Systematic review of outcomes and endpoints in acute migraine clinical trials.
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ABSTRACT:
SUBMITTER: Houts CR
PROVIDER: S-EPMC7986374 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
Publications
Systematic review of outcomes and endpoints in acute migraine clinical trials.
Houts Carrie R CR McGinley James S JS Nishida Tracy K TK Buse Dawn C DC Wirth R J RJ Dodick David W DW Goadsby Peter J PJ Lipton Richard B RB
Headache 20210221 2
<h4>Background/objective</h4>To review the acute migraine clinical trial literature and provide a summary of the endpoints and outcomes used in such trials.<h4>Method</h4>A systematic literature review, following a prespecified (but unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, was conducted to understand endpoints and outcomes used in acute migraine clinical trials. Predefined terms were searched in PubMe ...[more]
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Project description:BackgroundOver the last six decades (earliest included publication from 1959), clinical trials of migraine preventive treatments have led to the regulatory approval of many medications and devices. Despite similar clinical goals, the outcomes and endpoints used in these trials are broad and not well standardized.ObjectiveTo describe results from a systematic literature review focused on outcomes and endpoints used in preventive migraine clinical trials.MethodA systematic literature review, following a pre-specified (unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, was conducted to characterize the endpoints and outcomes used in preventive migraine clinical trials. Predetermined terms were searched in PubMed on October 28, 2019. Data related to trial design, subject characteristics, outcomes, and endpoints reported in each publication were extracted. Descriptive summaries of these features were tabulated for the recent subset of publications, published during or after 1988, that were randomized, blinded, and focused on pharmacological or device therapies for the preventive treatment of migraine.ResultsThe initial literature search identified 1506 publications, of which 757 publications were eligible for data extraction. Of specific clinical interest were the recent subset of 268 articles (268/757, 35.4%) fulfilling the targeted criteria. Results showed that the outcomes used to define endpoints varied substantially across publications. For example, in the recent subset of publications, 68.7% (184/268) of the publications examined ≥1 migraine-specific outcome, 39.6% (106/268) examined ≥1 headache-specific outcome, 50.7% (136/268) examined ≥1 acute/rescue medication use outcome, 40.3% (108/268) examined ≥1 headache-related patient-reported outcome measure (PROM), and 22.0% (59/268) examined ≥1 non-headache-specific PROM. Furthermore, the definition of the endpoints used (e.g., change from baseline, fixed timepoint comparisons, categorization of "responders" to treatment based on wide variety of "responder definitions") also differed across publications.ConclusionPublications from clinical trials of preventive migraine pharmacologic and device treatments differed in terms of study design, endpoint definitions, and how endpoints and outcomes were measured. Although there were common outcomes and endpoints used across publications, no clear "standardized" set of endpoints and outcomes emerged. The inconsistencies in endpoints and outcomes within this literature suggest that the development of a uniform set of outcomes and endpoints could improve the clinical meaningfulness of clinical trial results, facilitate cross-trial comparisons and better inform patient care. This standard set of outcomes and endpoints should be statistically robust and informed by the priorities of various stakeholders, most importantly, the needs and preferences of people living with migraine.
