Perrine Janiaud

Different treatment benefits were estimated by clinical trials performed in adults compared with those performed in children

OBJECTIVE Our main objective was to see whether the therapeutic benefit observed in placebo controlled randomized controlled trials (RCTs) is different between adults and children. STUDY DESIGN AND SETTING We searched three electronic databases for meta-analyses that included double-blind, placebo-controlled RCTs with separate results for adults and children. The selected reviews were classified according to disease and drug used. The heterogeneity of treatment response between adults and children was measured using ratio of odds ratios (RORs). RESULTS We selected 89 meta-analyses and calculated RORs for 124 drugs. Heterogeneity in the direction of the treatment effect was observed in one drug and heterogeneity in the quantity of the treatment effect for 13 drugs, indicating significantly different treatment effect in adults when compared with children. RORs were not significantly different from 1 for 110 drugs. For 36 of these drugs, the treatment effect was confirmed in both populations. CONCLUSION We found different treatment benefits estimated by clinical trials performed in adults compared with those performed in children for 14 of 124 drugs. Data on dose adjustment and child age groups from RCTs were not adequately reported to investigate their influence on the treatment benefit dissimilarities.

Impact of Aldosterone Antagonists on Sudden Cardiac Death Prevention in Heart Failure and Post-Myocardial Infarction Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background and Objectives Sudden cardiac death (SCD) is a severe burden of modern medicine. Aldosterone antagonist is publicized as effective in reducing mortality in patients with heart failure (HF) or post myocardial infarction (MI). Our study aimed to assess the efficacy of AAs on mortality including SCD, hospitalization admission and several common adverse effects. Methods We searched Embase, PubMed, Web of Science, Cochrane library and clinicaltrial.gov for randomized controlled trials (RCTs) assigning AAs in patients with HF or post MI through May 2015. The comparator included standard medication or placebo, or both. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Event rates were compared using a random effects model. Prospective RCTs of AAs with durations of at least 8 weeks were selected if they included at least one of the following outcomes: SCD, all-cause/cardiovascular mortality, all-cause/cardiovascular hospitalization and common side effects (hyperkalemia, renal function degradation and gynecomastia). Results Data from 19,333 patients enrolled in 25 trials were included. In patients with HF, this treatment significantly reduced the risk of SCD by 19% (RR 0.81; 95% CI, 0.67–0.98; p = 0.03); all-cause mortality by 19% (RR 0.81; 95% CI, 0.74–0.88, p<0.00001) and cardiovascular death by 21% (RR 0.79; 95% CI, 0.70–0.89, p<0.00001). In patients with post-MI, the matching reduced risks were 20% (RR 0.80; 95% CI, 0.66–0.98; p = 0.03), 15% (RR 0.85; 95% CI, 0.76–0.95, p = 0.003) and 17% (RR 0.83; 95% CI, 0.74–0.94, p = 0.003), respectively. Concerning both subgroups, the relative risks respectively decreased by 19% (RR 0.81; 95% CI, 0.71–0.92; p = 0.002) for SCD, 18% (RR 0.82; 95% CI, 0.77–0.88, p < 0.0001) for all-cause mortality and 20% (RR 0.80; 95% CI, 0.74–0.87, p < 0.0001) for cardiovascular mortality in patients treated with AAs. As well, hospitalizations were significantly reduced, while common adverse effects were significantly increased. Conclusion Aldosterone antagonists appear to be effective in reducing SCD and other mortality events, compared with placebo or standard medication in patients with HF and/or after a MI.

Is the perceived placebo effect comparable between adults and children? A meta-regression analysis

Background:A potential larger perceived placebo effect in children compared with adults could influence the detection of the treatment effect and the extrapolation of the treatment benefit from adults to children. This study aims to explore this potential difference, using a meta-epidemiological approach.Methods:A systematic review of the literature was done to identify trials included in meta-analyses evaluating a drug intervention with separate data for adults and children. The standardized mean change and the proportion of responders (binary outcomes) were used to calculate the perceived placebo effect. A meta-regression analysis was conducted to test for the difference between adults and children of the perceived placebo effect.Results:For binary outcomes, the perceived placebo effect was significantly more favorable in children compared with adults (β = 0.13; P = 0.001). Parallel group trials (β = −1.83; P < 0.001), subjective outcomes (β = −0.76; P < 0.001), and the disease type significantly influenced the perceived placebo effect.Conclusion:The perceived placebo effect is different between adults and children for binary outcomes. This difference seems to be influenced by the design, the disease, and outcomes. Calibration of new studies for children should consider cautiously the placebo effect in children.

