scholarly journals Results and lessons learnt from a randomized controlled trial: prophylactic treatment of vestibular migraine with metoprolol (PROVEMIG)

Trials ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Otmar Bayer ◽  
◽  
Christine Adrion ◽  
Amani Al Tawil ◽  
Ulrich Mansmann ◽  
...  
Keyword(s):  
Prophylactic Treatment ◽  
Controlled Trial ◽  
Psychometric Evaluation ◽  
Vestibular Migraine ◽  
Phase Iii ◽  
University Hospitals ◽  
Double Blind ◽  
Treatment Benefit ◽  
Episodic Vertigo ◽  
Patient Reported

Abstract Background Vestibular migraine (VM) is the most frequent cause of recurrent spontaneous attacks of vertigo causally related to migraine. The objective of the Prophylactic treatment of vestibular migraine with metoprolol (PROVEMIG) trial was to demonstrate that metoprolol succinate is superior to placebo in the prevention of episodic vertigo- and migraine-related symptoms in patients with VM. Methods This phase III, two-arm, parallel-group, double-blind, randomized placebo-controlled trial was designed to be conducted at tertiary referral centres at neurology and ear, nose and throat departments of eight German university hospitals. The planned sample size was a total of 266 patients to be allocated. Adults aged 18 years or above diagnosed with probable or definitive VM according to the Neuhauser criteria 2001 were randomly assigned 1:1 to 6 months blinded metoprolol (maintenance dosage of 95 mg daily) or placebo. The primary efficacy outcome was the self-reported number of vertiginous attacks per 30 days documented by means of a paper-based daily symptom diary. The pre-specified time period of primary interest was defined as months 4 to 6. Secondary outcomes included the patient-reported number of migraine days and vertigo days, the Dizziness Handicap Inventory, and clinical assessments. Adverse events were reported throughout the whole 9-month study period. Results At the time of trial termination, no evidence for a difference in the incidence of vertiginous attacks between groups was detected. For the full analysis set, the incidence rate ratio was 0.983 (95% confidence interval (CI) 0.902–1.071) for metoprolol versus placebo. In both groups, there was a significant decline over time in the overall monthly vertigo attacks by a factor of 0.830 (95% CI 0.776–0.887). Results were consistent for all subjective and objective key measures of efficacy. The treatment was well tolerated with no unexpected safety findings. Conclusions After randomizing 130 patients PROVEMIG had to be discontinued because of poor participant accrual not related to the tolerability of the study medication or safety concerns; no treatment benefit of metoprolol over placebo could be established. Additional preparatory work is much needed in the development, psychometric evaluation and interpretation of clinically meaningful end points in trials on episodic syndromes like VM taking into consideration the complexity of this disease entity comprising two domains (vertigo- and headache-related disability). Trial registration EudraCT, 2009-013701-34. Prospectively registered on 8 April 2011.

scholarly journals Results and lessons learnt from a randomized controlled trial: Prophylactic treatment of vestibular migraine with metoprolol (PROVEMIG)

2019 ◽  
Author(s):  
Otmar Bayer ◽  
Christine Adrion ◽  
Amani Al Tawil ◽  
Ulrich Mansmann ◽  
Michael Strupp
Keyword(s):  
Controlled Trial ◽  
Psychometric Evaluation ◽  
Placebo Treatment ◽  
Vestibular Migraine ◽  
University Hospitals ◽  
Double Blind ◽  
Treatment Benefit ◽  
Episodic Vertigo ◽  
Patient Reported ◽  
Full Analysis

Abstract BACKGROUND Vestibular migraine (VM) is the most frequent cause of recurrent spontaneous attacks of vertigo causally related to migraine. The objective of the PROVEMIG trial was to demonstrate that metoprolol succinate is superior to placebo treatment in the prevention of episodic vertigo- and migraine-related symptoms in patients with VM. METHODS This phase 3, two-arm parallel-group, double-blind, randomized placebo-controlled trial was designed to be conducted at tertiary referral centres at neurology and ENT departments of eight German university hospitals. The planned sample size was a total of 266 patients to be allocated. Adults aged 18 years or above diagnosed with probable or definitive VM according to the Neuhauser criteria 2001 were randomly assigned 1:1 to six months blinded metoprolol (maintenance dosage of 95 mg daily) versus placebo treatment policy. The primary efficacy outcome was the self-reported number of vertiginous attacks per 30 days documented by means of a paper-based daily symptom diary. The pre-specified time period of primary interest was defined within month 4 to 6. Secondary outcomes included the patient-reported number of migraine days and vertigo days, the Dizziness Handicap Inventory and clinical assessments. Adverse events were reported throughout the whole 9-month study period. RESULTS At the time of trial termination, no evidence for a difference in the incidence of vertiginous attacks between both treatment groups was detected. For the full analysis set, the incidence rate ratio (IRR) was 0.983 (95% confidence interval (CI), 0.902 to 1.071) for metoprolol vs. placebo. In both groups, there was a significant decline over time in the overall monthly vertigo attacks by the factor 0.830 (95% CI, 0.776 to 0.887). Results were consistent for all subjective and objective key measures of efficacy. The treatment was well tolerated with no unexpected safety findings. CONCLUSIONS After randomizing 130 patients PROVEMIG had to be discontinued due to poor participant accrual not related to the tolerability of the study medication or safety concerns and no treatment benefit of metoprolol over placebo could be established. Additional preparatory work is much-needed in the development, psychometric evaluation and interpretation of clinically meaningful endpoints in trials on episodic syndromes like VM taking into consideration the complexity of this disease entity comprising of two domains (vertigo- and headache-related disability). TRIAL REGISTRATION EudraCT no 2009-013701-34, prospectively registered on 08 April 2011, https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-013701-34/DE.

