Adjusting for switches to multiple treatments: Should switches be handled separately or combined?

Treatment switching is common in randomised controlled trials (RCTs). Participants may switch onto a variety of different treatments, all of which may have different treatment effects. Adjustment analyses that target hypothetical estimands - estimating outcomes that would have been observed in the absence of treatment switching - have focused primarily on a single type of switch.

Is inverse probability of censoring weighting a safer choice than per-protocol analysis in clinical trials?

Deviation from the treatment strategy under investigation occurs in many clinical trials. We term this intervention deviation. Per-protocol analyses are widely adopted to estimate a hypothetical estimand without the occurrence of intervention deviation.

Clinical outcomes for previously treated patients with advanced biliary tract cancer: a meta-analysis.

A systematic review and meta-analysis were performed to evaluate the efficacy of treatments for previously treated advanced biliary tract cancer (BTC) patients. Databases were searched for studies evaluating treatments for advanced (unresectable and/or metastatic) BTC patients who progressed on prior therapy. Pooled estimates of objective response rate (ORR), median overall survival (OS) and median progression-free survival (PFS) were calculated using random effects meta-analysis.

Exploratory analyses of clinical trial data used for health technology assessments: a retrospective evaluation.

Objectives: To examine the validity and statistical limitations of exploratory analyses of clinical trial data commonly requested by agencies responsible for determining which medical products may be financed or reimbursed by a healthcare system.

Design: This was a retrospective review of efficacy and safety analyses conducted for German Health Technology Assessment (HTA) evaluations with a decision date between 2015 and 2020, and an illustrative safety-related exploratory analysis of data from two phase III clinical trials of verubecestat (an anti-amyloid drug whose development was stopped for lack of efficacy) as would be mandated by the German HTA agency.

Results: We identified 422 HTA evaluations of 404 randomised controlled clinical trials.

A risk score for predicting mortality in patients with asymptomatic mild to moderate aortic stenosis.

Background: Prognostic information for asymptomatic patients with aortic stenosis (AS) from prospective studies is scarce and there is no risk score available to assess mortality.

Objectives: To develop an easily calculable score, from which clinicians could stratify patients into high and lower risk of mortality, using data from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study.

Method: A search for significant prognostic factors (p<0.

Outcome of patients with low-gradient "severe" aortic stenosis and preserved ejection fraction.

Background: Retrospective studies have suggested that patients with a low transvalvular gradient in the presence of an aortic valve area < 1.0 cm² and normal ejection fraction may represent a subgroup with an advanced stage of aortic valve disease, reduced stroke volume, and poor prognosis requiring early surgery. We therefore evaluated the outcome of patients with low-gradient "severe" stenosis (defined as aortic valve area < 1.

Impact of baseline severity of aortic valve stenosis on effect of intensive lipid lowering therapy (from the SEAS study).

Retrospective studies have suggested a beneficial effect of lipid-lowering treatment on the progression of aortic stenosis (AS) in milder stages of the disease. In the randomized, placebo-controlled Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, 4.3 years of combined treatment with simvastatin 40 mg and ezetimibe 10 mg did not reduce aortic valve events (AVEs), while ischemic cardiovascular events (ICEs) were significantly reduced in the overall study population.

Observed and predicted reduction of ischemic cardiovascular events in the Simvastatin and Ezetimibe in Aortic Stenosis trial.

In the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, combined ezetimibe (10 mg) and simvastatin (40 mg) decreased low-density lipoprotein cholesterol levels by 50% and ischemic cardiovascular event (ICE) risk by 22% compared to placebo. A larger decrease in ICE risk might have been expected for the degree of lipid-lowering observed. This analysis investigated relations between changes in lipoprotein components (LCs), and ICE risk decrease in the SEAS trial in all patients, by severity of aortic stenosis (AS), and compared to results of other clinical trials.

Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.

Background: Angiotensin-receptor blockers (ARBs) are effective treatments for patients with heart failure, but the relation between dose and clinical outcomes has not been explored. We compared the effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure.

Methods: This double-blind trial was undertaken in 255 sites in 30 countries.