| S-EPMC7986733 | biostudies-literature
Project description:In cancer cachexia trials, measures of physical function are commonly used as endpoints. For drug trials to obtain regulatory approval, efficacy in physical function endpoints may be needed alongside other measures. However, it is not clear which physical function endpoints should be used. The aim of this systematic review was to assess the frequency and diversity of physical function endpoints in cancer cachexia trials. Following a comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990-2021), records were retrieved. Eligible trials met the following criteria: adults (≥18 years), controlled design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a physical function endpoint. Physical function measures were classified as an objective measure (hand grip strength [HGS], stair climb power [SCP], timed up and go [TUG] test, 6-min walking test [6MWT] and short physical performance battery [SPPB]), clinician assessment of function (Karnofsky Performance Status [KPS] or Eastern Cooperative Oncology Group-Performance Status [ECOG-PS]) or patient-reported outcomes (physical function subscale of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaires [EORTC QLQ-C30 or C15]). Data extraction was performed using Covidence and followed PRISMA guidance (PROSPERO registration: CRD42022276710). A total of 5975 potential studies were examined and 71 were eligible. Pharmacological interventions were assessed in 38 trials (54%). Of these, 11 (29%, n = 1184) examined megestrol and 5 (13%, n = 1928) examined anamorelin; nutritional interventions were assessed in 21 trials (30%); and exercise-based interventions were assessed in 6 trials (8%). The remaining six trials (8%) assessed multimodal interventions. Among the objective measures of physical function (assessed as primary or secondary endpoints), HGS was most commonly examined (33 trials, n = 5081) and demonstrated a statistically significant finding in 12 (36%) trials (n = 2091). The 6MWT was assessed in 12 trials (n = 1074) and was statistically significant in 4 (33%) trials (n = 403), whereas SCP, TUG and SPPB were each assessed in 3 trials. KPS was more commonly assessed than the newer ECOG-PS (16 vs. 9 trials), and patient-reported EORTC QLQ-C30 physical function was reported in 25 trials. HGS is the most commonly used physical function endpoint in cancer cachexia clinical trials. However, heterogeneity in study design, populations, intervention and endpoint selection make it difficult to comment on the optimal endpoint and how to measure this. We offer several recommendations/considerations to improve the design of future clinical trials in cancer cachexia.
| S-EPMC10570071 | biostudies-literature
Project description:BackgroundIn October 2014, the US Food and Drug Administration released a draft guidance for the development of drugs for the acute treatment of migraine. This guidance offered the option of replacing the previously required 4 co-primary endpoints: pain freedom, freedom from nausea, freedom from photophobia, and freedom from phonophobia, all at 2 hours posttreatment, with 2 co-primary endpoints: pain freedom and freedom from most bothersome symptom (MBS) other than pain, both at 2 hours posttreatment. At the time the new draft guidance was released, no large clinical trials had been undertaken with these 2 co-primary endpoints, posing a challenge in determining the sample size that might be required to achieve statistical significance. As a number of trials have now been completed, we conducted a review of the observed placebo responses, drug effect sizes, and sample sizes to better inform the design of future trials.MethodsWe searched PubMed, Embase, Web of Science, and the Cochrane library for primary publications of phase 3 randomized, placebo-controlled, double-blind acute migraine treatment trials that used pain freedom and MBS freedom as primary or planned secondary endpoints. For each endpoint, placebo response rates were determined and used to generate estimates of sample size, assuming differences between placebo and active treatment groups of 10%, 15%, and 20%. Sample size calculations were based on 80% power using a 2-group continuity corrected chi-square test with a 5% 2-sided significance level.ResultsWe identified abstracts or full-length papers describing results of 8 clinical trials employing the new co-primary endpoints. The mean placebo response rate for 2-hour pain freedom was 16.75% (range 11.8-21.3%) and treatment effect (difference in response rates between active and placebo groups) ranged from 5.0% to 27.2%. For 2-hour MBS freedom, the mean placebo response rate was 32.8% (range 25.2-48.1%), and the range of treatment effect was 8.9% to 25.4%. Based on a placebo response rate of 17% for pain freedom, the sample sizes that would have been required to achieve statistical significance were n = 269, n = 128, and n = 77, for treatment effect sizes of 10%, 15%, and 20%, respectively. For MBS, assuming a placebo response rate of 33%, the corresponding required sample sizes would have been n = 389, n = 181, and n = 105.ConclusionsThe observed range of placebo response and treatment effect sizes suggests that use of the newly recommended 2 co-primary endpoints could reduce the sample sizes required to achieve significance compared with past trials using 4 primary endpoints (in which mean and median group sizes for recent trials were 375 and 362, respectively). However, the initial trials using the newly recommended co-primary endpoints tended to treat more participants than would have been minimally required. We anticipate that with the growing body of information regarding the use of these new endpoints, samples sizes may be more aligned with treatment efficacy, enabling faster and more cost-effective trials for acute migraine treatment.
