85542390
Health state utilities associated with attributes of migraine preventive treatments based on patient and general population preferences
PurposeWhile previous studies have estimated health state utilities associated with migraine severity and frequency, migraine treatments vary in other ways that may have an impact on patients’ quality of life, preference, and utility. The purpose of this study was to estimate utilities associated with migraine treatment attributes including route of administration and treatment-related adverse events (AEs).MethodsIn time trade-off interviews, migraine patients and general population participants in the UK valued health state vignettes drafted based on literature, medication labels, and clinician interviews. All respondents valued migraine health states varying in route of administration. Each participant also valued eight health states (randomly selected from a total of 15) that added the description of an AE to a migraine health state.ResultsA total of 400 participants completed interviews (200 general population [49.0% female; mean age = 43.6 years]; 200 migraine patients [74.5% female; mean age = 45.8 years]). In the general population sample, mean utilities of health states without aura were 0.79 with daily oral medication, 0.78 with one injection per month, and 0.72 with 31–39 injections once every 3 months. The greatest disutilities (i.e., decreases in utility) were for AEs associated with oral medications (e.g., − 0.060 [fatigue] and − 0.098 [brain fog]). Differences among health states followed the same pattern in the patient sample as in the general population sample.ConclusionsUtilities estimated from the general population sample may be used to represent route of administration and AEs in cost-utility models. Results from the patient sample indicate that these treatment characteristics have an impact on patient preference.
4764207
Estimating the clinical effectiveness and value-based price range of erenumab for the prevention of migraine in patients with prior treatment failures: a US societal perspective
Abstract Background: Frequent migraine with four or more headache days per month is a common, disabling neurovascular disease. From a US societal perspective, this analysis models the clinical efficacy and estimates the value-based price (VBP) for erenumab, a fully human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor. Methods: A Markov health state transition model was developed to estimate the incremental costs, quality-adjusted life-years (QALYs), and value-based price range for erenumab in migraine prevention. The model comprises “on preventive treatment”, “off preventive treatment”, and “death” health states across a 10-year time horizon. The evaluation compared erenumab to no preventive treatment in episodic and chronic migraine patients that have failed at least one preventive therapy. Therapeutic benefits are based on estimated changes in monthly migraine days (MMD) from erenumab pivotal clinical trials and a network meta-analysis of migraine studies. Utilities were estimated using previously published mapping algorithms. A VBP analysis was performed to identify maximum erenumab annual prices at willingness-to-pay (WTP) thresholds of $100,000–$200,000 per QALY. Estimates of VBP under different scenarios such as choice of different comparators, assumptions around inclusion of placebo effect, and exclusion of work productivity losses were also generated. Results: Erenumab resulted in incremental QALYs of 0.185 vs supportive care (SC) and estimated cost offsets due to reduced MMD of $8,482 over 10 years, with an average duration of treatment of 2.01 years. The estimated VBP at WTP thresholds of $100,000–$200,000 for erenumab compared to SC ranged from $14,238–$23,998. VBP estimates including the placebo effect and excluding work productivity ranged from $7,445–$13,809; increasing to $12,151–$18,589 with onabotulinumtoxinA as a comparator in chronic migraine. Conclusion: Erenumab is predicted to reduce migraine-related direct and indirect costs, and increase QALYs compared to SC.
25250084
The cost effectiveness of Botox in Italian patients with chronic migraine
Migraine is a primary headache which World Health Organization ranks in 19th place in the list of disabling diseases. In Europe, in 2004, the total costs for migraine were quantified by Stovner and Berg, Eur J Neurol, 12(s1) (2005) at €27 billion. The objective of this study is to provide an estimate of the incremental cost-effectiveness ratio (ICER) of the treatment of chronic migraine with Botox compared to treatment with placebo in the perspective of the Italian National Health Service and society. To do this we studied the disease progression in a cohort of 688 individuals (patients enrolled in the study PREEMPT) via the application of a Markov model. Over a period of 2 years, the total costs of the experimental arm of the model amounted to €3,274 compared with a gain of 1.34 QALYs. In contrast, the costs of the control arm amounted to €2,395 with a gain of 1.24 QALYs. It follows that the incremental costs amounted to €889 compared to an incremental gain of 0.09 QALYs in favor of the experimental arm. The relationship between costs and incremental QALYs generated an ICER of €9,407/QALY. The incremental cost-effectiveness ratio, therefore, is favorable compared to the value usually considered by NICE as a threshold limit for reimbursement which ranges between €20,000 and €40,000/QALY.
1647316
Measuring and valuing health benefits for economic evaluation in adolescence: an assessment of the practicality and validity of the child health utility 9D in the Australian adolescent population.
OBJECTIVES
The Child Health Utility 9D (CHU9D) is a new generic preference-based measure of health-related quality of life developed for children aged 7 to 11 years. There is increasing interest in its potential for application in adolescents, and previous research has demonstrated that it shows good construct validity here. This article further examines its practicality and validity in adolescents by comparing it with KIDSCREEN-10, a short generic measure for assessing children and adolescents' health-related quality of life and well-being.


METHODS
A Web-based survey, including the CHU9D, a general health question, questions on the presence of long-standing illness, disability, or medical conditions, sociodemographic variables, and KIDSCREEN-10, was administered to 961 consenting adolescents. The practicality and face and construct validity of the CHU9D were examined, and the CHU9D and KIDSCREEN-10 were compared in terms of their coverage, correlations between dimensions, and overall scores.


RESULTS
Both measures demonstrated good practicality and validity. The strongest degree of correlation was found with the only dimension in common for the CHU9D and KIDSCREEN (sad). The lowest correlations were found between all the CHU9D dimensions and the "have you had enough time for yourself" dimension of KIDSCREEN-10.