Design of the heart failure endpoint evaluation of AII-antagonist losartan (HEAAL) study in patients intolerant to ACE-inhibitor.

Background: In patients with heart failure and reduced left ventricular ejection fraction, angiotensin receptor blockers have been found to reduce mortality and morbidity and to prevent or reverse left ventricular remodelling, compared to optimized background treatment. In light of these data, The Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL) study was developed to determine whether losartan 150 mg is superior to losartan 50 mg (antihypertensive dose) in reducing morbidity and mortality among patients with symptomatic heart failure who are intolerant of angiotensin-converting enzyme (ACE)-inhibitors.

Aims/methods: To compare the effect of high and moderate doses of losartan on the primary endpoint of all-cause mortality and hospitalisation due to heart failure in patients (n = 3834) with symptomatic heart failure and an ejection fraction < or = 40% who are intolerant of ACE-inhibitor treatment.

Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.

Background: Hyperlipidemia has been suggested as a risk factor for stenosis of the aortic valve, but lipid-lowering studies have had conflicting results.

Methods: We conducted a randomized, double-blind trial involving 1873 patients with mild-to-moderate, asymptomatic aortic stenosis. The patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily.

Design and baseline characteristics of the simvastatin and ezetimibe in aortic stenosis (SEAS) study.

Aortic valve stenosis and atherosclerotic disease have several risk factors in common, in particular, hypercholesterolemia. Histologically, the diseased valves appear to have areas of inflammation much like atherosclerotic plaques. The effect of lipid-lowering therapy on the progression of aortic stenosis (AS) is unclear, and there are no randomized treatment trials evaluating cardiovascular morbidity and mortality in such patients.

Rofecoxib in the acute treatment of migraine: a randomized controlled clinical trial.

Objective: To investigate the efficacy, tolerability, and safety of rofecoxib and ibuprofen for acute migraine treatment.

Background: Rofecoxib was effective and well tolerated in a previous study of treatment of a single migraine attack. We sought to replicate these findings for a single attack and also study the clinical profile of rofecoxib in the acute treatment of multiple migraine attacks.

Montelukast for migraine prophylaxis: a randomized, double-blind, placebo-controlled study.

Objective: To evaluate the efficacy and tolerability of montelukast 20 mg in the prophylactic treatment of migraine.

Background: A previous small open-label study in migraine patients suggested prophylactic efficacy for montelukast, an antagonist of the cysteinyl leukotriene receptor that is used in the treatment of asthma. We sought to confirm these findings in a randomized controlled trial.

Randomized, placebo-controlled trial of rofecoxib in the acute treatment of migraine.

Objective: To investigate the clinical profile of rofecoxib, a long-acting (approximately 17-hour half-life) selective cyclo-oxygenase-2 inhibitor, for the acute treatment of migraine.

Methods: A randomized, double-blind, placebo-controlled, parallel-group study was conducted. Patients age > or =18 treated a moderate or severe migraine headache with placebo (n = 182), rofecoxib 25 mg (n = 183), or rofecoxib 50 mg (n = 192).

A comparison of visual analog scale and categorical ratings of headache pain in a randomized controlled clinical trial with migraine patients.

A visual analog scale (VAS) method of assessing headache pain was compared with a standard categorical four-grade scale (4GS) in a randomized, placebo-controlled, double-blind, clinical trial involving 792 treated migraine outpatients who received oral rizatriptan 5 mg, sumatriptan 50 mg, or placebo for a moderate or severe headache. The VAS and 4GS were equally useful in demonstrating that the active drugs were superior to placebo at reducing headache pain, and in showing that the active drugs were similarly effective. For both rizatriptan and sumatriptan, slightly larger effect sizes were observed with the 4GS compared with the VAS.

Oral rizatriptan versus oral sumatriptan: a direct comparative study in the acute treatment of migraine. Rizatriptan 030 Study Group.

