RESULT SUMMARY BE1116_3001. Acquired deficiency of prothrombin complex (reversal of oral anticoagulation)

Transcription

1 RESULT SUMMARY Efficacy and tolerance of BERIPLEX P/N in subjects with acquired deficiency of coagulation factors II, VII, IX and X due to oral anticoagulation BE1116_3001 Investigational product: Beriplex P/N (BE 1116) Indication studied: Phase: Design: Acquired deficiency of prothrombin complex (reversal of oral anticoagulation) III Prospective, multinational, open, uncontrolled Study dates: First subject in: October 24, 2005 Last subject out: November 9, 2006 Sponsor:, Federal Republic of Germany Report type: Result summary (based on CSR Version 1.0) Result summary date: 31 March 2015 The study was performed in compliance with Good Clinical Practice.

2 TITLE OF THE STUDY: Efficacy and tolerance of BERIPLEX P/N in subjects with acquired deficiency of coagulation factors II, VII, IX and X due to oral anticoagulation INVESTIGATOR(S): A total of 15 investigators in 8 countries enrolled subjects for the study. STUDY CENTRE(S): This study was conducted at 15 centers in Austria, Germany, Hungary, Israel, Lithuania, the Netherlands, Poland, and Switzerland: 1) Department of Internal Medicine, Division of Clinical Hematology and Hemostaseology, Medical University Vienna, Wahringer Gürtel 18-20, 1090 Vienna, Austria; 2) Department of Anesthesiology and Intensive Care, County Hospital Feldkirch, Carinagasse 47, 6800 Feldkirch, Austria; 3) Department of Hematology, Hemostaseology and Oncology, Center for Internal Medicine, Medical College Hannover, Carl-Neuberg-Str. 1, Hannover, Germany; 4) Department of Hematology and Oncology, Medical Clinic III, University Hospital Munich - Großhadern, Ludwig Maximilian University, Marchionistr. 15, Munich, Germany; 5) Institute for Transfusion Medicine and Clinical Hemostaseology, Municipal Clinic St Georg Leipzig, Delitzscher Str. 141, Leipzig, Germany; 6) Specialty Clinics, Bergmannstrost Medical Clinic, Merseburgerstraße 165, Halle/Saale, Germany; 7) Department of Surgery, Petz Aladàr Teaching Hospital, Vasvári Pál u. 2, 9023 Györ, Hungary; 8) Department of Surgery, Csolnoky Ferenc County Hospital, Kórház u. 1, 8220 Veszprém, Hungary; 9) Institute of Traumatology and Emergency, Fiumei út 13 17, 1081 Budapest, Hungary; 10) Thrombosis and Hemostasis Unit, Rambam Medical Center, P.O.B. 9602, Haifa, Israel; 11) Kaunas Medical University Clinic, Eiveniu str. 2, Kaunas, Lithuania; 12) Centre of Anesthesiology, Intensive Therapy and Pain Management, Santariskiu Clinics, Vilnius University Hospital, Santariskiu str. 2, Vilnius, Lithuania; 13) Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam Zuidoost, the Netherlands; 14) Department of General, Vascular and Transplant Surgery, Medical University of Warsaw, ul. Banacha 1a, Warsaw, Poland; 15) Clinical Department of Hematology, University Hospital Zürich, Rämistr. 100, 8901 Zürich, Switzerland. 31 March 2015 Page 2 of 6

3 PUBLICATION (REFERENCE): - Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann H. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: A prospective multinational clinical trial. J Thromb Haemost 2008 Jan 15;6(4): Pabinger I, Tiede A, Kalina U, Knaub S, Germann R, Ostermann H. Impact of infusion speed on the safety and effectiveness of prothrombin complex concentrate: A prospective clinical trial of emergency anticoagulation reversal. Ann Hematol 2010;89(3): STUDY PERIOD (YEARS): 1 (Date of first enrolment): October 24, 2005 (Date of last completed): November 9, 2006 PHASE OF DEVELOPMENT: III OBJECTIVES: Primary objective: To demonstrate the capability of Beriplex P/N to effectively reverse the oral anticoagulation effect by decreasing the INR values Secondary objectives: To demonstrate the capability of Beriplex P/N to adequately increase the plasma level of FII, FVII, FIX, FX and Protein C To demonstrate the cessation of spontaneously and traumatically induced bleedings or avoidance of excessive hemorrhages during and after emergency surgical interventions To determine the safety and tolerability of Beriplex P/N METHODOLOGY: Prospective, open, uncontrolled. NUMBER OF SUBJECTS (PLANNED AND ANALYZED): 44 enrolled, 43 were treated with the IMP (ITT, safety population). DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: Male and female subjects 18 years Subjects with anticoagulation therapy (coumarin or derivatives) in whom either an emergency surgical or an urgent invasive diagnostic intervention is indicated or with anticoagulation therapy (coumarin or derivatives) and acute bleedings in whom normalization of INR is indicated INR > 2 Informed consent has been obtained 31 March 2015 Page 3 of 6

