Factors Influencing the Placebo Effect in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension: An Analysis of Two Randomized Clinical Trials

<div><p>Objective</p><p>To explore factors related to the placebo effect in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OH).</p><p>Methods</p><p>This was a retrospective cohort study of patients with POAG and patients with OH who were treated with placebo. The patients’ data were extracted from two randomized, double-masked, parallel, multicenter clinical trials (trial 1 and trial 2) in Japan. We explored the baseline factors that were associated with the intraocular pressure (IOP)-lowering effect of placebo ophthalmic solution after 4 weeks of instillation treatment at two time points by using multivariable models. The time points were Hour 0 (between 08:30 and 10:30 before instillation) and Hour 2 (within 1.5 to 2.5 h after instillation and by 12:30) at the baseline date and after 4 weeks. The changes in IOP from baseline to 4 weeks at the two time points were evaluated for the IOP-lowering effect induced by placebo instillation.</p><p>Results</p><p>Of the 330 patients included in the two trials, 89 patients were eligible for the analysis. The results of the multivariable analysis for Hour 0 indicated a high IOP at the baseline date (coefficient: 0.24, 95% confidence interval (CI): 0.02 to 0.46, P = 0.03), and the magnitude of the IOP fluctuation at the baseline date (coefficient: 0.57, 95% CI: 0.24 to 0.90, P = 0.001) was associated with the IOP-lowering effect after 4 weeks. With respect to Hour 2, the trial type was associated with the IOP-lowering effect (coefficient: -1.15, 95% CI: -2.14 to -0.16, P = 0.02).</p><p>Conclusions</p><p>A large fluctuation in IOP during the day is associated with the IOP-lowering effect induced by placebo in patients with POAG or OH. This finding would be helpful to researchers when designing studies related to glaucoma in the early stages of clinical development of drugs.</p></div

Flow diagram of the subject selection process.

<p>Flow diagram of the subject selection process.</p

Meta-analysis of risk ratio of the adverse drug reaction for cough.

<p>Error bars indicate 95% CIs; ARB, angiotensin receptor blocker; ACEI, angiotensin converting enzyme inhibitor; RR, risk ratio. Diamonds represent pooled RR with 95% CI.</p

Headache incidence in clinical trials of angiotensin receptor blockers by comparator drugs.

a<p>Part of the data include number of events, instead of number of patients.</p>b<p>One trial included one Losartan arm and one Irbesartan arm (Yoshinaga, 2008 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075027#pone.0075027-Yoshinaga4" target="_blank">[21]</a>).</p><p>ARB, angiotensin receptor blocker; ACEI, angiotensin converting enzyme inhibitor; ADR, adverse drug reaction; AE, adverse event; NA, not applicable.</p

Cough incidence in clinical trials of angiotensin receptor blockers by comparator drugs.

a<p>Part of the data include number of events, instead of number of patients.</p>b<p>One trial included one Losartan arm and one Irbesartan arm (Yoshinaga, 2008 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075027#pone.0075027-Yoshinaga4" target="_blank">[21]</a>).</p><p>ARB, angiotensin receptor blocker; ACEI, angiotensin converting enzyme inhibitor; ADR, adverse drug reaction; AE, adverse event; NA, not applicable.</p

Features and prognosis of patients with lupus nephritis receiving glucocorticoid treatment: a descriptive study using a Japanese claims database

Objective: To evaluate the status of lupus nephritis treatment particularly regarding the need for intensification of treatment in Japan from 2010 to 2019 using a large-scale claims database. Methods: This descriptive study included adult lupus nephritis patients who were administered glucocorticoid equivalent to ≥15 mg prednisolone as the initial dose. After summarizing patient characteristics, we assessed the rate of treatment intensification using the Kaplan–Meier method among six groups based on initial dose of glucocorticoid. Results: We identified 403 patients (mean age, 42.7 years; 68.5% women) with the median initial glucocorticoid dose of 30 mg/day prednisolone equivalent. We observed 56 treatment intensifications; the incidence rate was 71.3 per 1,000 person-years (95% confidence interval: 52.6–90.0). The rate in higher glucocorticoid dose groups was higher than that in lower glucocorticoid dose groups. Conclusions: We found that the rate of treatment intensification was higher in the high-dose glucocorticoid groups than in the low-dose glucocorticoid groups. Further studies are needed to clarify the relationship between the initial dose of glucocorticoids and the prognosis of lupus nephritis patients.</p

