This clinical study synopsis is provided in line with Boehringer Ingelheim s Policy on Transparency and Publication of Clinical Study Data.

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1 abcd Clinical Study for Public Disclosure This clinical study synopsis is provided in line with 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 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.

2 Page 1 of 5 BI Trial No.: Name of Company: 1 of International GmbH or one or more of its affiliated companies. All rights reserved. Title of Trial: Coordinating Investigator: Trial Sites: Publications: Clinical Phase: Objectives: Methodology: No. of Subjects: Diagnosis: A multicenter, open-label, randomised, clinical trial to compare the efficacy and safety of Actilyse 2 mg/ 2 ml versus saline solution in restoring function of an occluded central venous access device This trial was prematurely discontinued due to slow recruitment rate 6 sites (all in Russia) Data from this trial have not been published. III Planned: Entered: 88 Actual: Enrolled: 17 Main Criteria for Inclusion: To evaluate the efficacy of Actilyse in comparison to saline solution in patients with central venous access device (CVAD) occlusion. Two-dose, randomised, open-label, saline solution controlled, parallel-group comparison Entered: 16 2 mg Entered: 6 Treated: 6 Analysed (for primary endpoint): 6 Saline solution Entered: 10 Treated: 10 Analysed (for primary endpoint): 10 CVAD occlusion Patients with CVAD occlusion (which occurred within 24-h before randomisation), where CVAD was indicated for any of the following: fluid maintenance, chemotherapy, intravenous feeding, haemodialysis, or longterm administration of antibiotics or other medications.

3 Page 2 of 5 BI Trial No.: of International GmbH or one or more of its affiliated companies. All rights reserved. Dose: Mode of Admin.: Batch No.: Comparator Product: Dose: Mode of Admin.: 2 mg Batch No.: Duration of Treatment: Criteria for Evaluation: Efficacy: Safety: Instil into the lumen of the catheter (2 mg); (Solvent) Saline solution Instil into the lumen of the catheter Up to two doses 2 hours apart The primary efficacy endpoint is the proportion of patients with restored CVAD function at 120 min after administration of the first dose of study medication (either Actilyse or saline solution). The study was not focused on testing a statistical hypothesis of no difference to demonstrate the efficacy of Actilyse, but to explore the extent of the efficacy of Actilyse by obtaining a relatively narrow confidence interval for the difference between the two treatment groups. Restored CVAD function is defined as the ability to withdraw at least 3 ml of blood from the CVAD. Secondary efficacy endpoints are: Restored CVAD function at other time points: o at 30 min after administration of study medication (i.e. Actilyse or saline solution) at T0; o at 30 min after administration of the second dose of study medication Actilyse (at 150 min after T0); o at 120 min after administration of the second dose of study medication Actilyse (at 240 min after T0). Number of doses required to achieve restored CVAD function in patients randomized to Actilyse. Adverse events including serious adverse events, laboratory evaluations, vital signs, ECG and physical examination.

4 Page 3 of 5 BI Trial No.: of International GmbH or one or more of its affiliated companies. All rights reserved. Statistical Methods: SUMMARY - CONCLUSIONS: Trial Subjects and Compliance with Trial Protocol: Primary Efficacy Analysis: The proportion of patients with restored catheter function at 120 minutes after administration of the first dose of study treatment is compared between treatment arms, and the 95% confidence interval for the difference in proportions is provided for all randomised patients who receive at least one dose of study drug (Full Analysis Set). Secondary Efficacy Analyses: The proportion of patients with restored CVAD function at 30 minutes after first dose is assessed similarly as the primary endpoint. The proportions of patients with restored CVAD function at 30 and 120 min after administration of the second dose of study medication Actilyse (at 150 min and 240 min after T0, respectively) are evaluated descriptively. The number of doses required to achieve restoration of the CVAD function is determined for the patients randomized to the Actilyse group. No interim analysis was planned or performed in this study. This study was stopped prematurely due to slow recruitment of patients. Five sites in Russia recruited patients. A total of 17 patients were enrolled and signed the informed consent form. One patient was a screen failure and was not randomised. A total of 16 patients were randomised and all received the planned study treatment. Nine (9, 56%) of the randomised patients completed all visits. Of the 7 patients who discontinued early, the majority of them, 5, were due to lost to follow up. The other two had SAEs leading to withdrawal from study but in neither patient were the SAEs considered related to the study medication. Six (6, 38%) patients had violated the protocol with respect to at least one inclusion or exclusion criterion but none were considered important violations. Demographic data at screening were comparable across the two treatment groups. The overall mean age of the patients was 60.9 years. Half (50.0%) of the total study population was male. Most of the patients (93.8%) were Caucasian and for one patient (6.2%) race was not reported. The majority of patients (62.5%) had nontunneled percutaneous CVAD. The mean time from CVAD insertion to the first administration of study treatment was 8.3 days. The mean time from CVAD dysfunction to the first dose