| S-EPMC6593965 | biostudies-literature
Project description:There is no consensus on the optimal endpoint(s) in cancer cachexia trials. Endpoint variation is an obstacle when comparing interventions and their clinical value. The aim of this systematic review was to summarize and evaluate endpoints used to assess appetite and dietary intake in cancer cachexia clinical trials. A search for studies published from 1 January 1990 until 2 June 2021 was conducted using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Eligible studies examined cancer cachexia treatment versus a comparator in adults with assessments of appetite and/or dietary intake as study endpoints, a sample size ≥40 and an intervention lasting ≥14 days. Reporting was in line with PRISMA guidance, and a protocol was published in PROSPERO (2022 CRD42022276710). This review is part of a series of systematic reviews examining cachexia endpoints. Of the 5975 articles identified, 116 were eligible for the wider review series and 80 specifically examined endpoints of appetite (65 studies) and/or dietary intake (21 studies). Six trials assessed both appetite and dietary intake. Appetite was the primary outcome in 15 trials and dietary intake in 7 trials. Median sample size was 101 patients (range 40-628). Forty-nine studies included multiple primary tumour sites, while 31 studies involved single primary tumour sites (15 gastrointestinal, 7 lung, 7 head and neck and 2 female reproductive organs). The most frequently reported appetite endpoints were visual analogue scale (VAS) and numerical rating scale (NRS) (40%). The appetite item from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30/C15 PAL (38%) and the appetite question from North Central Cancer Treatment Group anorexia questionnaire (17%) were also frequently applied. Of the studies that assessed dietary intake, 13 (62%) used food records (prospective registrations) and 10 (48%) used retrospective methods (24-h recall or dietary history). For VAS/NRS, a mean change of 1.3 corresponded to Hedge's g of 0.5 and can be considered a moderate change. For food records, a mean change of 231 kcal/day or 11 g of protein/day corresponded to a moderate change. Choice of endpoint in cachexia trials will depend on factors pertinent to the trial to be conducted. Nevertheless, from trials assessed and available literature, NRS or EORTC QLQ C30/C15 PAL seems suitable for appetite assessments. Appetite and dietary intake endpoints are rarely used as primary outcomes in cancer cachexia. Dietary intake assessments were used mainly to monitor compliance and are not validated in cachexia populations. Given the importance to cachexia studies, dietary intake endpoints must be validated before they are used as endpoints in clinical trials.
| S-EPMC10995275 | biostudies-literature
Project description:Migraine is considered one of the most disabling diseases. Currently, there are few studies on clinical migraine treatment based on sex-related differences, despite the important role of sex in migraine. Our aim was to evaluate gender bias in published clinical trials on monoclonal antibodies (erenumab, galcanezumab, fremanezumab and eptinezumab). We performed a systematic review of controlled clinical trials of erenumab, galcanezumab, fremanezumab and eptinezumab, searching the PubMed/MEDLINE database for articles published before December 2021. The search identified 760 articles, 25 of which met the inclusion criteria. Of all the patients included in these trials, 85.1% were women. Only one study had female lead authors. Two of the 25 studies included a sex-based analysis of the primary endpoint. None of the articles discussed the results separately for men and for women. The proportion of men recruited in trials is scarce and more studies are needed to guarantee the safety and tolerability of monoclonal antibodies used in male migraine. As observed in our study, despite the high number of women recruited, only 2 studies analysed the results separately by sex. Thus, a potential risk of gender bias was found in these clinical trials.
| S-EPMC10237417 | biostudies-literature
Project description:Non-invasive neuromodulation therapies for migraine and cluster headache are a practical and safe alternative to pharmacologics. Comparisons of these therapies are difficult because of the heterogeneity in study designs. In this systematic review of clinical trials, the scientific rigour and clinical relevance of the available data were assessed to inform clinical decisions about non-invasive neuromodulation. PubMed, Cochrane Library and ClinicalTrials.gov databases and the WHO's International Clinical Trials Registry Platform were searched for relevant clinical studies of non-invasive neuromodulation devices for migraine and cluster headache (1 January 1990 to 31 January 2018), and 71 were identified. This analysis compared study designs using recommendations of the International Headache Society for pharmacological clinical trials, the only available guidelines for migraine and cluster headache. Non-invasive vagus nerve stimulation (nVNS), single-transcranial magnetic stimulation and external trigeminal nerve stimulation (all with regulatory clearance) were well studied compared with the other devices, for which studies frequently lacked proper blinding, sham controls and sufficient population sizes. nVNS studies demonstrated the most consistent adherence to available guidelines. Studies of all neuromodulation devices should strive to achieve the same high level of scientific rigour to allow for proper comparison across devices. Device-specific guidelines for migraine and cluster headache will be soon available, but adherence to current guidelines for pharmacological trials will remain a key consideration for investigators and clinicians.