Rizatriptan is a potent, oral, 5-HT1B/1D agonist with more rapid absorption and higher bioavailability than oral sumatriptan. It was postulated that this would result in more rapid onset of effect. This randomized, double-blind, triple-dummy, parallel-groups study compared rizatriptan 5 mg, rizatriptan 10 mg, sumatriptan 100 mg, and placebo in 1268 outpatients treating a single migraine attack.

Time-to-event analysis, or who gets better sooner? An emerging concept in headache study methodology.

Survival analysis, or, more generally, time-to-event analysis, is of interest when the data represent the time to a defined event. While well established in oncology, it has not been widely applied to migraine research, possibly because the data are usually collected intermittently, rather than continuously, and because of the awkwardness of interpreting treatment effect in survival terms. However, it represents an interesting approach for the analysis of time-to-headache relief, which addresses the clinically relevant question of who gets better sooner.

Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females.

Purpose: The safety, tolerability, and pharmacokinetics of intravenous *i.v.) montelukast sodium (Singulair, MK-0476), and the oral bioavailability of montelukast sodium in healthy males and healthy females were studied.

Comparison of the efficacy of simvastatin and standard fibrate therapy in the treatment of primary hypercholesterolemia and combined hyperlipidemia.

Five multicenter, randomized, double-blind, placebo-controlled studies were conducted in France to compare the efficacy and safety of once-daily simvastatin treatment (10-40 mg/day) with conventional therapy with gemfibrozil 900 mg/day, ciprofibrate 100 mg/day, bezafibrate 400 mg/day, and fenofibrate 300 or 400 mg/day in a total of 800 patients with hypercholesterolemia. Simvastatin was associated with statistically significantly greater (p < or = 0.01) mean percent reductions in plasma low-density lipoprotein (LDL) cholesterol compared with each of the five fibrate regimens, even when administered at its recommended starting dose of 10 mg/day.

Comparison of finasteride (Proscar) and Serenoa repens (Permixon) in the inhibition of 5-alpha reductase in healthy male volunteers.

A total of 32 healthy male volunteers (age range 20-30 years) were enrolled in a 1-week open, randomized, placebo-controlled study comparing finasteride (Proscar), a 5 alpha-reductase inhibitor, with Permixon, the plant extract of Serenoa repens. The objective of the study was to evaluate the effect of single and multiple doses of the drugs on the inhibition of 5 alpha-reductase as assessed by serum dihydrotestosterone level determination. Following baseline measurements on day 1, the subjects were randomized to finasteride 5 mg once a day (n = 10), Permixon 80 mg x 2 twice a day (n = 11), or to placebo once a day (n = 11) for 7 days.

Comparison between lovastatin and gemfibrozil in the treatment of primary hypercholesterolemia: the Finnish Multicenter Study.

A randomized, double-blind 12-week comparison of lovastatin and gemfibrozil in the treatment of patients with primary hypercholesterolemia with normal or moderately elevated triglycerides was performed in 334 patients from 19 centers in Finland. Patients with "high" total serum cholesterol (240 to 300 mg/dl) constituted Stratum 1 and patients with "very high" total serum cholesterol (greater than 300 mg/dl) constituted Stratum 2. In Stratum 1, patients were randomly assigned to either lovastatin 20 mg nightly or gemfibrozil 600 mg twice daily, and in Stratum 2 to either lovastatin 40 mg nightly or gemfibrozil 600 mg twice daily.

Desynchronization of the oral temperature circadian rhythm and intolerance to shift work.

The present study tested the hypothesis that subjects with a good tolerance to shift work maintain the circadian period tau of their temperature rhythm equal to 24 h, while tau may differ from 24 h when subjects exhibit one or several clinical signs of intolerance. These latter are mainly: persisting sleep disturbance, persisting fatigue, changes in mood and behaviour, and digestive troubles, from gastritis to overt peptic ulcer. These symptoms were used here to classify the subjects studied.

[Desynchronization of the circadian rhythm of oral temperature in young human subjects with poor tolerance for night work].

15 night workers (mean age, 28 years; mean seniority 1.5 years) volunteered to measure their oral temperature (clinical thermometers 0.05 degrees C precision) 5 times/24 hrs.