5 Page 4 of 5 BI Trial No.: of International GmbH or one or more of its affiliated companies. All rights reserved. Efficacy / Clinical Pharmacology / Other Results: Safety Results: administration was 5.3 hours. Despite the small number of patients, the analysis of the primary endpoint has shown that administration of Actilyse resulted in higher rate of response compared to administration of saline solution: 5 out of 6 (83.3%) patients on Actilyse vs. 1 out of 10 (10%) on saline solution had restored function at 120 min after first dose. The lower and upper limits of the two-sided 95% confidence interval for the difference in response rate between the treatment groups are 23.3% and 89.3% respectively. The analysis of the secondary endpoint, the proportion of patients with restored CVAD function at 30 min after administration of the first dose of study medication, has shown that administration of Actilyse resulted in higher rate of response compared to administration of saline solution (4 out of 6 vs. 0 out of 10). The lower and upper limits of the two-sided 95% confidence interval for the difference in response rate between groups are 20.7% and 90.3% respectively. The analysis of the other secondary endpoints, the proportion of patients with restored CVAD function at 30 and 120 min after administration of the second dose of study medication (Actilyse for both groups), has shown that administration of the 2 nd dose of Actilyse in the one remaining patient in Group I resulted in restoration of CVAD function in that patient 30 min after administration of the second dose of Actilyse. The rate of response in Group II was 5 out of 9 at time 30 min and 7 out of 9 at time 120 min after the administration of the second dose of study medication (i.e. after a first dose of Actilyse ). The analysis of the secondary endpoint, the number of doses required to achieve restored CVAD function in patients randomized to Actilyse, has shown that administration of 1 dose of Actilyse resulted in restoration of catheter function in 5 of the 6 patients and administration of 2 doses of Actilyse resulted in restoration of catheter function in the remaining patient. Among the 16 patients randomized and treated in this study, 15 received at least one dose of Actilyse : 14 received one dose and 1 received two doses. Only 1 patient experienced an adverse event during the 1-day treatment period. There were no treatment discontinuations or dose reductions due to an adverse event in this study. The only adverse event reported by investigators during the 1-day treatment period in this study was the onset of arterial hypertension in 1 patient. This

6 Page 5 of 5 BI Trial No.: of International GmbH or one or more of its affiliated companies. All rights reserved. Conclusions: patient was administered one dose of Actilyse only. The intensity of arterial hypertension was classified as moderate. In this case, the investigator judged that there was no causal relationship between the adverse event and the test drug. Among the 16 patients randomized and treated in this study, 2 (12.5%) patients experienced serious adverse events and 1 (6.3%) patient died. All these events occurred during the post-treatment follow-up period and none of the reported SAEs was classified as 'related' to study treatment (one patient had SAEs after 19 days: pneumonia, toxic dystrophic syndrome, and septic shock leading to death; one after 4 days: artheriosclerosis). Both patients were in Group II and received saline solution followed by Actilyse. Clinical laboratory data have shown no notable trend as a result of administration of Actilyse. No clinically relevant changes could be found in vital signs, ECG or physical examination data. The study was prematurely terminated and therefore the number of patients with efficacy and safety results is limited. Administration of one dose of Actilyse resulted in a greater number of CVAD function restorations compared to the administration of one dose of saline solution, both 30 min after the start of study therapy and 120 min after the start of study therapy (primary endpoint). The difference in the proportion with restored CVAD function was statistically significant. After a second dose of Actilyse, the remaining patient in Group I achieved restored CVAD function. After a first dose of Actilyse (following first dose of saline solution), 77.8% of patients achieved restored function in Group II. There were no AEs considered to be related with administration of Actilyse in the 15 patients that were administered Actilyse at least once. Two patients with SAEs were reported in the follow-up, but no SAE was considered related to study treatment. There were no indications of any safety problems with Actilyse in this small study.