Baseline severity and the prediction of placebo response in clinical trials for alcohol dependence: A meta-regression analysis to develop an enrichment strategy.

BACKGROUND: There is considerable unexplained variability in alcohol abstinence rates (AR) in the placebo groups of randomized controlled trials (RCTs) for alcohol dependence (AD). This is of particular interest because placebo responses correlate negatively with treatment effect size. Recent evidence suggests that the placebo response is lower in very heavy drinkers who show no "spontaneous improvement" prior to treatment initiation (high-severity population) than in a mild-severity population and in studies with longer treatment duration. We systematically investigated the relationship between population severity, treatment duration, and the placebo response in AR to inform a strategy aimed at reducing the placebo response and thereby increasing assay sensitivity in RCTs for AD. METHODS: We conducted a systematic literature review on placebo-controlled RCTs for AD.We assigned retained RCTs to high- or mild-severity groups of studies based on baseline drinking risk levels and abstinence duration before treatment initiation. We tested the effects of population severity and treatment duration on the placebo response in AR using meta-regression analysis. RESULTS: Among the 19 retained RCTs (comprising 1996 placebo-treated patients), 11 trials were high-severity and 8 were mild-severity RCTs. The between-study variability in AR was lower in the high-severity than in the mild-severity studies (interquartile range: 7.4% vs. 20.9%). The AR in placebo groups was dependent on population severity (p = 0.004) and treatment duration (p = 0.017) and was lower in the high-severity studies (16.8% at 3 months) than the mild-severity studies (36.7% at 3 months). CONCLUSIONS: Pharmacological RCTs for AD should select high-severity patients to decrease the magnitude and variability in the placebo effect and and improve the efficiency of drug development efforts for AD.

Alcohol dependence and very high risk level of alcohol consumption: a life-threatening and debilitating disease.

Women and men with alcohol dependence and very high risk drinking level (VHRDL; defined as drinking >60 or 100 g of ethanol per day, respectively) experience severe health consequences; however, data on the number of these individuals and their health risks are limited. This study estimated (1) the prevalence of VHRDL in 13 European Union (EU) countries among people 15-65 years of age, (2) the risk of disease and injury occurrence associated with VHRDL, (3) the proportion of deaths in nine EU countries attributable to VHRDL and (4) the life expectancy of people in France with VHRDL. Prevalence estimates of VHRDL were based on data obtained from clinical trials and the Global Information System on Alcohol and Health. The risk of disease and injury occurrence was estimated using microsimulations. Population-attributable fractions (PAFs) were estimated using a Levin-based methodology. The estimated prevalence of VHRDL in the 13 EU countries examined was 0.74-0.85 percent, with a disease and injury occurrence risk of 13.5 per 100 people with VHRDL per year. For the nine EU countries examined, VHRDL caused 53.6 percent of all liver cirrhosis, 43.8 percent of all pancreatitis and 41.1 percent of oral cavity and pharyngeal cancers (all other PAFs were below 30 percent). Applying these PAFs to French mortality data resulted in a life expectancy of 47-61 years for people with VHRDL-21-35 years less than the general population. These results indicate that the health burdens of VHRDL are potentially large, and interventions targeting VHRDL should be considered when formulating public health policies.

Budget Impact Analysis of Expanding Gliflozin Coverage in the CKD Population: A French Perspective.