CONCLUSIONS
The findings from this study provide further support for the practicality and validity of the application of the CHU9D in the economic evaluation of adolescent health care and public health programs. Further research to test the psychometric performance of the CHU9D in more diverse clinical samples of adolescents is desirable including tests of reliability.
205665640
Migraine frequency and health utilities: findings from a multisite survey.
OBJECTIVES
Assess the relationship between migraine frequency and health utility.


METHODS
Patients aged >/=18 years diagnosed with episodic migraine were enrolled at three US sites representing varied models of health-care delivery. All subjects completed a questionnaire that included demographic and clinical information, a migraine-specific disability questionnaire, and the Health Utilities Index Mark 3 (HUI3). The HUI3 is a generic health status and health-related quality-of-life measure. HUI3 health status data are translated into utility scores anchored by 0 (dead) and 1 (perfect health).


RESULTS
The study enrolled 150 patients. The mean age was 44 years and 87% were female. Mean (+/-SD) monthly migraine frequency was 4.4 +/- 3.6, with 34% reporting </=2 migraines per month and 20% reporting >6 migraines per month. The mean (+/-SD) HUI3 score was 0.62 +/- 0.26. After controlling for study center, demographics, comorbidities, migraine characteristics, and level of migraine disruptiveness, migraine frequency was found to be significantly (P < 0.05) and negatively associated with HUI3 scores. Subjects with >6 migraines per month had an adjusted mean HUI3 score of 0.41; the corresponding mean for those reporting </=2 migraines per month was 0.67. Migraine frequency was positively associated with higher levels of disability for the emotion, cognition, and pain components of the HUI3.


CONCLUSIONS
Among this group of care-seeking patients, migraineurs' health utilities were inversely related to headache frequency. Although these data may not be generalizable to the entire migraine population, they may be useful in assessing the comparative cost-effectiveness of preventive migraine therapies.
20929696
Mapping from disease-specific measures to health-state utility values in individuals with migraine.
OBJECTIVE
The objective of this study was to develop empirical algorithms that estimate health-state utility values from disease-specific quality-of-life scores in individuals with migraine.


METHODS
Data from a cross-sectional, multicountry study were used. Individuals with episodic and chronic migraine were randomly assigned to training or validation samples. Spearman's correlation coefficients between paired EuroQol five-dimensional (EQ-5D) questionnaire utility values and both Headache Impact Test (HIT-6) scores and Migraine-Specific Quality-of-Life Questionnaire version 2.1 (MSQ) domain scores (role restrictive, role preventive, and emotional function) were examined. Regression models were constructed to estimate EQ-5D questionnaire utility values from the HIT-6 score or the MSQ domain scores. Preferred algorithms were confirmed in the validation samples.


RESULTS
In episodic migraine, the preferred HIT-6 and MSQ algorithms explained 22% and 25% of the variance (R(2)) in the training samples, respectively, and had similar prediction errors (root mean square errors of 0.30). In chronic migraine, the preferred HIT-6 and MSQ algorithms explained 36% and 45% of the variance in the training samples, respectively, and had similar prediction errors (root mean square errors 0.31 and 0.29). In episodic and chronic migraine, no statistically significant differences were observed between the mean observed and the mean estimated EQ-5D questionnaire utility values for the preferred HIT-6 and MSQ algorithms in the validation samples.


