Treatment switching in randomised controlled trials (RCTs) is a problem for health technology assessment when substantial proportions of patients switch onto effective treatments that would not be ...available in standard clinical practice. Often statistical methods are used to adjust for switching: these can be applied in different ways, and performance has been assessed in simulation studies, but not in real-world case studies. We assessed the performance of adjustment methods described in National Institute for Health and Care Excellence Decision Support Unit Technical Support Document 16, applying them to an RCT comparing panitumumab to best supportive care (BSC) in colorectal cancer, in which 76% of patients randomised to BSC switched onto panitumumab. The RCT resulted in intention-to-treat hazard ratios (HR) for overall survival (OS) of 1.00 (95% confidence interval CI 0.82-1.22) for all patients, and 0.99 (95% CI 0.75-1.29) for patients with wild-type KRAS (Kirsten rat sarcoma virus).
We tested several applications of inverse probability of censoring weights (IPCW), rank preserving structural failure time models (RPSFTM) and simple and complex two-stage estimation (TSE) to estimate treatment effects that would have been observed if BSC patients had not switched onto panitumumab. To assess the performance of these analyses we ascertained the true effectiveness of panitumumab based on: (i) subsequent RCTs of panitumumab that disallowed treatment switching; (ii) studies of cetuximab that disallowed treatment switching, (iii) analyses demonstrating that only patients with wild-type KRAS benefit from panitumumab. These sources suggest the true OS HR for panitumumab is 0.76-0.77 (95% CI 0.60-0.98) for all patients, and 0.55-0.73 (95% CI 0.41-0.93) for patients with wild-type KRAS.
Some applications of IPCW and TSE provided treatment effect estimates that closely matched the point-estimates and CIs of the expected truths. However, other applications produced estimates towards the boundaries of the expected truths, with some TSE applications producing estimates that lay outside the expected true confidence intervals. The RPSFTM performed relatively poorly, with all applications providing treatment effect estimates close to 1, often with extremely wide confidence intervals.
Adjustment analyses may provide unreliable results. How each method is applied must be scrutinised to assess reliability.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
1 Department of Information Engineering, University of Padua, Padua, Italy; and 2 Department of Internal Medicine, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic and ...Foundation, Rochester, Minnesota
Submitted 5 October 2004
; accepted in final form 30 August 2005
The liver is the principal site of insulin degradation, and assessing its ability to extract insulin is important to understand several pathological states. Noninvasive quantification of hepatic extraction (HE) in an individual requires comparing the profiles of insulin secretion (ISR) and posthepatic insulin delivery rate (IDR). To do this, we propose here the combined use of the classical C-peptide minimal model with a new minimal model of insulin delivery and kinetics. The models were identified on insulin-modified intravenous glucose tolerance test (IM-IVGTT) data of 20 healthy subjects. C-peptide kinetics were fixed to standard population values, whereas insulin kinetics were assessed in each individual, along with IDR parameters, thanks to the presence of insulin decay data observed after exogenous insulin administration. From the two models, profiles of ISR and IDR were predicted, and ISR and IDR indexes of -cell responsivity to glucose in the basal state, as well as during first- and second-phase secretion, were estimated. HE profile, obtained by comparing ISR and IDR profiles, showed a rapid suppression immediately after the glucose administration. HE indexes, obtained by comparing ISR and IDR indexes, indicated that the liver is able to extract 70 ± 9% of insulin passing through it in the basal state and 54 ± 14% during IM-IVGTT. In conclusion, insulin secretion, kinetics, and hepatic extraction can be reliably assessed during an IM-IVGTT by using insulin and C-peptide minimal models.
hepatic extraction; intravenous glucose tolerance test; parameter estimation
Address for reprint requests and other correspondence: Claudio Cobelli, Dept. of Information Engineering, Via Gradenigo 6a, 35131, Padua, Italy (e-mail: cobelli{at}dei.unipd.it )
Objectives and designA novel risk stratification algorithm estimating risk of death in patients with relapsed multiple myeloma starting second-line treatment was recently developed using ...multivariable Cox regression of data from a Czech registry. It uses 16 parameters routinely collected in medical practice to stratify patients into four distinct risk groups in terms of survival expectation. To provide insight into generalisability of the risk stratification algorithm, the study aimed to validate the risk stratification algorithm using real-world data from specifically designed retrospective chart audits from three European countries.Participants and settingPhysicians collected data from 998 patients (France, 386; Germany, 344; UK, 268) and applied the risk stratification algorithm.MethodsThe performance of the Cox regression model for predicting risk of death was assessed by Nagelkerke’s R2, goodness of fit and the C-index. The risk stratification algorithm’s ability to discriminate overall survival across four risk groups was evaluated using Kaplan-Meier curves and HRs.ResultsConsistent with the Czech registry, the stratification performance of the risk stratification algorithm demonstrated clear differentiation in risk of death between the four groups. As risk groups increased, risk of death doubled. The C-index was 0.715 (95% CI 0.690 to 0.734).ConclusionsValidation of the novel risk stratification algorithm in an independent ‘real-world’ dataset demonstrated that it stratifies patients in four subgroups according to survival expectation.