Biased Safety Reporting in Blinded Randomized Clinical Trials: Meta-Analysis of Angiotensin Receptor Blocker Trials

<div><p>Background</p><p>Cough is listed as an adverse drug reaction (ADR) on the labels of angiotensin receptor blockers (ARB). However, a causal association with cough has also been reported for angiotensin converting enzyme inhibitors (ACEI), which have frequently been used as comparator drugs in the registration clinical trials of ARBs. This prompted us to examine the possible influence of using comparator drugs with well-known ADRs on the safety reporting of investigational drugs in blinded randomized clinical trials.</p><p>Methods and Findings</p><p>The double-blinded, randomized clinical trials with comparator drugs were identified in the Japanese dossiers for the new drug applications of ARBs. The risk ratios (RR) of reporting cough and headache in ARB arms were calculated for each ARB by comparing trials using ACEIs and trials using non-ACEIs, were then combined with a meta-analysis. 23 trials with a total of 6643 patients were identified, consisting 6 trials using an ACEI comparator including 819 ARB patients and 17 trials using a non-ACEI comparator including 5824 ARB patients. The combined RR of cough reporting was significantly elevated (20.77; 95% confidence interval [CI], 7.47 to 57.76), indicating more frequent reporting of cough in clinical trials using an ACEI comparator. In contrast, the combined RR of headache, a negative control, was insignificant (1.45; 95% CI, 0.34 to 6.22).</p><p>Conclusion</p><p>The use of comparators with well-known ADRs in blinded randomized trials produces potential bias in the reporting frequency of ADRs for investigational drugs. The selection of appropriate comparator drugs should be critical in unbiased safety assessment in double-blinded, randomized clinical trials and thus have relevance in reviewing the safety results from a regulatory point of view.</p></div

Baseline characteristics of study participants (N = 89).

<p>Baseline characteristics of study participants (N = 89).</p

Association between dose reduction of renin-angiotensin-aldosterone system inhibitors before coronary artery angiography and acute kidney injury: a propensity score-matched study

Objective: The aim of this study was to investigate the association between dose reduction of renin-angiotensin-aldosterone system inhibitors (RAASis) and Acute kidney injury (AKI). AKI, which is commonly observed in hospitalized patients, increases mortality. Although RAASis and coronary artery angiography (CAG) are reported to be risk factors for AKI, whether dose reduction of RAASis can prevent AKI after CAG remains unknown. Methods: In this retrospective propensity score (PS)-matched cohort from the RWD database, which includes 20 million patients from 190 hospitals in Japan, we examined the impact of dose reduction of RAASis on the development of AKI after CAG. The subjects were patients with an estimated glomerular filtration rate (eGFR) of 15-60 ml/min/1.73 m2, and the exposure of interest was the presence of a dose reduction in RAASis within 3 days before CAG was performed. Propensity score matching was performed with 19 baseline characteristics using a logistic regression model. Results: We identified 3,329 patients who were prescribed RAASis at least one month before admission and underwent CAG. Six hundred seventy-nine patients had a dose reduction 3 days prior to undergoing CAG, and 2,655 patients did not. AKI was observed in 34 (5.0%) patients in the reduction group and 137 (5.2%) patients in the control group. There was no significant difference in the primary outcome between the two groups in the PS-matched cohort (OR: 1.08, 95% CI: 0.70-1.66). Conclusions: A reduction in the dose of RAASis did not prevent the development of AKI among patients undergoing CAG.</p

Meta-analysis of risk ratio of the adverse event for cough.

<p>Error bars indicate 95% CIs; ARB, angiotensin receptor blocker; ACEI, angiotensin converting enzyme inhibitor; RR, risk ratio. Diamonds represent pooled RR with 95% CI.</p