CONCLUSIONS
The relationship between the EQ-5D questionnaire and the HIT-6 or the MSQ is adequate to use regression equations to estimate EQ-5D questionnaire utility values. The preferred HIT-6 and MSQ algorithms will be useful in estimating health-state utilities in migraine trials in which no preference-based measure is present.
10603080
Are people consistent when trading time for health?
The conventional, or standard, time trade-off (TTO) procedure, which is used to elicit the values that people place on health states that are in turn required to calculate quality adjusted life-years (QALYs), asks respondents to trade off fewer life years for better health. It is possible to reverse the procedure to ask respondents to trade off less health for more life years. Theoretically, these two procedures should generate the same TTO values for any given health state. This article reports that for health states defined by differing frequencies of migraine attack, the standard TTO gives health state values that are significantly higher than those given by the reverse TTO. The observed systematic procedural invariance, which substantiates some previous findings reported in the literature and is consistent with a loss aversion effect, challenges the validity of the TTO for generating reliable valuations of health states.
705347
EQ-5D™-derived utility values for different levels of migraine severity from a UK sample of migraineurs
BackgroundTo estimate utility values for different levels of migraine pain severity from a United Kingdom (UK) sample of migraineurs.MethodsOne hundred and six migraineurs completed the EQ-5D to evaluate their health status for mild, moderate and severe levels of migraine pain severity for a recent migraine attack, and for current health defined as health status within seven days post-migraine attack. Statistical tests were used to evaluate differences in mean utility scores by migraine severity.ResultsUtility scores for each health state were significantly different from 1.0 (no problems on any EQ-5D dimension) (p < 0.0001) and one another (p < 0.0001). The lowest mean utility, − 0.20 (95% confidence interval [CI]: -0.27 – -0.13), was for severe migraine pain. The smallest difference in mean utility was between mild and moderate migraine pain (0.13) and the largest difference in mean utility was between current health (without migraine) and severe migraine pain (1.07).ConclusionsResults indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. Results can be used in cost-utility models examining the relative economic value of therapeutic strategies for migraine in the UK.
205161851
The CGRP Pathway in Migraine as a Viable Target for Therapies
The neuropeptide calcitonin gene‐related peptide is well established as a key player in the pathogenesis of migraine. Clinical studies show calcitonin gene‐related peptide levels correlate with migraine attacks, and decreases in this neuropeptide can indicate antimigraine therapy effectiveness. Research has revealed a wide distribution of expression sites for calcitonin gene‐related peptide in the central and peripheral nervous system. Of these, the calcitonin gene‐related peptide receptor, which binds calcitonin gene‐related peptide with high affinity, has attracted growing interest as a viable target for antimigraine therapies. An incentive to pursue such research is the continuing unmet medical need of patients. Triptans have offered some clinical benefit, but many patients do not respond and these drugs have important safety considerations. Initial calcitonin gene‐related peptide‐focused research led to development of the “gepant” small‐molecule calcitonin gene‐related peptide receptor blockers. Positive efficacy reports concerning the gepants have been tempered by safety findings which led to the discontinuation of some of these agents. Currently, there is considerable excitement regarding monoclonal antibodies against calcitonin gene‐related peptide (eptinezumab, galcanezumab, fremanezumab) and the calcitonin gene‐related peptide receptor (erenumab). To date, these monoclonal antibodies have shown promising efficacy in clinical trials, with no major safety concerns. If ongoing long‐term studies show that their efficacy can be maintained, this may herald a new era for effective antimigraine therapies.
206522582
CGRP, a target for preventive therapy in migraine and cluster headache: Systematic review of clinical data
Introduction Migraine and cluster headache are challenging to manage, with no tailored preventive medications available. Targeting the calcitonin gene-related peptide (CGRP) pathway to treat these headaches may be the first focused therapeutic option to date, with the potential for promising efficacy. Methods We systematically searched PubMed and clinicaltrials.gov for randomized controlled trials investigating the preventive potential of monoclonal antibodies against the CGRP pathway in the treatment of migraine and cluster headache. Results The literature search returned a total of 136 records, of which 32 were eligible for review. Discussion Clinical data from phase II and III trials of the four monoclonal antibodies targeting the CGRP pathway: Eptinezumab, erenumab, fremanezumab, and galcanezumab, collectively show a positive effect in the preventive treatment of episodic and chronic migraine. Multiple phase II and III trials are under way to further determine the efficacy and safety of this new drug class. It may be particularly important to assess the cardiovascular effects of long-term CGRP blockade. Phase III trials are also currently in progress for the preventive treatment of cluster headache. Conclusion Efficacy of anti-CGRP monoclonal antibodies spells a promising future for the many patients suffering from migraine, and possibly also for the smaller but severely-affected population with cluster headache.
46105364
Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: comparisons across randomized controlled studies
Purpose of review The results of phase 2 randomized controlled trials for the prevention of episodic and chronic migraine demonstrating the efficacy and safety of four mAbs targeting the calcitonin gene-related peptide (CGRP) pathway [ALD403 (eptinezumab), AMG334 (erenumab), LY2951742 (galcanezumab) and TEV48125 (fremanezumab)] have been published recently, and phase 3 trials are in process. This development will change headache management fundamentally. We aim to summarize and compare the phase 2 data. Recent findings The change from baseline in the number of migraine days at the end of treatment in high-frequency episodic migraine was −1 (at weeks 5–8), −1.1 (at weeks 9–12), −1.2 (at weeks 9–12) and −2.6 (at weeks 9–12) days for ALD403, AMG344, LY2951742 and TEV48125 (225 mg), respectively. Number needed to treats for responders and odds ratio for any adverse event were 4.7, 6.2, 4.0 and 4.0 and 1.09, 0.96, 1.07 and 1.05, respectively. Summary All four CGRP antibodies display comparable efficacy that does not differ significantly from that of the currently available oral antimigraine drugs. However, their safety and tolerability profiles as well as low frequency of administration looks promising but remains to be verified in long-term and large-scale trials. Considerations related to pregnancy, risk for cardiovascular effects and cost are subject for further evaluation.
8623521
Anti-CGRP Monoclonal Antibodies: the Next Era of Migraine Prevention?
Opinion statementMigraine is a very disabling disorder with severe impact on patients’ lives and substantive costs to society in terms of healthcare costs and lost productivity. Prevention is a key component of migraine therapy, and while numerous preventive options exist, each is burdened by either troublesome side effects or insufficient efficacy. All migraine preventives currently in clinical use were licensed for other purposes and, by chance, have efficacy against migraine. As our understanding of migraine has evolved, calcitonin gene-related peptide (CGRP) has moved to the forefront as a neuropeptide central to migraine pathophysiology. Six small molecule CGRP receptor antagonists were shown to be effective for acute treatment of migraine; two were stopped for hepatotoxicity or one for formulation concern issues and one is now in phase III. Monoclonal antibodies against CGRP or the CGRP receptor have a longer duration of action and have been investigated for migraine prevention. Four are in development and three have completed phase II and one phase III trials; every reported study has been positive. Furthermore, no safety issues have arisen to date, including hepatic or cardiovascular effects, and initial tolerability appears to be excellent. Monoclonal antibodies antagonizing the CGRP pathway represent a novel approach to prevention: a mechanism-specific migraine-targeted therapy. While we must await the results of all the phase III trials, cautious excitement seems warranted as we enter a new era of better tolerated, well-understood, bespoke migraine treatment for this common and disabling neurological disorder.
3656983
ARISE: A Phase 3 randomized trial of erenumab for episodic migraine
Background Calcitonin gene-related peptide plays an important role in migraine pathophysiology. Erenumab, a human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor, is being evaluated for migraine prevention. Methods In this randomized, double-blind, placebo-controlled, phase 3 study, 577 adults with episodic migraine were randomized to placebo or 70 mg erenumab; 570 patients were included in efficacy analyses. Primary endpoint was change in monthly migraine days. Secondary endpoints were ≥50% reduction in monthly migraine days, change in acute migraine-specific medication treatment days, and ≥5-point reduction in Physical Impairment and Impact on Everyday Activities domain scores measured by the Migraine Physical Function Impact Diary. All endpoints assessed change from baseline at month 3. Results Patients receiving erenumab experienced −2.9 days change in monthly migraine days, compared with −1.8 days for placebo, least-squares mean (95% CI) treatment difference of −1.0 (−1.6, −0.5) (p < 0.001). A ≥ 50% reduction in monthly migraine days was achieved by 39.7% (erenumab) and 29.5% (placebo) of patients (OR:1.59 (95% CI: 1.12, 2.27) (p = 0.010). Migraine-specific medication treatment days were reduced by −1.2 (erenumab) and −0.6 (placebo) days, a treatment difference of −0.6 (−1.0, −0.2) (p = 0.002). The ≥5-point reduction rates in Migraine Physical Function Impact Diary – Physical Impairment were 33.0% and 27.1% (OR:1.33 (0.92, 1.90) (p = 0.13) and in Migraine Physical Function Impact Diary – Everyday Activities were 40.4% and 35.8% (OR:1.22 (0.87, 1.71) (p = 0.26). Safety and adverse event profiles of erenumab were similar to placebo. Most frequent adverse events were upper respiratory tract infection, injection site pain, and nasopharyngitis. Conclusions As a preventive treatment of episodic migraine, erenumab at a dosage of 70 mg monthly significantly reduced migraine frequency and acute migraine-specific medication use. (Funded by Amgen). Trial registration ClinicalTrials.gov, NCT02483585.
205102461
Fremanezumab for the Preventive Treatment of Chronic Migraine
BACKGROUND Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene–related peptide (CGRP), is being investigated as a preventive treatment for migraine. We compared two fremanezumab dose regimens with placebo for the prevention of chronic migraine. METHODS In this phase 3 trial, we randomly assigned patients with chronic migraine (defined as headache of any duration or severity on ≥15 days per month and migraine on ≥8 days per month) in a 1:1:1 ratio to receive fremanezumab quarterly (a single dose of 675 mg at baseline and placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), or matching placebo. Both fremanezumab and placebo were administered by means of subcutaneous injection. The primary end point was the mean change from baseline in the average number of headache days (defined as days in which headache pain lasted ≥4 consecutive hours and had a peak severity of at least a moderate level or days in which acute migraine–specific medication [triptans or ergots] was used to treat a headache of any severity or duration) per month during the 12 weeks after the first dose. RESULTS Of 1130 patients enrolled, 376 were randomly assigned to fremanezumab quarterly, 379 to fremanezumab monthly, and 375 to placebo. The mean number of baseline headache days (as defined above) per month was 13.2, 12.8, and 13.3, respectively. The least‐squares mean (±SE) reduction in the average number of headache days per month was 4.3±0.3 with fremanezumab quarterly, 4.6±0.3 with fremanezumab monthly, and 2.5±0.3 with placebo (P<0.001 for both comparisons with placebo). The percentage of patients with a reduction of at least 50% in the average number of headache days per month was 38% in the fremanezumab‐quarterly group, 41% in the fremanezumab‐monthly group, and 18% in the placebo group (P<0.001 for both comparisons with placebo). Abnormalities of hepatic function occurred in 5 patients in each fremanezumab group (1%) and 3 patients in the placebo group (<1%). CONCLUSIONS Fremanezumab as a preventive treatment for chronic migraine resulted in a lower frequency of headache than placebo in this 12‐week trial. Injection‐site reactions to the drug were common. The long‐term durability and safety of fremanezumab require further study. (Funded by Teva Pharmaceuticals; ClinicalTrials.gov number, NCT02621931.)
