Application and impact of run-in studies

Fralick, Michael; Avorn, Jerry; Franklin, Jessica M.; Abdurrob, Abdurrahman; Kesselheim, Aaron S.

doi:10.1007/s11606-018-4344-7

Cited by 17 publications

(18 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, it should be noted that clinical trialists have used very similar principles to modify conventional RCT design via the use of placebo run-in periods prior to the RCT. 74,75 One of the primary aims of the placebo run-in is to identify and exclude high placebo responders due to concerns that elevated placebo effects may negatively impact the interpretation of the trial and its results. We are not arguing in favor of this somewhat contentious protocol but using it as an example to show precedent for trial design modifications based on interpreting enhanced placebo effects.…”

Section: Discussionmentioning

confidence: 99%

Challenges of differential placebo effects in contemporary medicine: The example of brain stimulation

Burke

Kaptchuk

Pascual‐Leone

2019

Annals of Neurology

View full text Add to dashboard Cite

‘Differential placebo effects’ is the concept that different types of placebos (e.g. inert pill versus sham device) may yield different magnitudes of placebo effects. This issue has been pushed into the spotlight by recent clinical trials of new technologies reporting unexpectedly large placebo effects from sham devices/procedures needed to maintain blinding integrity. In this Neurology Grand Rounds, we use transcranial magnetic stimulation as a model to explore the principles and implications of differential placebo effects. We highlight emerging research on the neurobiology of placebo effects and analyze fundamental questions of measuring efficacy in contemporary medicine.

show abstract

Section: Discussionmentioning

confidence: 99%

Challenges of differential placebo effects in contemporary medicine: The example of brain stimulation

Burke

Kaptchuk

Pascual‐Leone

2019

Annals of Neurology

View full text Add to dashboard Cite

show abstract

“…Data were collected for each patient (table 1 and appendix 3) on the basis of diagnoses and procedures recorded during health encounters, including chronic medical conditions, diabetes severity, amputation risk, healthcare use, recent clinic appointments, drugs for treatment of diabetes and non-diabetes related drugs. These variables were selected a priori based on available literature, clinical experience, and expert opinion 222324…”

Section: Methodsmentioning

confidence: 99%

“…These variables were selected a priori based on available literature, clinical experience, and expert opinion. 22 23 24 …”

Section: Methodsmentioning

confidence: 99%

Risk of amputation with canagliflozin across categories of age and cardiovascular risk in three US nationwide databases: cohort study

Fralick

Kim

Schneeweiß

et al. 2020

BMJ

View full text Add to dashboard Cite

ObjectiveTo estimate the rate of lower limb amputation among adults newly prescribed canagliflozin according to age and cardiovascular disease.DesignPopulation based, new user, cohort study.Data sourcesTwo commercial and Medicare claims databases, 2013-17.ParticipantsPatients newly prescribed canagliflozin were propensity score matched 1:1 with patients newly prescribed a glucagon-like peptide-1 (GLP-1) receptor agonist. Hazard ratios and rate differences per 1000 person years were computed for the rate of lower limb amputation in the following four groups: group 1, patients aged less than 65 years without baseline cardiovascular disease; group 2, patients aged less than 65 with baseline cardiovascular disease; group 3, patients aged 65 or older without baseline cardiovascular disease; group 4, patients aged 65 or older with baseline cardiovascular disease. Within each group, pooled hazard ratio and rate difference per 1000 person years were calculated by meta-analysis.InterventionCanagliflozin versus a GLP-1 agonist.Main outcome measuresLower limb amputation requiring surgery.ResultsAcross the three databases, 310 840 propensity score matched adults who started canagliflozin or a GLP-1 agonist were identified. The hazard ratio and rate difference per 1000 person years for amputation in adults receiving canagliflozin compared with a GLP-1 agonist for each group was: group 1, hazard ratio 1.09 (95% confidence interval 0.83 to 1.43), rate difference 0.12 (−0.31 to 0.55); group 2, hazard ratio 1.18 (0.86 to 1.62), rate difference 1.06 (−1.77 to 3.89); group 3, hazard ratio 1.30 (0.52 to 3.26), rate difference 0.47 (−0.73 to 1.67); and group 4, hazard ratio 1.73 (1.30 to 2.29), rate difference 3.66 (1.74 to 5.59).ConclusionsThe increase in rate of amputation with canagliflozin was small and most apparent on an absolute scale for adults aged 65 or older with baseline cardiovascular disease, resulting in a number needed to treat for an additional harmful outcome of 556 patients at six months (that is, 18 more amputations per 10 000 people who received canagliflozin). These results help to contextualize the risk of amputation with canagliflozin in routine care.