INTRODUCTION: Gliflozins have historically been indicated for type 2 diabetes in France. However, their efficacy has recently been demonstrated in heart failure and chronic kidney disease (CKD), with positive recommendations by Haute Autorité de Santé for gliflozin therapies in these indications. The study objective was to investigate the 5-year budget impact associated with the introduction of gliflozins in addition to standard therapy in people with CKD and elevated albuminuria, regardless of diabetes status, from the perspective of the French healthcare system. METHODS: A budget impact model was developed to estimate the 5-year implications of incorporating gliflozins in the treatment of patients with CKD in France, using efficacy data from the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial. Direct medical costs associated with drug acquisition and management, treatment-related adverse events, dialysis and kidney transplantation, and adverse clinical outcomes were considered. Market share forecasts were estimated from historical data and expert opinions. Event rates were derived from trial data, while cost data were sourced from published estimates. RESULTS: The introduction of gliflozins was estimated to be cost saving compared to the no gliflozins scenario, with an expected cumulative 5-year budget impact of -€650 million, driven by slowed disease progression in patients treated with gliflozins, with fewer patients cumulatively progressing to end-stage kidney disease (84,526 vs. 92,062). This, in addition to fewer hospitalisations for heart failure and deaths from any cause, led to substantial medical care cost offsets (kidney-related: - €894 million; hospitalisation for heart failure: - €14.3 million; end-of-life care: - €17.3 million) to the additional drug acquisition (€273 million) and treatment-related adverse events costs (€2.98 million). CONCLUSION: In concert with early diagnosis and proactive management of CKD, the expansion of the gliflozin indications into the French CKD population presents the opportunity to reduce the substantial burden associated with cardio-renal complications which outweighs the additional cost of the new treatment. INFOGRAPHIC.

Sodium oxybate for the maintenance of abstinence in alcohol-dependent patients: An international, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Sodium oxybate (SMO) has been shown to be effective in the maintenance of abstinence (MoA) in alcohol-dependent patients in a series of small randomized controlled trials (RCTs). These results needed to be confirmed by a large trial investigating the treatment effect and its sustainability after medication discontinuation. AIMS: To confirm the SMO effect on (sustained) MoA in detoxified alcohol-dependent patients. METHODS: Large double-blind, randomized, placebo-controlled trial in detoxified adult alcohol-dependent outpatients (80% men) from 11 sites in four European countries. Patients were randomized to 6 months SMO (3.3-3.9 g/day) or placebo followed by a 6-month medication-free period. Primary outcome was the cumulative abstinence duration (CAD) during the 6-month treatment period defined as the number of days with no alcohol use. Secondary outcomes included CAD during the 12-month study period. RESULTS: Of the 314 alcohol-dependent patients randomized, 154 received SMO and 160 received placebo. Based on the pre-specified fixed-effect two-way analysis of variance including the treatment-by-site interaction, SMO showed efficacy in CAD during the 6-month treatment period: mean difference +43.1 days, 95% confidence interval (17.6-68.5; p = 0.001). Since significant heterogeneity of effect across sites and unequal sample sizes among sites (n = 3-66) were identified, a site-level random meta-analysis was performed with results supporting the pre-specified analysis: mean difference +32.4 days, p = 0.014. The SMO effect was sustained during the medication-free follow-up period. SMO was well-tolerated. CONCLUSIONS: Results of this large RCT in alcohol-dependent patients demonstrated a significant and clinically relevant sustained effect of SMO on CAD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04648423.

Treating alcohol dependence with an abuse and misuse deterrent formulation of sodium oxybate: Results of a randomised, double-blind, placebo-controlled study.

Sodium oxybate (SMO) has been approved in Italy and Austria for the maintenance of abstinence in alcohol dependent (AD) patients. Although SMO is well tolerated in AD patients, cases of abuse and misuse have been reported outside the therapeutic setting. Here we report on a phase IIb double-blind, randomized, placebo-controlled trial for the maintenance of abstinence in AD patients with a new abuse and misuse deterrent formulation of SMO. A total of 509 AD patients were randomized to 12 weeks of placebo or one of four SMO doses (0.75, 1.25, 1.75 or 2.25 g t.i.d.) followed by a one-week medication-free period. The primary endpoint was the percentage of days abstinent (PDA) at end of treatment. An unexpectedly high placebo response (mean 73%, median 92%) was observed. This probably compromised the demonstration of efficacy in the PDA, but several secondary endpoints showed statistically significant improvements. A post-hoc subgroup analysis based on baseline severity showed no improvements in the mild group, but statistically significant improvements in the severe group: PDA: mean difference +15%, Cohen's d = 0.42; abstinence: risk difference +18%, risk ratio = 2.22. No safety concerns were reported. Although the primary endpoint was not significant in the overall population, several secondary endpoints were significant in the intent-to-treat population and post-hoc results showed that treatment with SMO was associated with a significant improvement in severe AD patients which is consistent with previous findings. New trials are warranted that take baseline severity into consideration.