nine per cent of IVIG use in adult and 17% in pediatric settings was not reported and is therefore unknown. Although off-label use by definition is approximately 53% in adults and 38% in pediatrics, the majority of overall IVIG use (89% in both populations) is considered appropriate by guideline definition. Hematologists and neurologists were the most prevalent prescribers of IVIG. CONCLUSIONS: Based on guideline definition, appropriate off-label use of IVIG is very high in Canada.

Symptom resolution in patients with Mycoplasma pneumoniae pneumonia.

BACKGROUND: Mycoplasma pneumoniae generally causes pneumonia of mild to moderate severity in adults. However, little is known about the time course of the resolution of symptoms in this illness. OBJECTIVES: To determine the time course of the resolution of symptoms in M pneumoniae pneumonia. METHODS: The severity of fatigue, cough, dyspnea, sputum and pleuritic chest pain were self-scored and recorded daily for 14 days and on days 30 and 42. Each symptom was scored on a scale of 0 to 5. The sum of the five symptom scores had a range of 0 to 25 and was transformed into a value from zero to 100 by multiplying by four. RESULTS: The mean composite symptom score for 76 patients was 59 (out of 100) at presentation, which declined to a score of 17 on day 14. Patients with a score of greater than 20 on day 14 had significantly higher scores throughout the course of the illness. Thirty-four per cent of those who were employed did not take time off work. CONCLUSIONS: Most patients with M pneumoniae pneumonia had resolution of their symptoms within two weeks; however, 12.6% were still symptomatic at 42 days.

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.

Dialysis patients treated with Epoetin α show improved exercise tolerance and physical function: A new analysis of the Canadian Erythropoietin Study Group trial.

The risks/benefits of anemia treatment in dialysis patients have been redefined in the US Epoetin α label. This analysis was carried out to determine if increasing hemoglobin (Hb) levels improve exercise tolerance and physical function in anemic dialysis patients. This is a new analysis of the Canadian Erythropoietin Study Group trial, a double-blind, randomized, placebo-controlled trial in dialysis patients. Subjects were 18 to 75 years old, on hemodialysis for >3 months, and had a baseline Hb <9.0 g/dL. Patients with a history of diabetes mellitus, ischemic heart disease, or severe/uncontrolled hypertension were excluded. Patients were randomized to receive Epoetin α to a target Hb of 9.5 to 11.0 g/dL (n=40) or a target of 11.5 to 13.0 g/dL (n=38), or receive placebo (n=40). Results from patients in the Epoetin-α-treated arms were combined for this analysis. Hb level, exercise tolerance (Treadmill Stress Test and 6-Minute Walk Test) and patient-reported physical function measures (Physical Summary domain from the Kidney Disease Questionnaire, and 4 domains from the Sickness Impact Profile) were reported at baseline and months 2, 4, and 6. Differences in measures were statistically significant for exercise tolerance (Treadmill Stress, P=0.0001) and patient-reported physical function (Kidney Disease Questionnaire Physical, P=0.0001; Sickness Impact Profile Physical, P=0.0015) across all time points for Epoetin-α-treated patients compared with placebo. Improvements were seen at 2 months and were maintained through months 4 and 6. Dialysis patients receiving Epoetin α showed improved exercise tolerance and physical function. These findings should be considered as physicians weigh the risks and benefits of treatment.