OBJECTIVE:--We sought to determine whether, and if so the mechanism by which, testosterone replacement improves carbohydrate tolerance. RESEARCH DESIGN AND METHODS--Fifty-five elderly men with ...relative testosterone deficiency ingested a labeled mixed meal and underwent a frequently sampled labeled intravenous glucose tolerance test before and after either placebo or treatment with testosterone patch (5 mg/day) for 2 years. RESULTS:--Despite restoring bioavailable testosterone to values observed in young men, the change (24 months minus baseline values) in fasting and postprandial glucose, insulin, and C-peptide concentrations and meal appearance, glucose disposal, and endogenous glucose production were virtually identical to those observed after 2 years of placebo. The change over time in insulin and C-peptide concentrations post-intravenous glucose injection also did not differ. Furthermore, the change over time in insulin action and glucose effectiveness (measured with the unlabeled and labeled "oral" and "intravenous" minimal models), as well as insulin secretion and hepatic insulin clearance (measured with the C-peptide model), did not differ in the testosterone and placebo groups. CONCLUSIONS:--We conclude that 2 years of treatment with testosterone in elderly men does not improve carbohydrate tolerance or alter insulin secretion, insulin action, glucose effectiveness, hepatic insulin clearance, or the pattern of postprandial glucose metabolism. Thus, testosterone deficiency is unlikely the cause of the age-associated deterioration in glucose tolerance commonly observed in elderly men.
Introduction
Risk stratification tools provide valuable information to inform treatment decisions. Existing algorithms for patients with multiple myeloma (MM) were based on patients with newly ...diagnosed disease, and these have not been validated in the relapsed setting or in routine clinical practice. We developed a risk stratification algorithm (RSA) for patients with MM at initiation of second-line (2L) treatment, based on data from the Czech Registry of Monoclonal Gammopathies.
Methods
Predictors of overall survival (OS) at 2L treatment were identified using Cox proportional hazards models and backward selection. Risk scores were obtained by multiplying the hazard ratios for each predictor. The K-adaptive partitioning for survival (KAPS) algorithm defined four groups of stratification based on individual risk scores.
Results
Performance of the RSA was assessed using Nagelkerke’s
R
2
test and Harrell’s concordance index through Kaplan–Meier analysis of OS data. Prognostic groups were successfully defined based on real-world data. Use of a multiplicative score based on Cox modeling and KAPS to define cut-off values was effective.
Conclusion
Through innovative methods of risk assessment and collaboration between physicians and statisticians, the RSA was capable of stratifying patients at 2L treatment by survival expectations. This approach can be used to develop clinical decision-making tools in other disease areas to improve patient management.
Funding
Amgen Europe GmbH.
Background. We aimed to develop and validate a conceptual model of multiple myeloma (MM) that characterizes the attributes affecting disease progression and patient outcomes, and the relationships ...between them. Methods. Systematic and targeted literature reviews identified disease- and patient-specific attributes of MM that affect disease progression and outcomes. These attributes were validated by a Delphi panel of four international MM experts, and a physician-validated model was constructed. Real-world clinical data from the Czech Registry of Monoclonal Gammopathies (RMG) was used to confirm the relationships between attributes using pairwise correlations and multiple Cox regression analysis. Results. The Delphi panel reached consensus that most cytogenetic abnormalities influenced disease activity, which results in symptoms and complications and affects overall survival (OS). Comorbidities and complications also affect OS. The entire panel agreed that quality of life was influenced by comorbidities, age, complications, and symptoms. Consensus was not reached in some cases, in particular, the influence of del(17p) on complications. The relationships between attributes were confirmed using pairwise analysis of real-world data from the Czech RMG; most of the correlations identified were statistically significant and the strength of the correlations changed with successive relapses. Czech RMG data were also used to confirm significant predictors of OS included in the model, such as age, Eastern Cooperative Oncology Group performance status, and extramedullary disease. Conclusions. This validated conceptual model can be used for economic modeling and clinical decision making. It could also inform the development of disease-based models to explore the impact of disease progression and treatment on outcomes in patients with MM.