scholarly journals Results and lessons learnt from a randomized controlled trial: Prophylactic treatment of vestibular migraine with metoprolol (PROVEMIG)

2019 ◽  
Author(s):  
Otmar Bayer ◽  
Christine Adrion ◽  
Amani Al Tawil ◽  
Ulrich Mansmann ◽  
Michael Strupp
Keyword(s):  
Controlled Trial ◽  
Psychometric Evaluation ◽  
Placebo Treatment ◽  
Vestibular Migraine ◽  
University Hospitals ◽  
Double Blind ◽  
Episodic Vertigo ◽  
Efficacy Outcome ◽  
Patient Reported ◽  
Full Analysis

Abstract BACKGROUND Vestibular migraine (VM) is the most frequent cause of recurrent spontaneous attacks of vertigo causally related to migraine. The objective of the PROVEMIG trial was to demonstrate that metoprolol succinate is superior to placebo treatment in the prevention of episodic vertigo- and migraine-related symptoms in patients with VM. METHODS This phase 3, two-arm parallel-group, double-blind, randomized placebo-controlled trial was designed to be conducted at tertiary referral centres at neurology and ENT departments of eight German university hospitals. The planned sample size was a total of 266 patients to be allocated. Adults aged 18 years or above diagnosed with probable or definitive VM according to the Neuhauser criteria 2001 were randomly assigned 1:1 to six months blinded metoprolol (maintenance dosage of 95 mg daily) versus placebo treatment policy. The primary efficacy outcome was the self-reported number of vertiginous attacks per 30 days documented by means of a paper-based daily symptom diary. The pre-specified time period of primary interest was defined within month 4 to 6. Secondary outcomes included the patient-reported number of migraine days and vertigo days, the Dizziness Handicap Inventory and clinical assessments. Adverse events were reported throughout the whole 9-month study period. RESULTS At the time of trial termination, no evidence for a difference in the incidence of vertiginous attacks between both treatment groups was detected. For the full analysis set, the incidence rate ratio (IRR) was 0.983 (95% confidence interval (CI), 0.902 to 1.071) for metoprolol vs. placebo. There was a significant decline in the overall monthly vertigo attacks by the factor 0.830 (95% CI, 0.776 to 0.887). Results were consistent for all subjective and objective key measures of efficacy. The treatment was well tolerated with no unexpected safety findings. CONCLUSIONS Due to poor participant accrual not related to the tolerability of the study medication or safety concerns PROVEMIG had to be discontinued after randomizing 130 patients. Additional preparatory work is much-needed in the development, psychometric evaluation and interpretation of clinically meaningful endpoints in trials on episodic syndromes like VM taking into consideration the two-dimensional aspect of this disease entity. TRIAL REGISTRATION EudraCT no 2009-013701-34, prospectively registered on 08 April 2011, https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-013701-34/DE.

scholarly journals Efficacy and safety of abatacept in active primary Sjögren’s syndrome: results of a phase III, randomised, placebo-controlled trial

2020 ◽  
pp. annrheumdis-2020-218599
Author(s):  
Alan N Baer ◽  
Jacques-Eric Gottenberg ◽  
E William St Clair ◽  
Takayuki Sumida ◽  
Tsutomu Takeuchi ◽  
...  
Keyword(s):  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Controlled Trial ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Phase Iii ◽  
Open Label ◽  
Double Blind ◽  
Patient Reported ◽  
Sjögren‘S Syndrome