44062799
Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial
Importance Migraine is a disabling neurological disease characterized by severe headache attacks. Treatment options reduce migraine frequency for many patients, but adverse effects lead to discontinuation in many patients. Objective To demonstrate that galcanezumab is superior to placebo in the prevention of episodic migraine with or without aura. Design, Setting, and Participants The EVOLVE-1 (Evaluation of LY2951742 in the Prevention of Episodic Migraine 1) trial was a double-blind, randomized, placebo-controlled (January 11, 2016, to March 22, 2017) trial comparing galcanezumab (120 mg and 240 mg) vs placebo. Patients received treatments once monthly for 6 months (subcutaneous injection via prefilled syringe) and were followed up for 5 months after their last injection. It was a multicenter, clinic-based study involving 90 sites in North America. Participants in the study were adults (aged 18 to 65 years) with at least a 1-year history of migraine, 4 to 14 migraine headache days per month and a mean of at least 2 migraine attacks per month within the past 3 months, and were diagnosed prior to age 50 years. During the study, no other preventive medications were allowed. A total of 1671 patients were assessed; 809 did not meet study entry or baseline criteria, and 858 were included in the intent-to-treat population. Interventions Patients were randomized (2:1:1) to monthly placebo, galcanezumab, 120 mg, and galcanezumab, 240 mg. Main Outcomes and Measures The primary outcome was overall mean change from baseline in the number of monthly migraine headache days during the treatment period. Secondary measures included at least 50%, at least 75%, and 100% reduction in monthly migraine headache days, migraine headache days with acute medication use, and scores from the Migraine-Specific Quality of Life questionnaire, Patient Global Impression of Severity, and Migraine Disability Assessment. Treatment-emergent adverse events and serious adverse events were reported. Results Of the 1671 patients assessed, 858 (mean age, 40.7 years; 718 women [83.7%]) met study entry criteria and received at least 1 dose of investigational product. The primary objective was met for both galcanezumab doses; treatment with galcanezumab significantly reduced monthly migraine headache days (both P < .001) by 4.7 days (120 mg) and 4.6 days (240 mg) compared with placebo (2.8 days). All key secondary objectives were also significant after multiplicity adjustment. There were no meaningful differences between 120-mg and 240-mg doses of galcanezumab on measures of efficacy. Completion rate during treatment was high (81.9%; n = 718), and the incidence of discontinuation owing to adverse events was less than 5% across all treatment groups. Conclusions and Relevance Galcanezumab 120-mg and 240-mg monthly injections provided clinical benefits and improved functioning. The incidence rate of adverse events was low, demonstrating the favorable tolerability profile of galcanezumab. Trial Registration ClinicalTrials.gov Identifier: NCT02614183
41559737
Current practice and future directions in the prevention and acute management of migraine
Migraine is a common and disabling brain disorder with a strong inherited component. Because patients with migraine have severe and disabling attacks usually of headache with other symptoms of sensory disturbance (eg, light and sound sensitivity), medical treatment is often required. Patients can be managed by use of acute attack therapies (eg, simple analgesics or non-steroidal anti-inflammatory drugs) or specific agents with vasoconstrictor properties (ie, triptans or ergot derivatives). Future non-vasoconstrictor approaches include calcitonin gene-related peptide receptor antagonists. Preventive therapy is probably indicated in about a third of patients with migraine, and a broad range of pharmaceutical and non-pharmaceutical options exist. Medication overuse is an important concern in migraine therapeutics and needs to be identified and managed. In most patients, migraine can be improved with careful attention to the details of therapy, and in those for whom it cannot, neuromodulation approaches, such as occipital nerve stimulation, are currently being actively studied and offer much promise.
23025676
OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial
Objectives: This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine. Methods: The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U–195 U; n = 341) or placebo (n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24. Results: No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (−5.2 vs. −5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days (p = .006) and migraine days (p = 0.002). OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few subjects discontinued due to adverse events. Conclusions: There was no between-group difference for the primary endpoint, headache episodes. However, significant reductions from baseline were observed for onabotulinumtoxinA for headache and migraine days, cumulative hours of headache on headache days and frequency of moderate/severe headache days, which in turn reduced the burden of illness in adults with disabling chronic migraine.
729510
OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial
Objectives: This is the second of a pair of studies designed to evaluate the efficacy and safety of onabotulinumtoxinA (BOTOX®) for prophylaxis of headaches in adults with chronic migraine. Methods: PREEMPT 2 was a phase 3 study, with a 24-week, double-blind, placebo-controlled phase, followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections of onabotulinumtoxinA (155U–195U; n = 347) or placebo (n = 358) every 12 weeks for two cycles. The primary efficacy endpoint was mean change in headache days per 28 days from baseline to weeks 21–24 post-treatment. Results: OnabotulinumtoxinA was statistically significantly superior to placebo for the primary endpoint, frequency of headache days per 28 days relative to baseline (−9.0 onabotulinumtoxinA/−6.7 placebo, p < .001). OnabotulinumtoxinA was significantly favoured in all secondary endpoint comparisons. OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few patients (3.5% onabotulinumtoxinA/1.4% placebo) discontinued due to adverse events. Conclusions: The results of PREEMPT 2 demonstrate that onabotulinumtoxinA is effective for prophylaxis of headache in adults with chronic migraine. Repeated onabotulinumtoxinA treatments were safe and well tolerated.
46416779
Incorporating Process Utility into Quality Adjusted Life Years: A Systematic Review of Empirical Studies
ObjectiveThis review aimed to identify published studies that provide an empirical measure of process utility, which can be incorporated into estimates of QALY calculations.MethodsA literature search was conducted in PubMed to identify published studies of process utility. Articles were included if they were written in the English language and reported empirical measures of process utility that could be incorporated into the QALY calculation; those studies reporting utilities that were not anchored on a scale of 0 representing dead and 1 representing full health were excluded from the review.ResultsFifteen studies published between 1996 and 2012 were included. Studies included respondents from the USA, Australia, Scotland and the UK, Europe and Canada. Eight of the included studies explored process utility associated with treatments; six explored process utility associated with screening procedures or tests; and one was performed in preventative care. A variety of approaches were used to detect and measure process utility: four studies used standard gamble techniques; four studies used time trade-off (TTO); one study used conjoint analysis and one used a combination of conjoint analysis and TTO; one study used SF-36 data; one study used both TTO and EQ-5D; and three studies used wait trade-off techniques. Measures of process utility for different drug delivery methods ranged from 0.02 to 0.27. Utility estimates associated with different dosing strategies ranged from 0.005 to 0.09. Estimates for convenience (able to take on an empty stomach) ranged from 0.001 to 0.028. Estimates of process utility associated with screening and testing procedures ranged from 0.0005 to 0.031. Both of these estimates were obtained for management approaches to cervical cancer screening.ConclusionThe identification of studies through conventional methods was difficult due to the lack of consistent indexing and terminology across studies; however, the evidence does support the existence of process utility in treatment, screening and preventative care settings. There was considerable variation between estimates. The range of methodological approaches used to identify and measure process utility, coupled with the need for further research into, for example, the application of estimates in economic models, means it is difficult to know whether these differences are a true reflection of the amount of process utility that enters into an individual’s utility function, or whether they are associated with features of the studies’ methodological design. Without further work, and a standardised approach to the methodology for the detection and measurement of process utility, comparisons between estimates are difficult. This literature review supports the existence of process utility and indicates that, despite the need for further research in the area, it could be an important component of an individual’s utility function, which should at least be considered, if not incorporated, into cost-utility analyses.
23312079
Topiramate in migraine prophylaxis--results from a placebo-controlled trial with propranolol as an active control.
Topiramate (TPM) has shown efficacy in migraine prophylaxis in two large placebo-controlled, dose-ranging trials. We conducted a randomised, double-blind, multicentre trial to evaluate the efficacy and safety of two doses of topiramate vs placebo for migraine prophylaxis, with propranolol (PROP) as an active control. Subjects with episodic migraine with and without aura were randomised to TPM 100 mg/d, TPM 200 mg/d, PROP 160 mg/d (active control), or placebo. The primary efficacy measure was the change in mean monthly migraine frequency from the baseline phase relative to the double-blind treatment phase. Five hundred and seventy-five subjects were enrolled from 61 centres in 13 countries. TPM 100 mg/d was superior to placebo as measured by reduction in monthly migraine frequency, overall 50% responder rate, reduction in monthly migraine days, and reduction in the rate of daily rescue medication use. The TPM 100 mg/d and PROP groups were similar with respect to reductions in migraine frequency, responder rate, migraine days, and daily rescue medication usage. TPM 100 mg/d was better tolerated than TPM 200 mg/d, and was generally comparable to PROP. No unusual or unexpected safety risks emerged. These findings demonstrate that TPM 100 mg/d is effective in migraine prophylaxis. TPM 100 mg/d and PROP 160 mg/d exhibited similar efficacy profiles.
31832331
Topiramate versus amitriptyline in migraine prevention: a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority trial in adult migraineurs.
OBJECTIVE
The primary objective of this study was to compare the efficacy and tolerability of topiramate and amitriptyline in the prophylaxis of episodic migraine headache.


