Clinical Study Synopsis for Public Disclosure

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1 abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with Boehringer Ingelheim s Policy on Transparency and Publication of Clinical Study Data. The synopsis - which is part of the clinical study report - had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non-approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country. Additional information on this study and the drug concerned may be provided upon request based on Boehringer Ingelheim s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of Boehringer Ingelheim. V1.0/2014

2 BI Trial No.: Page3 2. SYNOPSIS Talsaclidine Volume: to Addendum No.: Study period (years): itle of study: Efficacy and safety of 6, 12, 24, and 36 mg tid po and 36 mg bid po (free base) for 12 weeks in a double-blind, randomised, placebo-controlled parallel group comparison in patients with mild to moderate dementia of Alzheimer type. Investigator: Study centre(s): Australia: Canada: France: Germany: New Zealand: United Kingdom: United States: Publication (reference): Clinical phase: Objectives: Methodology: lib The objective of the trial was to assess the dose-response relationship of symptomatic efficacy of based on ADAScog and to assess safety an tolerability Double-blind, randomised, placebo-controlled parallel group comparison with 24 January 200 I

3 BI Trial No.: Page4 Boehringer Ingelheim Volume: to Addendum No.: Study period (years): No. of subjects entered: total: each treatment: Diagnosis and main criteria for inclusion: Test product: dose: mode of admin.: batch no.: Duration of treatment: Reference therapy: dose: mode of admin.: batch no.: Criteria for evaluation: Efficacy: Safety: Statistical methods: mg tid: 60; 12 mg tid: 55; 24 mg tid: 59; 36 mg tid: 66; 36 mg bid: 62; placebo: 60 Patients with mild to moderate DAT defined by DSM IV and NINCDS-ADRDA criteria (MMS: 10-24, Rosen Ischemia Score:::; 2), over 40 years old with normal liver and kidney function Talsaclidine, free base, tablets 6, 12, 24, 36 mg p.o., tid, 36 mg additionally bid 6 mg: mg: mg: mg: , weeks Placebo p.o , Primary endpoint: ADAScog; Secondary endpoints: ADAScog( +extension, total), MMS, ADCS-CGIC, IADL, NPI, HAMD, Living status Vital functions, ECG, laboratory examination, plasma trough values and adverse event recording Descriptive analysis including confidence intervals of primary and secondary endpoints and of safety variables; linear regression of ADAScog changes from baseline for examining dose-response effects. Plasma levels were evaluated to check drug accumulation and compliance. 24 January 200 I

4 BI Trial No.: Pages Boehringer Ingelheim Volume: to Addendum No.: Study period (years): SUMMARY - CONCLUSIONS: Efficacy results: Cognitive performance as measured by ADAScog, the primary endpoint ofthis study, showed neither a clinically relevant nor any statistically significant effect nor a dose response relationship towards efficacy under treatment with. No difference between total groups and placebo was observed. The results in ADAScog extension were comparable to those in ADAScog. Mini Mental State (MMS) was neither clinically nor statistically significantly improved under treatment with and no dose response was observed. Global impression of change (ADCS-CGIC) was significantly improved in two dose groups (12 mg tid, 36 mg bid). Although the placebo group was the worst, no dose response relationship was detectable. Instrumental activities of daily living (IADL) and analysis of behavioural symptoms (NPI) were not clinically meaningfully or statistically significantly influenced in comparison to placebo, and no dose response relationship was observed. A responder analysis only displayed a significant benefit of 36 mg tid in ADCS-CGIC and IADL. Additionally in ADCS-CGIC the 12 mg tid group improved significantly. This improvement could not be validated by a dose response relationship. Subgroup analyses were performed including segregation of less or more severely ill patients but no clear efficacy signal in any subgroup could be detected. Patients with a MMS score equal or smaller than 18 at baseline (population of more severely ill patients) showed consistently no significant improvement. Influence of different baseline characteristics on efficacy outcome measures remained unclear as these varied between doses and countries. Patients with cholinergic adverse events tend to perform worse in ADAScog. An impact of pre-treatment with AChE-I on efficacy results remains unclear as country differences regarding pre-treatment affected analysis. These country effects concerned both and placebo treated patients. All improvements observed seem to be by chance as these were not consistent with dose. 24 January 2001

5 BI Trial No.: Page 6 Boehringer Ingelheim Volume: to Addendum No.: Study period (years): Safety results: Pharmacokinetics No specific safety concerns resulted from analysis of this trial. Particularly in lower dose ranges (6-12 mg) was well tolerated. There were no clinically relevant changes in vital signs from. Generally a tendency towards more adverse events in the higher dose ranges - especially higher than 24 mg tid - was observed. This becomes particularly obvious, if treatment duration is taken into account. Regarding frequency of adverse events no clear advantage of bid application was observable, however patients under bid regimen showed the longest mean treatment duration as a hint for better tolerability. Cholinergic side effects such as sweating, salivation, nausea, vomiting and others were the most frequently reported adverse events and occurred increasingly with escalating dose in the initial treatment phase, but were in most cases transient. Talsaclidine led to transiently increased mean liver enzymes mainly within the first 4 weeks of treatment. No clear dose response was observed. An increase above 3 times upper limit normal was seen in 4.5 % of patients on drug but none under placebo. No clear influence of on renal function in comparison to placebo was detectable. Nevertheless, as the adverse event "decreased creatinine clearance" was reported more frequently under treatment with than under placebo an impact of finally cannot be excluded. Some patients reported impairment of vigilance to various extents, and a number of patients suffered falls, regarding which a drug relationship might be possible but a dose response relationship was missing. There was a high variability in the data of plasma trough levels according to concentration and a wide range in the given time points. This might have been triggered by taking the blood sample outside the prescribed time window. However, given three times a day to patients with Alzheimer's disease showed no significant deviation from dose proportionality within the given doses (6 mg, 12 mg, 24 mg, and 36 mg). That means the overall results of the analysis of plasma trough levels do support the validity of the acquired efficacy and safety data. 24 January 2001

6 Boehringer lngelheim Pharma KG BI Trial No.: Page 7 Boehringer Ingelheim Conclusions: Volume: to Addendum No.: Study period (years): Altogether symptomatic treatment of patients suffering from dementia of Alzheimer's type with in doses of 6 mg, 12 mg, 24 mg, 36 mg tid and 36 mg bid over 3 months appears safe overall but does not show relevant efficacy with regard to cognition measured by the primary endpoint change in ADAScog. In contrast with the already established treatment with AChEis, significant symptomatic improvement in DAT can be demonstrated. The overall negative outcome of this trial, taking into consideration several additional descriptive sub-analyses, does not support relevant symptomatic improvement in mild to moderate DAT. Under this condition, with small benefit risk ratio, further clinical trials are not recommendable. 24 January 2001