show abstract

“…DPP-4 inhibitors were selected as the comparator medication because they are commonly prescribed to older adults, are a second-line medication for adults with diabetes, and are not associated with a decreased risk of heart failure. [17][18][19] In addition, DPP-4 inhibitors are the most commonly used comparator medications for pharmacoepidemiological studies of SGLT2 inhibitors. [20][21][22] While there is controversy about whether DPP-4 inhibitors are associated with an increased risk of heart failure, a recent meta-analysis of randomized trials suggested no increased risk of heart failure (relative risk 1.06, 95% confidence interval [CI] 0.96,1.17).…”

Section: Methodsmentioning

confidence: 99%

Sodium‐glucose co‐transporter‐2 inhibitors versus dipeptidyl peptidase‐4 inhibitors and the risk of heart failure: A nationwide cohort study of older adults with diabetes mellitus

Fralick

Colacci

Thiruchelvam

et al. 2021

Diabetes Obesity Metabolism

Self Cite

View full text Add to dashboard Cite

Aims To analyse the rate of heart failure hospitalization for older adults prescribed a sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor. Materials and Methods The study cohort included adults aged 66 years and older diagnosed with diabetes mellitus in Ontario, Canada, between July 2015 and March 2019, who received either an SGLT2 inhibitor or a dipeptidyl peptidase‐4 (DPP‐4) inhibitor. The primary outcome was a composite of heart failure hospitalization and all‐cause mortality. Secondary outcomes included diabetic ketoacidosis and hypoglycaemia. Results A total of 29 916 adults prescribed an SGLT2 inhibitor were compared with 29 916 adults prescribed a DPP‐4 inhibitor. The mean age was 72 years, 60% were men, the baseline glycated haemoglobin concentration was 8.2% and the baseline creatinine was 89 μmol/L. The incidence rate of the primary outcome was 19/1000 person‐years for adults prescribed an SGLT2 inhibitor compared to 38/1000 person‐years in those prescribed a DPP‐4 inhibitor. This resulted in a hazard ratio (HR) of 0.49 (95% confidence interval [CI] 0.45, 0.54) and a rate difference (RD) of 19 fewer events per 1000 person‐years (RD –19 [95% CI –22, –17]). Patients prescribed an SGLT2 inhibitor also had a lower rate of hypoglycaemia (HR 0.61 [95% CI 0.46, 0.81); RD –1.6 [95% CI –2.4, –0.8]), but a higher rate of diabetic ketoacidosis (HR 1.84 [95% CI 1.26, 2.70]; RD 1.0 [95% CI 0.4, 1.6]). Conclusions Older adults prescribed an SGLT2 inhibitor had a lower rate of heart failure hospitalization or death, and a lower rate of hypoglycaemia, but an increased rate of diabetic ketoacidosis compared to older adults prescribed a DPP‐4 inhibitor.

show abstract

Application and impact of run-in studies

Abstract: Trials with run-in phases provided similar estimates for medication efficacy and safety compared to trials without run-in phases. Because run-in phases are costly and time-consuming, these results call their utility into question for clinical trials of short duration.

Cited by 17 publications

References 19 publications

Challenges of differential placebo effects in contemporary medicine: The example of brain stimulation

Challenges of differential placebo effects in contemporary medicine: The example of brain stimulation

Risk of amputation with canagliflozin across categories of age and cardiovascular risk in three US nationwide databases: cohort study

Sodium‐glucose co‐transporter‐2 inhibitors versus dipeptidyl peptidase‐4 inhibitors and the risk of heart failure: A nationwide cohort study of older adults with diabetes mellitus

Contact Info

Product

Resources

About