METHODS
This was a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority study. Adults with 3 to 12 migraines per month were randomized in a 1:1 ratio to receive an initial dose of 25 mg/d of either topiramate or amitriptyline, subsequently titrated to a maximum of 100 mg/d (or the maximum tolerated dose). The primary efficacy outcome was the change from prospective baseline in the mean monthly number of migraine episodes. Secondary efficacy variables included changes from the prospective baseline phase to the end of the double-blind phase in the mean monthly (28-day) rate of days with migraine, mean monthly rate of days with headache (migraine and nonmigraine), mean monthly rate of acute abortive medication use, mean monthly migraine duration, and mean monthly migraine severity. Additional secondary efficacy variables included changes in the mean monthly severity of migraine-associated symptoms (photophobia, phonophobia, and nausea), change in the mean monthly frequency f migraine-associated vomiting, and response rates (based on monthly migraine days and total headache days). The Migraine-Specific Quality of Life Questionnaire (MSQ) and the Weight Satisfaction Scale Questionnaire, which measures subjective satisfaction with current weight, were administered. Treatment-emergent adverse events (TEAEs) were monitored through the end of double-blind treatment.


RESULTS
The intent-to-treat population included 331 subjects (172 topiramate, 159 amitriptyline; 84.9% female; 84.6% white; mean [SD] age, 38.8 [11.0] years; mean weight, 77.1 [20.1] kg) who provided at least 1 efficacy assessment. The least squares mean (LSM) change from baseline in the mean monthly number of migraine episodes was not significantly different between the topiramate and amitriptyline groups (-2.6 and -2.7, respectively; 95% CI, -0.6 to 0.7). There were no significant differences between treatment groups in any of the prespecified secondary outcome measures. Subjects receiving topiramate had a significantly greater improvement in mean functional disability scores during migraine attacks compared with amitriptyline (LSM change: -0.33 vs -0.19; 95% CI, -0.3 to 0.0; P = 0.040) and in the role function-restrictive, role function-preventive, and emotional function domains of the MSQ (P = 0.012, P = 0.014, and P = 0.029, respectively). Subjects receiving topiramate had a mean weight loss of 2.4 kg, compared with a mean weight gain of 2.4 kg in subjects receiving amitriptyline. Subjects in the topiramate group reported an overall improvement from baseline in weight satisfaction, whereas the amitriptyline group reported an overall deterioration in weight satisfaction (P < 0.001, topiramate vs amitriptyline). TEAEs of mild or moderate severity were reported in 118 subjects (66.7%) in the topiramate group and 112 subjects (66.3%) in the amitriptyline group. Among the most common TEAEs (reported in +/-5% of subjects during the double-blind phase) in the topiramate group were paresthesia (29.9%), fatigue (16.9%), somnolence (11.9%), hypoesthesia (10.7%), and nausea (10.2%). The most commonly reported TEAEs in the amitriptyline group were dry mouth (35.5%), fatigue (24.3%), somnolence (17.8%), weight increase (13.6%), dizziness (10.7%), and sinusitis (10.7%).