| S-EPMC6585264 | biostudies-literature
Project description:There are numerous ongoing studies assessing treatment options for preventing, treating, and managing complications of coronavirus disease-2019 disease. The objective of this study was to do a systematic review and critical appraisal of the ongoing clinical trials with an aim to provide insight into the various interventions tested, clinical rationale, geographical distribution of the trials as well as the endpoints assessed in the studies. ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and PubMed were assessed till 11 May 2020. The search resulted in 3242 ongoing studies of which 829 studies were included. There are 134 different drug-based interventions being assessed in 463 clinical trials as treatment options China accounts for 35% of all ongoing clinical studies followed by USA 23% and other countries together account for 42%. Amongst the 463 studies assessing drug-based treatment options, studies that are funded by federal and academic institutions are 79.6%, pharmaceutical company-funded studies are 15.11%, and no funding information is available in 5.10%. The definitive outcomes like mortality are being assessed as primary outcome in 22.8% of the studies only and need for ventilator in 6.2% of the studies. Amongst the pharmaceutical company-funded drug-based studies, only 20% of the studies had mortality as the primary outcome. Only 5.5% of the ongoing clinical trials are specifically designed to assess the most vulnerable population like elderly, patients with comorbidities and cancer. Multiple intervention-based clinical studies against severe acute respiratory syndrome-related coronavirus-2 are being performed throughout the world with a high concentration of clinical trials in the developed world with concern that of elderly and patients with comorbidities are being underrepresented and definite endpoints like mortality are being assessed in only one-fifth of the studies.
| S-EPMC7404496 | biostudies-literature
Project description:ObjectiveThis update of a systematic review evaluates the effectiveness of spinal manipulations as a treatment for migraine headaches.BackgroundSpinal manipulation therapy (SMT) is sometimes used to treat migraine headaches; however, the biological plausibility and safety of SMT have repeatedly been questioned.MethodsAmed, Embase, MEDLINE, CINAHL, Mantis, Index to Chiropractic Literature, and Cochrane Central were searched from inception to September 2023. Randomized clinical trials (RCTs) investigating spinal manipulations (performed by various healthcare professionals including physiotherapists, osteopaths, and chiropractors) for treating migraine headaches in human subjects were considered. Other types of manipulative therapy, i.e., cranial, visceral, and soft tissue were excluded. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the certainty of evidence.ResultsThree more RCTs were published since our first review; amounting to a total of 6 studies with 645 migraineurs meeting the inclusion criteria. Meta-analysis of six trials showed that, compared with various controls (placebo, drug therapy, usual care), SMT (with or without usual care) has no effect on migraine intensity/severity measured with a range of instruments (standardized mean difference [SMD] - 0.22, 95% confidence intervals [CI] - 0.65 to 0.21, very low certainty evidence), migraine duration (SMD - 0.10; 95% CI - 0.33 to 0.12, 4 trials, low certainty evidence), or emotional quality of life (SMD - 14.47; 95% CI - 31.59 to 2.66, 2 trials, low certainty evidence) at post-intervention. A meta-analysis of two trials showed that compared with various controls, SMT (with or without usual care) increased the risk of AEs (risk ratio [RR] 2.06; 95% CI 1.24 to 3.41, numbers needed to harm = 6; very low certainty evidence). The main reasons for downgrading the evidence were study limitations (studies judged to be at an unclear or high risk of bias), inconsistency (for pain intensity/severity), imprecision (small sizes and wide confidence intervals around effect estimates) and indirectness (methodological and clinical heterogeneity of populations, interventions, and comparators).ConclusionsThe effectiveness of SMT for the treatment of migraines remains unproven. Future, larger, more rigorous, and independently conducted studies might reduce the existing uncertainties.