Two Years of Treatment With Dehydroepiandrosterone Does Not Improve Insulin Secretion, Insulin Action, or Postprandial Glucose
Turnover in Elderly Men or Women
Rita Basu 1 ,
Chiara Dalla Man 2 ,
...Marco Campioni 2 ,
Ananda Basu 1 ,
K. Sree Nair 1 ,
Michael D. Jensen 1 ,
Sundeep Khosla 1 ,
George Klee 3 ,
Gianna Toffolo 2 ,
Claudio Cobelli 2 and
Robert A. Rizza 1
1 Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, Minnesota
2 Department of Electronics and Informatics, University of Padova, Padova, Italy
3 Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota
Address correspondence and reprint requests to Robert A. Rizza, MD, Mayo Clinic College of Medicine, 200 1st St. SW, Rm. 5-194
Joseph, Rochester, MN 55905. E-mail: rizza.robert{at}mayo.edu
Abstract
To determine if dehydroepiandrosterone (DHEA) replacement improves insulin secretion, insulin action, and/or postprandial
glucose metabolism, 112 elderly subjects with relative DHEA deficiency ingested a labeled mixed meal and underwent a frequently
sampled intravenous glucose tolerance test before and after 2 years of either DHEA or placebo. Despite restoring DHEA sulphate
concentrations to values observed in young men and women, the changes over time in fasting and postprandial glucose concentrations,
meal appearance, glucose disposal, and endogenous glucose production were identical to those observed after 2 years of placebo.
The change over time in postmeal and intravenous glucose tolerance test insulin and C-peptide concentrations did not differ
in men treated with DHEA or placebo. In contrast, postmeal and intravenous glucose tolerance test change over time in insulin
and C-peptide concentrations were greater ( P < 0.05) in women after DHEA than after placebo. However, since DHEA tended to decrease insulin action, the change over time
in disposition indexes did not differ between DHEA- and placebo-treated women, indicating that the slight increase in insulin
secretion was a compensatory response to a slight decrease in insulin action. We conclude that 2 years of replacement of DHEA
in elderly men and women does not improve insulin secretion, insulin action, or the pattern of postprandial glucose metabolism.
DHEA, dehydroepiandrosterone
DHEA-S, DHEA sulphate
GE, glucose effectiveness
Footnotes
R.A.R. has served on an advisory board for Merck, Novo Nordisk, Takeda, Mankind, and Eli Lilly; has acted as a consultant
for Abbot, Takeda, Symphony Capital, and Eli Lilly; and holds stock in Diobex.
Clinical trial reg. no. NCT00254371, clinicaltrials.gov .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted November 20, 2006.
Received October 26, 2006.
DIABETES
Effects of Nonglucose Nutrients on Insulin Secretion and Action in People With Pre-Diabetes
Gerlies Bock 1 ,
Chiara Dalla Man 2 ,
Marco Campioni 2 ,
Elizabeth Chittilapilly 1 ,
Rita Basu 1 ,
Gianna ...Toffolo 2 ,
Claudio Cobelli 2 and
Robert Rizza 1
1 Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, Minnesota
2 Department of Electronics and Informatics, University of Padova, Padova, Italy
Address correspondence and reprint requests to Robert A. Rizza, MD, Mayo Clinic, 200 1st St. S.W., Rm. 5-194 Joseph, Rochester,
MN 55905. E-mail: rizza.robert{at}mayo.edu
Abstract
To determine whether nonglucose nutrient–induced insulin secretion is impaired in pre-diabetes, subjects with impaired or
normal fasting glucose were studied after ingesting either a mixed meal containing 75 g glucose or 75 g glucose alone. Despite
comparable glucose areas above basal, glucose-induced insulin secretion was higher ( P < 0.05) and insulin action lower ( P < 0.05) during the meal than the oral glucose tolerance test (OGTT) in all subgroups regardless of whether they had abnormal
or normal glucose tolerance (NGT). However, the nutrient-induced δ (meal minus OGTT) in insulin secretion and glucagon concentrations
did not differ among groups. Furthermore, the decrease in insulin action after meal ingestion was compensated in all groups
by an appropriate increase in insulin secretion resulting in disposition indexes during meals that were equal to or greater
than those present during the OGTT. In contrast, disposition indexes were reduced ( P < 0.01) during the OGTT in the impaired glucose tolerance groups, indicating that reduced glucose induced insulin secretion.