CONCLUSIONS
In this noninferiority study, topiramate was at least as effective as amitriptyline in terms of reducing the rate of mean monthly migraine episodes and all prespecified secondary efficacy end points. Topiramate was associated with improvement in some quality-of-life indicators compared with amitriptyline and was associated with weight loss and improved weight satisfaction.
9621285
OnabotulinumtoxinA for Treatment of Chronic Migraine: Pooled Results From the Double‐Blind, Randomized, Placebo‐Controlled Phases of the PREEMPT Clinical Program
(Headache 2010;50:921‐936)
22020563
Exercise performance and beta-blockade.
beta-Adrenoceptor blockers (beta-blockers) are common first-choice drugs in the treatment of various cardiovascular disorders. Physical exercise performed during single-dose administration of beta-blockers, however, is associated with an increased rate of perceived exertion; an effect which appears to be partly reduced with long term treatment. Although clinical doses of beta-blockade may reduce heart rate by 30 to 35%, during maximal exercise cardiac output is not equally reduced. Accordingly, most studies have demonstrated increased stroke volume after beta-blockade. This reduction in heart rate is typically accompanied by a decreased VO2max (5 to 15%) in both patients and healthy, trained subjects. This smaller reduction in VO2max, as compared with the decrease in cardiac output, is the result of a partly compensating increased arteriovenous O2 difference. Work capacity as reflected by the ability to perform intense short term or more prolonged steady-state exercise is also impaired following beta-blockade. beta-Adrenoceptors can be subdivided into types beta 1- and beta 2. Blockers which are specific for either beta 1-receptors (beta 1-selective blockers) or both beta 1- and beta 2 receptors (non-selective blockers) differ with regard to their effect on exercise performance. Exercise performance ability, irrespective of exercise intensity and duration, is impaired to a greater extent following non-selective than beta 1-selective blockade at equal reductions in heart rate. This response stems from a decreased energy flux through glycogenolysis during non-selective blockade treatment. Individuals receiving beta-blockade medication therefore show greater adaptive response to physical conditioning during treatment with beta 1-selective than non-selective blockade probably because of greater training intensity with the former therapy. Neither psychomotor performance nor muscular strength and power is negatively affected by beta-blockade. Nevertheless, the ability to perform athletic events requiring high levels of motor control under emotional stress but not high levels of aerobic or anaerobic energy release, is probably increased during beta-blockade.
25981571
Framing and labelling effects in health descriptions: quality adjusted life years for treatment of breast cancer.
At present there is a growing interest in the use of cost-utility analysis (CUA) to a point where it merits serious consideration by health care decision makers. However, there remain a number of theoretical and practical issues to be resolved including the way in which quality of life information is presented and described to subjects. Two potential sources of influence in the construction of the quality adjusted life year (QALY) values elicited for a recent Australian CUA of mammography screening have been investigated. 180 subjects were randomly allocated to nine different presentations of two breast cancer health descriptions to investigate the impact of some framing and labelling effects. No statistically significant differences were found in the valuations placed on these descriptions when framing and labelling effects were taken into account, either as separate framing and labelling factors or as interactions with one another. A significant difference was found in the particular values of descriptions that were written in the third person that differed in terms of whether the word "cancer" was used. The main contribution of these data is to the robustness of the health descriptions used in the cost-utility analysis of mammography screening.
44702577
The utility of different health states as perceived by the general public.
Abstract A series of ‘scenarios’ describing the physical, social and emotional characteristics, limitations and duration of different health states have been successfully applied to a random sample of the general public in order to determine their social utility. The resulting mean daily health state utilities differ among disorders and vary with age, the duration of the disorder, the ‘label’ used to describe the disorder and the health status of the respondent. These health state utilities have considerable potential application in the planning and financing of health services.
7147834
Topiramate 100 mg/day in migraine prevention: a pooled analysis of double‐blind randomised controlled trials
Topiramate has been shown to be effective as a preventive treatment for migraine in three large placebo‐controlled, dose‐ranging trials. Because the protocols were similar in design using the same primary and secondary endpoints, data from these studies were pooled to evaluate the consistency of efficacy, efficacy by gender and tolerability of topiramate 100 mg/day (n = 386) versus placebo (n = 372). Topiramate was superior to placebo as measured by the reduction in mean monthly migraine frequency, monthly migraine days and monthly migraine duration. The responder rates, defined as at least 50% reduction for the respective parameters, were significantly in favour of topiramate (p < 0.001), for example 46.3% of patients on topiramate achieved at least 50% reduction in monthly migraine period frequency compared with 22.8% on placebo (p < 0.001). Use of medication to treat the acute migraine attack was significantly reduced by topiramate compared with placebo (p < 0.001). The therapeutic effect was consistent throughout the different studies and independent of gender. The most common adverse effect was paraesthesia, mostly of mild‐to‐moderate severity. The findings confirm that, at a dose of 100 mg/day, topiramate is an effective and well‐tolerated drug for migraine prevention.
16955303
Pooled analysis of the safety and tolerability of onabotulinumtoxinA in the treatment of chronic migraine
OnabotulinumtoxinA was effective and well tolerated for prophylaxis of headache in patients with chronic migraine (CM) in two randomized, double‐blind, placebo‐controlled, phase 3 trials. To further assess the safety and tolerability of onabotulinumtoxinA in CM prophylaxis in adults, the pooled safety data from four double‐blind, placebo‐controlled trials were analyzed.
54503041
Migraine: The seventh disabler
On 15 December 2012, a special edition of Lancet published the principal findings of the Global Burden of Disease Survey 2010 (GBD2010). Few reports are likely to have more profound meaning for people with headache, or carry greater promise for a better future, than the seven papers (and one in particular (1)) that were presented. GBD2010 was not the first such survey to be conducted, nor the first to give some recognition to the burden of migraine. The Global Burden of Disease Survey 2000 (GBD2000), conducted 12 years ago by the World Health Organization (WHO), listed migraine as the 19th cause of disability in the world, responsible for 1.4% of all years of life lost to disability (YLDs) (2). This finding has been cited repeatedly ever since; it has fuelled attempts to generate political acceptance of headache as a public-health priority (3), and given credibility to calls for greater investment in headache care and research. It pushed headache into WHO’s field of view, and became an essential part of the platform on which the Global Campaign against Headache has
1449227
Utility values in National Institute for Health and Clinical Excellence (NICE) Technology Appraisals.
OBJECTIVE
To review the selection and use of health-related utility values for economic models included in National Institute for Health and Clinical Excellence (NICE) Technology Appraisals.