ObjectivesTo evaluate efficacy and safety of abatacept in adults with active primary Sjögren’s syndrome (pSS) in a phase III, randomised, double-blind, placebo-controlled trial.MethodsEligible patients (moderate-to-severe pSS [2016 ACR/European League Against Rheumatism (EULAR) criteria], EULAR Sjögren’s Syndrome Disease Activity Index [ESSDAI] ≥5, anti-SS-related antigen A/anti-Ro antibody positive) received weekly subcutaneous abatacept 125 mg or placebo for 169 days followed by an open-label extension to day 365. Primary endpoint was mean change from baseline in ESSDAI at day 169. Key secondary endpoints were mean change from baseline in EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) and stimulated whole salivary flow (SWSF) at day 169. Other secondary clinical endpoints included glandular functions and patient-reported outcomes. Selected biomarkers and immune cell phenotypes were examined. Safety was monitored.ResultsOf 187 patients randomised, 168 completed double-blind period and 165 continued into open-label period. Mean (SD) baseline ESSDAI and ESSPRI total scores were 9.4 (4.3) and 6.5 (2.0), respectively. Statistical significance was not reached for primary (ESSDAI −3.2 abatacept vs −3.7 placebo, p=0.442) or key secondary endpoints (ESSPRI, p=0.337; SWSF, p=0.584). No clinical benefit of abatacept over placebo at day 169 was seen with other clinical and PRO endpoints. Relative to baseline, abatacept was associated with significant differences vs placebo in some disease-relevant biomarkers (including IgG, IgA, IgM-rheumatoid factor) and pathogenic cell subpopulations (post hoc analyses). No new safety signals were identified.ConclusionsAbatacept treatment did not result in significant clinical efficacy compared with placebo in patients with moderate-to-severe pSS, despite evidence of biological activity.

A phase III, multicenter, randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine (G) as first-line therapy for metastatic adenocarcinoma of the pancreas: The GAMMA trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4135-TPS4135 ◽  
Author(s):  
Charles S. Fuchs ◽  
Sergio Jobim Azevedo ◽  
Alfredo Carrato ◽  
Vincent Haddad ◽  
Lara Rachel Lipton ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Human Monoclonal Antibody ◽  
Objective Response ◽  
Data Monitoring Committee ◽  
Phase Iii ◽  
Rank Test ◽  
Metastatic Adenocarcinoma ◽  
Double Blind ◽  
Patient Reported ◽  
Adenocarcinoma Of The Pancreas

TPS4135 Background: Ganitumab (AMG 479) is an investigational, fully human, monoclonal antibody inhibitor of the IGF1R. In a randomized phase II study in patients with metastatic pancreatic cancer, addition of ganitumab 12 mg/kg every 2 weeks (Q2W) to G prolonged progression-free survival (PFS) and overall survival (OS) (Kindler. Ann Onc. 2010;21:741P). Exposure-efficacy analysis showed that patients with higher ganitumab exposure levels (AUCss at or above median) had longer PFS and OS (Lu. JCO. 2011;29:4049). Methods: In this phase III study, patients are randomized 2:2:1 to placebo + G, ganitumab 12 mg/kg + G, or ganitumab 20 mg/kg + G. Patients receive ganitumab or placebo IV days (D) 1 and 15 and G 1000 mg/m2 IV D 1, 8, and 15 every 28 D. Patients receiving 20 mg/kg ganitumab are expected to achieve ganitumab levels above the median in phase 2. Key eligibility criteria: untreated metastatic adenocarcinoma of the pancreas; ECOG score 0 or 1; ≥ 18 years old; adequate organ function; and fasting (or non-fasting) glucose ≤ 160 mg/dL. The primary endpoint is OS. A log-rank test stratified by ECOG, presence of liver metastases, and geographic region will compare OS independently for each ganitumab arm at an overall one-sided 2.5% significance level for declaring superiority of ganitumab + G vs placebo + G. Key secondary endpoints include PFS, objective response, safety, and patient-reported outcomes. An additional objective is to define a subpopulation with improved OS based upon baseline levels of circulating biomarkers. Enrollment began in April 2011. As of January 23, 2012, 463 of 825 patients have been enrolled. The study is overseen by an independent data monitoring committee. Status: open. Supported by Amgen Inc. in collaboration with Takeda Global Research & Development Center, Inc.; ClinicalTrials.gov: NCT01231347.

scholarly journals Placebo-Controlled Trial to Determine the Effectiveness of a Urea/Lactic Acid–Based Topical Keratolytic Agent for Prevention of Capecitabine-Induced Hand-Foot Syndrome: North Central Cancer Treatment Group Study N05C5

2010 ◽  
Vol 28 (35) ◽  
pp. 5182-5187 ◽  
Author(s):  
Sherry L. Wolf ◽  
Rui Qin ◽  
Smitha P. Menon ◽  
Kendrith M. Rowland ◽  
Sachdev Thomas ◽  
...  
Keyword(s):  
Lactic Acid ◽  
Controlled Trial ◽  
Skin Toxicity ◽  
Phase Iii ◽  
Double Blind ◽  
North Central ◽  
Exact Test ◽  
Patient Reported ◽  
Hand Foot Syndrome ◽  
Hands And Feet