| S-EPMC11606176 | biostudies-literature
Project description:IntroductionTranscatheter aortic valve implantation (TAVI) has been demonstrated to be an alternative treatment for severe aortic stenosis in patients considered as high surgical risk. Since its first human implantation by Cribier et al., TAVI has been shown to increase survival rate and quality of life for high surgical risks patients. The objective of this study is to provide an overview of TAVI registries and the reporting clinical outcomes based on the VARC-2 definitions. In addition, the comparability and adherence of VARC-2 reporting within the identified TAVI registries was reviewed.Materials and methodsA systematic review of TAVI registries reporting VARC-2 definitions has been performed in line with PRISMA guidelines in PubMed, ScienceDirect, Scopus databases and EMBASE. Based on VARC-2, patients' characteristics and procedure characteristics, 30-day clinical outcomes, 1-year mortality and composited endpoints were extracted from each registry's publications.ResultsThis review identified 466 studies that were potentially relevant, and 20 TAVI registries reported VARC-2 definitions involved in our present review. Of all 20 registries, an overall sample size of 12,583 patients was involved. The 30-day all-cause mortality ranged from 0 to 12.7%. From 20 registries, 14 registries reported the cardiovascular mortality at 30 days. 9 registries reported myocardial infarction (MI) rate based on VARC-2 definitions, and 7 registries reported peri-procedural MI rate (<72h). In our review, most of registries presented MI rates ranging from 0.5% to 2%. The majority of registries have reported complications such as bleeding, vascular complications and new pacemaker implantation.ConclusionSince the introduction of VARC definitions from 2011, VARC and VARC-2 definitions are still not systematically used by all TAVI studies. These endpoint definitions warrant a concise and systemic analysis of outcome measures. Reporting TAVI-outcome uniformly makes study result comparison feasible. This definitely will increase patient safety, additionally to provide sufficient evidence to support decision makers like regulatory bodies, HTA agencies, payers.
| S-EPMC5598923 | biostudies-literature
Project description:Summary Background Cancer immunotherapy shows unique efficacy kinetics that differs from conventional treatment. These characteristics may lead to the prolongation of trial duration, hence reliable surrogate endpoints are urgently needed. We aimed to systematically evaluate the study-level performance of commonly reported intermediate clinical endpoints for surrogacy in cancer immunotherapy. Methods We searched the Embase, PubMed, and Cochrane databases, between database inception and October 18, 2022, for phase 3 randomised trials investigating the efficacy of immunotherapy in patients with advanced solid tumours. An updated search was done on July, 15, 2023. No language restrictions were used. Eligible trials had to set overall survival (OS) as the primary or co-primary endpoint and report at least one intermediate clinical endpoint including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and 1-year overall survival. Other key inclusion and exclusion criteria included: (1) adult patients (>18 years old) with advanced solid tumour; (2) no immunotherapy conducted in the control arms; (3) follow-up is long enough to achieve OS; (4) data should be public available. A two-stage meta-analytic approach was conducted to evaluate the magnitude of the association between these intermediate endpoints and OS. A surrogate was identified if the coefficient of determination (R2) was 0.7 or greater. Leave-one-out cross-validation and pre-defined subgroup analysis were conducted to examine the heterogeneity. Potential publication bias was evaluated using the Egger's and Begg's tests. This trial was registered with PROSPERO, number CRD42022381648. Findings 52,342 patients with 15 types of tumours from 77 phase 3 studies were included. ORR (R2 = 0.11; 95% CI, 0.00–0.24), DCR (R2 = 0.01; 95% CI, 0.00–0.01), and PFS (R2 = 0.40; 95% CI, 0.23–0.56) showed weak associations with OS. However, a strong correlation was observed between 1-year survival and clinical outcome (R2 = 0.74; 95% CI, 0.64–0.83). These associations remained relatively consistent across pre-defined subgroups stratified based on tumour types, masking methods, line of treatments, drug targets, treatment strategies, and follow-up durations. No significant heterogeneities or publication bias were identified. Interpretation 1-year milestone survival was the only identified surrogacy endpoint for outcomes in cancer immunotherapy. Ongoing investigations and development of new endpoints and incorporation of biomarkers are needed to identify potential surrogate markers that can be more robust than 1-year survival. This work may provide important references in assisting the design and interpretation of future clinical trials, and constitute complementary information in drafting clinical practice guidelines. Funding None.
| S-EPMC10432823 | biostudies-literature