METHOD
A cross-sectional review of reports of economic models submitted to the Technology Appraisals program was undertaken to review the health-related utility data included. Data reviewed included identification and selection of data and the methods used for utility elicitation. The methods used were compared with those from the 2004 Methods Guide issued by NICE.


RESULTS
Appraisals conducted after the implementation of the NICE 2004 Methods Guide were reviewed. After exclusion of documents that did not include a de novo cost-utility analysis, 71 submissions (53 manufacturer submissions, 18 assessment group reports) from 39 appraisals were identified, containing 284 unique utility values. Variation was found in the selection, elicitation, valuation, and use of the utility values. Thirty-nine submissions (55%) took utility values from published studies, of which only 31% were identified through a systematic review. Forty-seven (66%) submissions contained health state descriptions reported by patients, and 55 (77%) submissions applied a valuation set derived from the general population. The EQ-5D was used in 35 (49%) submissions, and mapping to a generic health-related quality of life measure was performed in 19 (27%) submissions.


CONCLUSIONS
Only 56% of submissions to NICE and assessment reports included utility values that met the NICE 2004 reference case. This highlights variation in the methods used to select and incorporate utility values in economic models for NICE Technology Appraisals.
29687402
Does convenience matter in health care delivery? A systematic review of convenience-based aspects of process utility.
OBJECTIVES
To systematically review the existing literature on the value associated with convenience in health care delivery, independent of health outcomes, and to try to estimate the likely magnitude of any value found.


METHODS
A systematic search was conducted for previously published studies that reported preferences for convenience-related aspects of health care delivery in a manner that was consistent with either cost-utility analysis or cost-benefit analysis. Data were analyzed in terms of the methodologies used, the aspects of convenience considered, and the values reported.