We conclude that, whereas glucose-induced insulin secretion is impaired in people with abnormal glucose tolerance, nonglucose
nutrient–induced secretion is intact, suggesting that a glucose-specific defect in the insulin secretory pathway is an early
event in the evolution of type 2 diabetes.
DI, disposition index
IFG, impaired fasting glucose
IGT, impaired glucose tolerance
IGT-D, impaired glucose tolerance/diabetes
NFG, normal fasting glucose
NGT, normal glucose tolerance
OGTT, oral glucose tolerance test
Footnotes
R.A.R. is a consultant for Abbott and Symphony Capital, is on the Scientific Advisory Board for Merck and Mankind, holds stock
in Diobex, and is both a consultant of and on the Scientific Advisory Boards for Takeda and Eli Lilly.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted December 18, 2006.
Received September 8, 2006.
DIABETES
Abstract only
e18356
Background: Carfilzomib plus dexamethasone (Kd) dosed once weekly at 70 mg/m
2
(QW Kd70) was recently approved in the US for treating patients with relapsed and refractory ...multiple myeloma (RRMM). To assess the cost-effectiveness (CE) of QW Kd70 vs twice weekly Kd dosed at 27 mg/m
2
(BIW Kd27), data from the phase 3 ARROW trial, which directly compared these regimens in patients with 2-3 prior lines of therapy were used. Methods: A partitioned survival model was developed for the CE analysis. Time to treatment discontinuation, progression-free survival, and overall survival (OS) were estimated from the ARROW trial. Long-term OS was extrapolated using Surveillance Epidemiology and End Results registry data after matching characteristics of patients in the registry and ARROW trial. Direct costs were estimated from a US health care payer perspective. Utilities collected in the ARROW trial using the five-level version of the EuroQol questionnaire (EQ-5D-5L) were applied to estimate the quality-adjusted life years (QALYs). Uncertainty was explored using sensitivity analyses. Two subgroups of patients refractory to lenalidomide or bortezomib were assessed. Main outcomes were mean life-years (LYs), QALYs, lifetime costs, and incremental cost-effectiveness ratios (ICERs). Results: For QW Kd70 and BIW Kd27, the model predicted mean LYs of 4.17 and 3.07 years, QALYs of 2.98 and 2.03 years, and mean total lifetime costs of $444,563 and $373,364, respectively. The incremental LYs gain, QALY gain, and incremental costs of QW Kd70 vs BIW Kd27 were estimated to be 1.10 years, 0.95 year, and $71,199, respectively, resulting in an ICER of $64,595 per LY gained and $75,204 per QALY gained. For patients refractory to lenalidomide and bortezomib, similar results were found with ICERs of $79,988 and $76,793, respectively. Conclusions: In line with ARROW trial results, this CE analysis showed that QW Kd70 is expected to provide considerable additional benefit in terms of LYs and QALYs gained compared with BIW Kd27. In the RRMM setting, QW Kd70 is cost-effective with ICERs below accepted willingness to pay thresholds in US and represents an efficient utilization of the health care budget.
Abstract only
e18359
Background: To estimate Incremental CE Ratio (ICER) of BLIN vs INO in adults with R/R S0/S1 ALL based on matching-adjusted indirect comparison (MAIC) of TOWER and INO-VATE trials ...from a UK healthcare perspective. Methods: CE was estimated by a partitioned-survival model with outcomes based on published aggregate data from INO-VATE (cutoff: 01/05/2017) and individual patient data from TOWER weighted to match patients in INO-VATE using MAIC. Five analyses were conducted based on alternative approach for the MAIC (anchored through Standard of Care SOC vs unanchored), proportional hazard (PH) assumptions, and reference overall survival (OS) distributions. Rates of complete remission and HSCT, utilities, duration of therapy, and use of subsequent therapies also were MAIC adjusted. Due to inconsistent definitions of event-free survival (EFS) between the trials, EFS was assumed to be equal for BLIN and INO complete responders. Costs were estimated from published sources and included those of medicine and administration, key adverse events, HSCT, salvage therapy, and terminal care. Utilities were based on EORTC-8D values derived from EORTC QLQ-C30 assessments in TOWER. A 50-year time horizon was used. Results: In all analyses, BLIN was more costly and more effective than INO. The ICER for BLIN vs INO ranged from £4,014 to £13,371 per QALY. Conclusions: For various approaches for conducting MAIC of BLIN vs INO, BLIN was highly cost effective vs INO in R/R ALL adults with S0/S1 from a UK healthcare perspective. Table: see text
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