TachoSil (Page 4 of 6)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of TachoSil is based on the interaction between the active biological substances (human fibrinogen and human thrombin) and the physiology of the fibrin clot formation (Fig. 3A). Upon contact with a bleeding wound surface, the active substances coated onto the equine collagen patch become dissolved and partly diffuse into the wound surface. The subsequent fibrinogen-thrombin reaction initiates the last step in the cascade of biochemical reactions-conversion of fibrinogen into fibrin monomers that further polymerize to form the fibrin clot.

Hemostasis is achieved when the formed fibrin clot adheres the collagen patch to the wound surface, thus providing a physical barrier to bleeding (Fig 3B). TachoSil exhibits flexibility to accommodate for the physiological movements of tissues and organs and can withstand pressures up to 61.4 hPa (46.1 mmHg).

Figure 3: Scanning Electron Microscopy Photos of TachoSil

12a12b
A. The side view of the TachoSil patch shows the coating of the human plasma components anchored to the indentations of the collagen carrier. B. The deposition of a fibrin clot formed from fibrinogen and thrombin of the coating results in hemostasis and conglutination of the TachoSil patch to the wound surface.
A. The side view of the TachoSil patch shows the coating of the human plasma components anchored to the indentations of the collagen carrier.B. The deposition of a fibrin clot formed from fibrinogen and thrombin of the coating results in hemostasis and conglutination of the TachoSil patch to the wound surface.

12a12b

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of TachoSil or studies to determine the genotoxicity or the effect of TachoSil on fertility have not been performed. An assessment of the carcinogenic potential of TachoSil was completed to demonstrate minimal carcinogenic risk from product use.

13.2 Animal Toxicology and/or Pharmacology

In a study conducted in swine, TachoSil was applied to liver wounds and showed progressive degradation. However, remnants of the TachoSil patch may remain present for more than 12 months. Histologic examination at 26 and 52 weeks revealed that granulation tissue encapsulates TachoSil remnants and forms a firm capsule around them. Remnants were found in all treated animals after 26 weeks (12/12) and in most animals (6/8) after 52 weeks. No other local reactivity or toxicities were noted.

14 CLINICAL STUDIES

14.1 Cardiovascular

An open-label, multi-center, randomized, parallel-group study comparing TachoSil with comparator (hemostatic fleece without additional active coagulation stimulating compounds) treatment was conducted to evaluate TachoSil for control of bleeding in 119 patients undergoing cardiovascular surgery requiring cardiopulmonary bypass procedure. Of the 119 subjects, 88 (74%) were male and 31 (26%) female. Mean (range) age was 67 (23 to 86) years; subjects older than 65 years constituted 58% of the male and 74% of the female population. All subjects were White/Caucasian.

In the Intent-to-Treat (ITT) population, 59 patients were randomized to treatment with TachoSil and 60 patients were randomized to treatment with the comparator. A larger proportion of patients in the TachoSil treatment group (44/59; 75%) than in the comparator treatment group (20/60; 33%) achieved hemostasis within three minutes, which was a statistically significant difference (p<0.0001).

Fifty-six out of 59 (95%) patients in the TachoSil treatment group achieved hemostasis at six minutes compared to 43 out of 60 (72%) in the comparator treatment group, which also was statistically significant (p=0.0006) (see Table 7).

*
Normal approximation to the binominal distribution is used to construct the asymptotic confidence intervals
Cochran-Mantel-Haenszel test controlling for center
Hemostatic fleece material without additional active coagulation stimulating compounds

Table 7. Efficacy Results in Cardiovascular Surgery, by Treatment, Intent-to-Treat Population

Treatment

Total numberof patients whoachieved hemostasis

Percentage ofpatients whoachieved hemostasis

95% CI forproportion *

p-value

Hemostasis at 3 min

TachoSil (n=59)

44

75%

[0.635; 0.857]

<0.0001

Comparator (n=60)

20

33%

[0.214; 0.453]

Hemostasis at 6 min

TachoSil (n=59)

56

95%

[0.893;1.000]

0.0006

Comparator (n=60)

43

72%

[0.603; 0.831]

14.2 Hepatic

A randomized, open-label, parallel group, multi-center trial comparing TachoSil with comparator was conducted to evaluate TachoSil for the secondary treatment of local bleeding in patients undergoing hepatic surgery.

A total of 114 patients were randomized to treatment with TachoSil and 110 patients were randomized to treatment with comparator. A similar proportion of male patients and female patients were randomly assigned in the trial (53% and 47%, respectively). The mean (SD) age of patients was 58.1 (13.95) years and in both treatment groups approximately 30% of the patients were above 65 years. The majority of patients were White/Caucasian (80%) and the most common ethnicity was non-Hispanic/non-Latino (88%).

A larger proportion of patients in the TachoSil treatment group (81%) than in the comparator treatment group (50%) achieved hemostasis within the first three minutes after treatment application. The primary analysis of the proportion of patients who achieved hemostasis within three minutes showed a statistically significant difference between treatment groups in favor of TachoSil (p<0.001) and obtained a clinical relevant difference between the two groups defined from the estimated odds ratio (see Table 8).

With respect to one of the two secondary endpoints, 108 (95%) patients in the TachoSil group and 84 (76%) patients in the comparator group achieved hemostasis within five minutes in which the secondary analysis also showed a statistically significant difference between the group in favor of TachoSil (p<0.001, multiplicity adjusted) (see Table 8).

*
Hochberg’s adjustment for multiplicity
Hemostatic fleece material made of oxidized cellulose polymer
Analyzed by a log rank test for equality over treatments. Patients who did not achieve hemostasis after 10 minutes were censored in the analysis.

Table 8. Efficacy Results in Hepatic Surgery, by Treatment, Intent-To-Treat Population

Treatment

Total number of patientswho achieved hemostasis

Percentage of patientswho achieved hemostasis

Odds ratio[95% CI]

p-value *

Hemostasis at 3 min

TachoSil (n=114)

92

81%

4.87[2.55; 9.29]

<0.001

Comparator (n=110)

55

50%

Hemostasis at 5 min

TachoSil (n=114)

108

95%

6.24[2.39;16.30]

<0.001

Comparator (n=110)

84

76%

Time to hemostasis

<0.001

TachoSil (n=114)

Comparator (n=110)

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