Extrapolation will never replace randomized clinical trials

Current regulatory guidelines suggest that randomized controlled trials for children become mandatory when there are uncertainties on PK-PD data. Our results show, however, that the similarities between efficacies of medicines evaluated both in adults and children are commonly unclear, sometimes conflicting or differ quantitatively. We suggest that the extrapolation process for drug development and clinical practice should be based on a prior synthesis of all available evidence in adults and children and include at least one randomized controlled trial in children. Response to commentary by R. Oostenbrink and S.N. de Wildt (1) on our article (2).

Use of available clinical evidence to extrapolate drug effects from adults to children

The extrapolation of the benefit risk ratio from adults to children is performed during drug development and often implicitly used by many paediatricians when prescribing off-label drugs in children. This is due to the specific constraints of paediatric clinical research leading to a lack of safety and efficacy data in children. Extrapolation frameworks for drug development have been proposed by several regulatory agencies. Using a meta-epidemiological approach, we explored the similarities and differences of the benefit, the benefit risk ratio and the perceived placebo effect between adults and children from meta-analyses including randomized double-blinded placebo-controlled trials evaluating a drug intervention in an indication in adults and children with separate data for both populations. We also explored the use of the effect model using adult data to predict the treatment effect in children and to calibrate future paediatric clinical trials. Our research highlights the importance of using all available evidence and quantitative methods before extrapolating the benefit risk ratio from adults to children and carrying out new studies in the context of the existing evidence. More generally, this should be applied to any research to avoid a waste of time and resources invested.

Mathematical model of T-cell lymphoblastic lymphoma: disease, treatment, cure or relapse of a virtual cohort of patients

T lymphoblastic lymphoma (T-LBL) is a rare type of lymphoma with a good prognosis with a remission rate of 85%. Patients can be completely cured or can relapse during or after a 2-year treatment. Relapses usually occur early after the remission of the acute phase. The median time of relapse is equal to 1 year, after the occurrence of complete remission (range 0.2-5.9 years) (Uyttebroeck et al., 2008). It can be assumed that patients may be treated longer than necessary with undue toxicity.The aim of our model was to investigate whether the duration of the maintenance therapy could be reduced without increasing the risk of relapses and to determine the minimum treatment duration that could be tested in a future clinical trial.We developed a mathematical model of virtual patients with T-LBL in order to obtain a proportion of virtual relapses close to the one observed in the real population of patients from the EuroLB database. Our simulations reproduced a 2-year follow-up required to study the onset of the disease, the treatment of the acute phase and the maintenance treatment phase.

Assessing the effects of solid versus liquid dosage forms of oral medications on adherence and acceptability in children

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of solid versus liquid dosage forms on adherence to and acceptability of oral medications in children. Secondary objectives include assessment of elements of the medication risk/benefit balance influenced by the drug dosage form, such as clinical efficacy and safety, treatment costs and adverse events related to oral administration.

Efficiency of physical therapy on postural imbalance after stroke: study protocol for a systematic review and meta-analysis

Introduction Stroke frequently results in balance disorders, leading to lower levels of activity and a diminution in autonomy. Current physical therapies (PT) aiming to reduce postural imbalance have shown a large variety of effects with low levels of evidence. The objectives are to determine the efficiency of PT in recovering from postural imbalance in patients after a stroke and to assess which PT is more effective. Methods and analysis We will search several databases from inception to October 2015. Only randomised controlled trials assessing PT to recover from poststroke postural imbalance in adults will be considered. Outcome measures will be the Berg Balance Scale (BBS), the Postural Assessment Scale for Stroke (PASS), the ‘weight-bearing asymmetry’ (WBA), the ‘centre of pressure’ (COP) and the ‘limit of stability’ (LOS). WBA, COP and LOS are measured by a (sitting or standing) static evaluation on force plate or another device. Two independent reviewers will screen titles, abstracts and full-text articles, evaluate the risk of bias and will perform data extraction. In addition to the outcomes, measures of independence will be analysed. This study will aim at determining the effects of PT on the function (WBA, COP, LOS), the activity (BBS, PASS) and the independence of patients. Subgroup analyses will be planned according to the location of brain lesion (hemispheric, brainstem or cerebellum), the time since stroke (early, late, chronic), the PT (type, main aim (direct effect or generalisation), overall duration), the type of approaches (top-down or bottom-up) and the methodological quality of studies. Ethics and dissemination No ethical statement will be required. The results will be published in a peer-reviewed journal. This meta-analysis aims at managing the rehabilitation after postural imbalance by PT after a stroke. Trial registration number Prospero CRD42016037966;Pre-results.