RESULTS
Literature searches generated 4715 records. Following a review of abstracts or full-text articles, 27 were selected for inclusion. Twenty-six studies reported some evidence of convenience-related process utility, in the form of either a positive utility or a positive willingness to pay. The aspects of convenience valued most often were mode of administration (n = 11) and location of treatment (n = 6). The most common valuation methodology was a discrete-choice experiment containing a cost component (n = 15).


CONCLUSIONS
A preference for convenience-related process utility exists, independent of health outcomes. Given the diverse methodologies used to calculate it, and the range of aspects being valued, however, it is difficult to assess how large such a preference might be, or how it may be effectively incorporated into an economic evaluation. Increased consistency in reporting these preferences is required to assess these issues more accurately.
35582002
Quality of life related to oral, subcutaneous, and intravenous biologic treatment of inflammatory bowel disease: a time trade-off study
Objectives Novel oral treatments (including biologics) of inflammatory bowel disease (IBD) are emerging. Apart from improvement of health, treatment convenience may be of value to patients. This ‘process utility’ can be estimated under the quality-of-life framework. We investigated the process utility associated with subcutaneous and intravenous biologic treatments compared with a hypothetical oral biologic treatment of IBD. Materials and methods A time trade-off study to estimate utilities for health states among adult patients with IBD was carried out. Respondents rated the anchor state (no description of the route of administration; the reference) and three states described: the once-daily oral, 2-weekly subcutaneous, and 8-weekly intravenous administration of biologic treatment for advanced IBD. Results Data from 127 respondents (age, 34.4 years; women, 52.9%) were collected. The oral state was valuated higher than the anchor state more frequently than subcutaneous and intravenous states (P=0.001). The process utility of the oral state adjusted for confounders was estimated at 0.147 (95% confidence interval: 0.087–0.208) and 0.164 (95% confidence interval: 0.096–0.233) in comparison with subcutaneous and intravenous states, respectively. The results were consistent across the respondents irrespective of their characteristics and unaffected by the change in the assumptions of data analysis. Conclusion Oral administration is preferred over the available routes of administration of biologics by patients with IBD. The utility gains from oral treatment were significant, indicating higher value of that treatment within a cost-utilitarian approach. The additional process-related benefit can justify higher expenditures for the research of oral biologics.
38471894
Effect of Regimen Complexity on Patient Satisfaction and Compliance With Warfarin Therapy
This study sought to determine patient satisfaction with anticoagulation care in a pharmacist-managed clinic and assess the effect of warfarin regimen complexity on patient satisfaction, compliance, and international normalized ratios (INRs). Retrospective chart reviews of 476 anticoagulation clinic patients were conducted. Patients were divided into groups by complexity of warfarin regimen (whole tablet, split tablet, alternating dose) for comparisons of compliance and INRS. An oral Likert scate satisfaction survey was administered to a convenience sample of 100 patients. Degree of satisfaction was compared based on warfarin regimen. Compliant patients were more likely to have therapeutic INRs (p < 0.01) and to be taking whole tablet dosage regimens ( p < 0.01). Patients were generally satisfied with the pharmacist-managed clinic. There was a significantly (p < 0.025) higher score for patients on split tablet regimens, indicating a greater likelihood for agreement that alternating doses made taking their medication more difficult. A relationship exists between patient compliance and prescribed dosage regimen, as well as with therapeutic INR values.
45704251
Medication compliance: the patient's perspective.
There has been increasing interest in using outcomes-based research to evaluate quality of care. Compliance with prescribed regimens is an intermediate outcome measure that presumes that a positive health outcome will follow, which is why clinicians and researchers are interested in compliance. Patients, however, use a variety of criteria to determine the value of medication. They may place equal or greater value on personal and often competing nonclinical outcomes. A small but growing literature explores the influence of physical, economic, psychological, and social factors that influence medication use behavior. This literature supports the notion that patients evaluate medication based not only on its clinical effectiveness, but also how it affects all aspects of their lives. Outcomes research on compliance with prescribed medicine should recognize the outcomes valued from the patient's perspective.
9720015
Satisfaction with medication: an overview of conceptual, methodologic, and regulatory issues.
OBJECTIVE
Patients' satisfaction with their medication or medical device has been of increasing interest over the past decade. This is reflective of the rise of the patient as consumer and the desire of pharmaceutical and device manufacturers to obtain feedback from the consumers about their products. Satisfaction with medication is more narrowly focused and should be distinguished from other aspects of satisfaction. The purpose of this article is to place the concept of patient satisfaction with medication in an appropriate theoretical context, to explore the challenges of performing this research, and to offer recommendations for the basis of satisfaction claims.


METHODS
We reviewed the literature on satisfaction with medication or medical devices. We summarize and discuss the background, conceptual issues, and theoretical justification for studying satisfaction with medication. We offer examples of domains to be included and suggestions on how to develop a psychometrically sound satisfaction measure. We also address additional issues for consideration.


RESULTS
Medication satisfaction is a type of patient-reported outcome, but is distinguished from other patient-reported outcomes-specifically health-related quality of life (HRQL) and self-reports of symptoms. The Theory of Reasoned Action provides one theoretical justification for the concept. The heuristic value of this theory leads to implications regarding the relation between satisfaction and adherence. In addition, the theory is consistent with the need to focus on the patient's beliefs and values concerning the impact of taking his/her medication. Although the beliefs will differ according to the specific drug-disease combination, the beliefs can often be categorized in several domains of satisfaction: symptom relief/efficacy, side effects, ease and convenience, impact on HRQL, general satisfaction, and additional domains specific to the given research question.


CONCLUSION
Patient satisfaction instruments should be subjected to the same psychometrically rigorous standards and procedures as any other patient-reported outcome and should also be subject to the same regulatory standards as other patient-reported outcomes with respect to advertising and promotion.