4 TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, BATCH NO.: Dosage is based on the baseline INR according to the following guideline: Baseline INR Dosage of (intravenously) IU of FIX per kg b.w IU of FIX per kg b.w. > 6 50 IU of FIX per kg b.w. Batch numbers were: E, F, G, G, H, C, B, F REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, BATCH NO.: Not applicable DURATION OF TREATMENT: Single dose CRITERIA FOR EVALUATION: Efficacy: Primary efficacy variable: Rapid decrease of the INR (i.e. INR 1.3 within 30 minutes after end of Beriplex P/N infusion) Secondary efficacy variables: Response and in-vivo recovery of FII, FVII, FIX, FX and Protein C Clinical Efficacy: Physician s judgment concerning the adequacy of stopping an ongoing bleeding or avoidance of excessive bleeding during surgical intervention (very good satisfactory questionable none) Safety: Hematological parameters, vital signs, adverse events, thrombogenicity, virus safety STATISTICAL METHODS: Estimation of proportion of subjects with rapid decrease of INR with 95% confidence intervals according to Blyth and Casella (StatXact). Exploratory univariate and multivariate analysis of covariance for the course of INR. Descriptive and graphical analysis of secondary endpoints and routine and central laboratory data, descriptive analysis of adverse event and virus safety data. SUMMARY - CONCLUSIONS Efficacy results: Forty out of 43 subjects (ITT, 93%), and 32 out of 34 (94 %, PP30min) reached an INR of 1.3 or lower. An additional three subjects had an INR of 1.4, which could from a clinical point of 31 March 2015 Page 4 of 6

5 view be considered almost normalized. The single infusion of the IMP led to a direct increase of all IMP component plasma levels, reaching normal or near-normal median values. From the data obtained for IVR of coagulation factors, in general an increase of approximately 1.5% increase in plasma level could be expected for each IU per kg b.w. of FIX, FVII, FX administered, and an approximately 2% increase for each IU per kg b.w. of FII, Protein C and S, see details in the table below. The IVR decreased with increasing baseline INR values. Table: IVR of coagulation factors Parameter (n=42) Median Range Factor IX Factor II Factor VII Factor X Protein C Protein S In 40 out of 43 (93%) of all cases the investigators assessed the clinical efficacy as very good. Safety results: The median duration of infusion was 12 minutes, with a median infusion speed of 188 IU/min (range IU/min), which was tolerated well by the subjects. A total of 25 subjects experienced AEs, only two AEs were assessed as related to the IMP (increase of F1+2, pulmonary embolism). Six subjects experienced SAEs, and of those three subjects died. One of the SAEs leading to death was assessed as related to the IMP. It was a case of pulmonary embolism, an adverse effect known for all PCCs. The embolism occurred shortly after infusion of the IMP in a subject with several risk factors for thromboembolism. The administration of the IMP could be considered as one contributory factor. A further two subjects died during the virus safety follow-up phase, both SAEs were assessed as not related to the IMP. The number of SAEs and cases of deaths were expected for this type of study involving acutely and severely ill subjects. The course of thrombogenicity parameters supported the low risk of thromboembolic events for the IMP. Increases of F1+2 and TAT directly after the infusion could clearly be attributed to the content of these factors in the IMP. A second smaller increase of TAT values might be indicative of coagulation activation, however, that could be non-significant or physiological activation of coagulation after surgery and hemorrhage. D-dimers showed only a very small increase over time. From the assessments of vital signs and physical examination no indication was found for any risk due to the IMP. 31 March 2015 Page 5 of 6

6 No transmission of HIV, HAV, HBV, HCV, and Parvovirus B19 could be seen. One case of occurrence of anti-hav IgG remained unclear, however, an infection with HAV was excluded. In conclusion, this study demonstrated that the IMP is effective with a very fast onset of action and safe in the indication reversal of oral anticoagulation. Date of the report: 31 March 2015 RELEVANT PROTOCOL AMENDMENTS: There were 3 substantial amendments (Amendments 1, 2, 3) to the original study protocol (summarized below) and a country-specific amendment for Switzerland. Amendment No. 1 adapted the recommended dose of concomitant vitamin K to the current recommendations by the American College of Chest Physicians (change from 5 mg to 5 10 mg). With Amendment No. 2, an additional exclusion criterion (history of heparin-induced thrombocytopenia type II) was included for safety reasons. In addition, details on the laboratory methods used for coagulation factor testing were added. With Amendment No. 3, weight for dosage calculation had been limited to 100 kg for safety reasons; as the effect of the IMP depends on distribution in plasma, and plasma volume does not increase linearly with increasing weight. Also with this amendment, a new central laboratory was added to the study. had established an internal central laboratory for the testing of the coagulation factors and thrombogenicity parameters. Therefore, the protocol was changed and the parameters mentioned above were determined at this central laboratory. At this time point none of the parameters for none of the subjects had been determined in the originally planned central laboratory. This laboratory performed all tests for determination of virus safety parameters. 31 March 2015 Page 6 of 6