Purpose Hand-foot syndrome (HFS) is a dose-limiting toxicity of capecitabine for which no effective preventative treatment has been definitively demonstrated. This trial was conducted on the basis of preliminary data that a urea/lactic acid–based topical keratolytic agent (ULABTKA) may prevent HFS. Patients and Methods A randomized, double-blind phase III trial evaluated 137 patients receiving their first ever cycle of capecitabine at a dose of either 2,000 or 2,500 mg/m2 per day for 14 days. Patients were randomly assigned to a ULABTKA versus a placebo cream, which was applied to the hands and feet twice per day for 21 days after the start of capecitabine. Patients completed an HFS diary (HFSD) daily. HFS toxicity grade (Common Terminology Criteria for Adverse Events [CTCAE] v3.0) was also collected at baseline and at the end of each cycle. The primary end point was the incidence of moderate/severe HFS symptoms in the first treatment cycle, based on the patient-reported HFSD. Results The percentage of patients with moderate/severe HFS symptoms was not different between groups, being 13.6% in the ULABTKA arm and 10.2% in the placebo arm (P = .768 by Fisher's exact test). The odds ratio was 1.37 (95% CI, 0.37 to 5.76). Cycle 1 CTCAE skin toxicity was higher in the ULABTKA arm but not significantly so (33% v 27%; P = .82). No significant differences were observed in other toxicities between groups. Conclusion These data do not support the efficacy of a ULABTKA cream for preventing HFS symptoms in patients receiving capecitabine.

Brivanib in Patients With Advanced Hepatocellular Carcinoma Who Were Intolerant to Sorafenib or for Whom Sorafenib Failed: Results From the Randomized Phase III BRISK-PS Study

2013 ◽  
Vol 31 (28) ◽  
pp. 3509-3516 ◽  
Author(s):  
Josep M. Llovet ◽  
Thomas Decaens ◽  
Jean-Luc Raoul ◽  
Eveline Boucher ◽  
Masatoshi Kudo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Controlled Trial ◽  
Objective Response ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Time To Progression ◽  
Fibroblast Growth Factor Receptors ◽  
Double Blind ◽  
Dual Inhibitor

Purpose Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib. Patients and Methods In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety. Results Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%). Conclusion In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.

scholarly journals Melatonin for prevention of postoperative delirium after lower limb fracture surgery in elderly patients (DELIRLESS): study protocol for a multicentre randomised controlled trial

BMJ Open ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. e053908
Author(s):  
Stéphanie Sigaut ◽  
Camille Couffignal ◽  
Marina Esposito-Farèse ◽  
Vincent Degos ◽  
Serge Molliex ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Lower Limb ◽  
Postoperative Delirium ◽  
Controlled Trial ◽  
Functional Decline ◽  
Assessment Method ◽  
Phase Iii ◽  
Double Blind ◽  
Prolonged Length ◽  
Surgery In Elderly

IntroductionPostoperative delirium (POD) is one of the most frequent complication after surgery in elderly patients, and is associated with increased morbidity and mortality, prolonged length of stay, cognitive and functional decline leading to loss of autonomy, and important additional healthcare costs. Perioperative inflammatory stress is a key element in POD genesis. Melatonin exhibits antioxidative and immune-modulatory proprieties that are promising concerning delirium prevention, but in perioperative context literature are scarce and conflicting. We hypothesise that perioperative melatonin can reduce the incidence of POD.Methods and analysisThe DELIRLESS trial is a prospective, national multicentric, phase III, superiority, comparative randomised (1:1) double-blind clinical trial. Among patients aged 70 or older, hospitalised and scheduled for surgery of a severe fracture of a lower limb, 718 will be randomly allocated to receive either melatonin 4 mg per os or placebo, every night from anaesthesiologist preoperative consultation and up to 5 days after surgery. The primary outcome is POD incidence measured by either the French validated translation of the Confusion Assessment Method (CAM) score for patients hospitalised in surgery, or CAM-ICU score for patients hospitalised in ICU (Intensive Care Unit). Daily delirium assessment will take place during 10 days after surgery, or until the end of hospital stay if it is shorter. POD cumulative incidence function will be compared at day 10 between the two randomised arms in a competing risks framework, using the Fine and Grey model with death as a competing risk of delirium.Ethics and disseminationThe DELIRLESS trial has been approved by an independent ethics committee the Comité de Protection des Personnes (CPP) Sud-Est (ref CPP2020-18-99 2019-003210-14) for all study centres. Participant recruitment begins in December 2020. Results will be published in international peer-reviewed medical journals.Trial registration numberNCT04335968, first posted 7 April 2020.Protocol version identifierN°3–0, 3 May 2021.

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