Missing data in clinical trials can have a major effect on the validity of the inferences that can be drawn from the trial. This article reviews methods for preventing missing data and, failing that, ...dealing with data that are missing.
Background
Missing data have seriously compromised inferences from clinical trials, yet the topic has received little attention in the clinical-trial community.
1
Existing regulatory guidances
2
–
4
on the design, conduct, and analysis of clinical trials have little specific advice on how to address the problem of missing data. A recent National Research Council (NRC) report
5
on the topic seeks to address this gap, and this article summarizes some of the main findings and recommendations of that report. The authors of this article served on the panel that prepared the report.
Missing data have seriously compromised inferences from clinical trials.
1
For example, . . .
Revisiting FDA Approval of Aducanumab Alexander, G. Caleb; Knopman, David S; Emerson, Scott S ...
The New England journal of medicine,
08/2021, Letnik:
385, Številka:
9
Journal Article
Recenzirano
Given the scientific, regulatory, and clinical implications of the accelerated FDA approval of aducanumab for Alzheimer’s disease, it’s essential to consider beta-amyloid’s suitability as a surrogate ...end point. Doing so casts doubt on the wisdom of the decision.
In a trial in patients with cardiovascular disease and overweight or obesity but no diabetes, semaglutide was superior to placebo in lowering the risk of major adverse cardiovascular events at a mean ...follow-up of 39.8 months.
Aims/hypothesis
The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed ...the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality.
Methods
In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population.
Results
There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96;
p
= 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50;
p
< 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA
1c
, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group.
Conclusions/interpretation
The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect.
Trial registration
ClinicalTrials.gov
NCT01959529
Cardiovascular disease (CVD) is a major cause of morbidity and mortality. Although it has been widely appreciated that obesity is a major risk factor for CVD, treatments that produce effective, ...durable weight loss and the impact of weight reduction in reducing cardiovascular risk have been elusive. Instead, progress in CVD risk reduction has been achieved through medications indicated for controlling lipids, hyperglycemia, blood pressure, heart failure, inflammation, and/or thrombosis. Obesity has been implicated as promoting all these issues, suggesting that sustained, effective weight loss may have independent cardiovascular benefit. GLP-1 receptor agonists (RAs) reduce weight, improve glycemia, decrease cardiovascular events in those with diabetes, and may have additional cardioprotective effects. The GLP-1 RA semaglutide is in phase 3 studies as a medication for obesity treatment at a dose of 2.4 mg subcutaneously (s.c.) once weekly. Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) is a randomized, double-blind, parallel-group trial testing if semaglutide 2.4 mg subcutaneously once weekly is superior to placebo when added to standard of care for preventing major adverse cardiovascular events in patients with established CVD and overweight or obesity but without diabetes. SELECT is the first cardiovascular outcomes trial to evaluate superiority in major adverse cardiovascular events reduction for an antiobesity medication in such a population. As such, SELECT has the potential for advancing new approaches to CVD risk reduction while targeting obesity.
Aims/hypothesis
The Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) was a double-blind, ...randomised, event-driven, treat-to-target prospective trial comparing the cardiovascular safety of insulin degludec with that of insulin glargine U100 (100 units/ml) in patients with type 2 diabetes at high risk of cardiovascular events. This paper reports a secondary analysis investigating associations of day-to-day fasting glycaemic variability (pre-breakfast self-measured blood glucose SMBG) with severe hypoglycaemia and cardiovascular outcomes.
Methods
In DEVOTE, patients with type 2 diabetes were randomised to receive insulin degludec or insulin glargine U100 once daily. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In this article, day-to-day fasting glycaemic variability was based on the standard deviation of the pre-breakfast SMBG measurements. The variability measure was calculated as follows. Each month, only the three pre-breakfast SMBG measurements recorded before contact with the site were used to determine a day-to-day fasting glycaemic variability measure for each patient. For each patient, the variance of the three log-transformed pre-breakfast SMBG measurements each month was determined. The standard deviation was determined as the square root of the mean of these monthly variances and was defined as day-to-day fasting glycaemic variability. The associations between day-to-day fasting glycaemic variability and severe hypoglycaemia, MACE and all-cause mortality were analysed for the pooled trial population with Cox proportional hazards models. Several sensitivity analyses were conducted, including adjustments for baseline characteristics and most recent HbA
1c
.
Results
Day-to-day fasting glycaemic variability was significantly associated with severe hypoglycaemia (HR 4.11, 95% CI 3.15, 5.35), MACE (HR 1.36, 95% CI 1.12, 1.65) and all-cause mortality (HR 1.58, 95% CI 1.23, 2.03) before adjustments. The increased risks of severe hypoglycaemia, MACE and all-cause mortality translate into 2.7-, 1.2- and 1.4-fold risk, respectively, when a patient’s day-to-day fasting glycaemic variability measure is doubled. The significant relationships of day-to-day fasting glycaemic variability with severe hypoglycaemia and all-cause mortality were maintained after adjustments. However, the significant association with MACE was not maintained following adjustment for baseline characteristics with either baseline HbA
1c
(HR 1.19, 95% CI 0.96, 1.47) or the most recent HbA
1c
measurement throughout the trial (HR 1.21, 95% CI 0.98, 1.49).
Conclusions/interpretation
Higher day-to-day fasting glycaemic variability is associated with increased risks of severe hypoglycaemia and all-cause mortality.
Trial registration
ClinicalTrials.gov
NCT01959529
Background Overtreatment poses a challenge to healthcare systems due to harmful consequences of avoidable side-effects and costs. This study presents the first account for examining the feasibility ...of placebo use for reducing overtreatment in primary care, including whether public attitudes support the use of different placebo types in place of inappropriate prescriptions of antibiotics, antidepressants, or analgesics. Methods We used a multi-study, mixed-methods design, including patient and public (PPI) consultations, focus groups (Study 1) and two pre-registered online experiments (Studies 2 and 3). Results Study 1 (N = 16) explored everyday conceptions and practicalities of potential placebo use in the context of respiratory infections. Findings highlighted the importance of trusting doctor-patient relationships and safety-netting. Study 2 employed a randomised experiment with a representative UK sample (N = 980), investigating attitudes towards 5 different treatment options for respiratory infections: (1) blinded + pure placebo, (2) open-label + pure placebo, (3) open-label + impure placebo, (4) antibiotic treatment, and (5) no treatment. Study 2 also examined how attitudes varied based on wording and individual differences. Findings indicated general support (η.sub.p.sup.2 = .149, large effect size) for replacing inappropriate antibiotics with open-label + impure placebos, although personal placebo acceptability was lower. Also, older people, individuals suffering from chronic illness or those showing higher levels of health anxiety appeared less amenable to placebo use. Study 3 (N = 1177) compared attitudes towards treatment options across three clinical scenarios: respiratory infection, depression and pain. Findings suggested significant differences in the acceptability of placebo options based on the clinical context. In the infection scenario, options for open-label + pure placebos, open-label + impure placebos and no treatment were rated significantly more acceptable (η.sub.p.sup.2 = .116, medium effect size) compared to the depression and pain scenarios. Again, general support for placebos was higher than placebo acceptability for personal use. Conclusions Findings from PPI and three studies indicate general support for combatting overprescribing in primary care through clinical placebo use. This is an indicator for wider UK public support for a novel, behavioural strategy to target a long-standing healthcare challenge. General acceptability appears to be highest for the use of open-label + impure placebos in the context of antibiotic overprescribing. Keywords: Placebos, Open-label placebos, Overtreatment, Overprescribing, Antibiotics, Antidepressants, Analgesics, Antimicrobial resistance, Antimicrobial stewardship, Primary care
Objective
This paper describes the baseline characteristics of the Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) study, one of the largest ...cardiovascular (CV) outcome studies in the field of obesity, which evaluates the effect of semaglutide versus placebo on major CV events.
Methods
SELECT enrolled individuals with overweight or obesity without diabetes, with prior myocardial infarction, stroke, and/or peripheral artery disease. This study reports participants' baseline characteristics in the full study population and subgroups defined by baseline glycated hemoglobin (HbA1c; <5.7%, ≥5.7 to <6.0%, ≥6.0 to <6.5%), baseline waist to height ratio tertile, and qualifying prior CV event or condition.
Results
The study enrolled 17,605 participants (72.5% male) with an average (SD) age of 61.6 (8.9) years and BMI of 33.34 (5.04) kg/m2. The most common prior CV event was myocardial infarction (76.3% of participants), followed by stroke (23.3%) and peripheral artery disease (8.6%). Furthermore, 24.3% had a heart failure diagnosis. Two‐thirds of participants (66%) had HbA1c in the prediabetes range (5.7%‐6.4%). Across groups of increasing HbA1c, prevalence of all CV risk factors increased.
Conclusions
The enrolled population in SELECT includes participants across a broad range of relevant risk categories. This will allow the study to garner information about the CV benefits of semaglutide across these relevant clinical subgroups.
The plasma membrane (PM) contains redox enzymes that provide electrons for energy metabolism and recycling of antioxidants such as coenzyme Q and α-tocopherol. Brain aging and neurodegenerative ...disorders involve impaired energy metabolism and oxidative damage, but the involvement of the PM redox system (PMRS) in these processes is unknown. Caloric restriction (CR), a manipulation that protects the brain against aging and disease, increased activities of PMRS enzymes (NADH-ascorbate free radical reductase, NADH-quinone oxidoreductase 1, NADH-ferrocyanide reductase, NADH-coenzyme Q10 reductase, and NADH-cytochrome c reductase) and antioxidant levels (α-tocopherol and coenzyme Q10) in brain PM during aging. Age-related increases in PM lipid peroxidation, protein carbonyls, and nitrotyrosine were attenuated by CR, levels of PMRS enzyme activities were higher, and markers of oxidative stress were lower in cultured neuronal cells treated with CR serum compared with those treated with ad libitum serum. These findings suggest important roles for the PMRS in protecting brain cells against age-related increases in oxidative and metabolic stress.
DEVOTE was designed to evaluate the cardiovascular safety of insulin degludec (IDeg) vs insulin glargine U100 (IGlar) in patients with T2D at high risk of cardiovascular events. DEVOTE is a phase 3b, ...multicenter, international, randomized, double-blind, active comparator-controlled trial, designed as an event-driven trial that would continue until 633 positively adjudicated primary events were accrued. The primary end point was the time from randomization to a composite outcome consisting of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Patients with T2D at high risk of cardiovascular complications were randomized 1:1 to receive either IDeg or IGlar, each added to background therapies. This trial was designed to demonstrate statistical noninferiority of IDeg vs IGlar for the primary end point. DEVOTE enrolled 7,637 patients between October 2013 and November 2014 at 436 sites in 20 countries. Of these, 6,506 patients had prior cardiovascular disease or chronic kidney disease, and the remainder had multiple cardiovascular risk factors. DEVOTE was designed to provide conclusive evidence regarding the cardiovascular safety of IDeg relative to IGlar in a high-risk population of patients with T2D.
PDF
