TW201309304A - Idrabiotaparinux for the treatment of pulmonary embolism and for the secondary prevention of venous thromboembolic events - Google Patents

Abstract

The invention relates to idrabiotaparinux for use in the treatment of pulmonary embolism in patients with or without deep venous thrombosis and for the secondary prevention of venous thromboembolic events in said patients, wherein the efficacy and safety of said uses are clinically proven by a phase III clinical trial.

Description

Treatment of pulmonary embolism and biotinylated idrabiparin for secondary prevention of venous thromboembolism (IDRABIOTAPARINUX)

The present invention relates to the use of biotinylated idrabiotaparinux for pulmonary embolism in patients with or without deep venous thromboembolism and secondary prevention of venous thromboembolism in such patients.

Biotinylated idrabiparin (international non-exclusive name) or SSR126517 (laboratory code) is the first subcutaneous route discovered by Sanofi-aventis. A long-acting anticoagulant having unique properties that can be almost instantly and specifically neutralized by intravenous administration of avidin. It is considered a substitute for a vitamin K antagonist (VKA).

The biotinylated idrabiparin corresponds to the biotinylated pentose of the structure shown below.

The pentose structure of biotinylated idrabiparin is identical to another antithrombotic agent discovered by Sanofi-Aventis, idraparinux (see structure below). However, in biotinylated idrabiparin, the presence of a biotin hook covalently linked to the first saccharide unit allows the compound to be protected by biotin The protein or streptavidin is neutralized as described in International Patent Application WO 02/24754.

In the EQUINOX trial, 757 patients were screened for 6-month DVT treatment with a molar dose of biotinylated idrabiparin or edeparin, confirming the administration of biotinylated idrabiparin in symptomatic deep veins Bioequivalence results in pharmacokinetics and pharmacodynamics with acecoparin are provided in patients with thromboembolism (Journal of Thrombosis and Haemostasis, 2010, Vol. 9, pp. 92-99). The results of this bioequivalence test indicate that biotinylated idrabiparin is suitable for the treatment of patients with deep venous thrombosis. However, the apparent failure of aceparin in patients with pulmonary embolism indicates a formal assessment of biotinylated idrabiparin in this patient population (N. Eng. J. Med., 2007, Vol. 357, 1094-104).

It has been confirmed that in the Phase 3 study of 3202 patients with pulmonary embolism, biotinylated idrabiparin is used to treat pulmonary embolism in patients with or without deep venous thromboembolism and A safe and effective drug for secondary prevention of venous thromboembolism in patients.

Accordingly, the present invention relates to the use of biotinylated idrabis in the treatment of pulmonary embolism in patients suffering from or without deep venous thromboembolism and in the secondary prevention of venous thromboembolism in such patients, Which effect is used for this purpose Energy and safety are clinically proven by Phase III clinical trials.

According to the invention, the following terms have the following meanings: - "Biotinylated idrabiparin" means a sodium salt of the compound as defined above, or any other pharmaceutically acceptable salt thereof; - "phase III clinical trial" means A large patient population (3,202 patients in the present invention), designed to be internationally, multicenter, randomized, double-blind, with a definitive assessment of the efficacy and safety of the drug compared to existing standard therapies Shuangming, parallel group study; - "Deep venous thrombosis" refers to blood clotting in the deep veins of the lower extremities; - "patients" refers to the early stage of acute symptomatic pulmonary embolism or pulmonary embolism Symptoms, patients suffering from or suffering from symptomatic deep venous thromboembolism of the lower extremities; - "treatment" means administering a therapy to at least one of a manifested disease or condition (in the case of the present invention, pulmonary embolism) A symptom or an individual who has previously demonstrated at least one symptom of the disease or condition. Therefore, the term "treatment" within the framework of the present invention encompasses the treatment of curative treatment and prevention of recurrence of pulmonary embolism; - "secondary prevention" refers to the lungs associated with (or not associated with) deep venous thrombosis Prevention of recurrence of thrombotic embolism (including pulmonary embolism and deep venous thrombosis) after embolism.

As used herein, the term "biotinylated idrabiparin for use" shall be considered equivalent to the term "biotinylated idrabiparin for use" or "biotinylated AI" The use of heparin for the preparation of a medicament for use.

In the present invention, the third phase clinical trial selected 3,202 patients. Patients selected for this clinical trial were confirmed to have acute symptomatic pulmonary embolism with or without deep venous thrombosis of the lower extremities, as described in detail below.

In one embodiment of the invention, biotinylated idrabiparin is administered for up to 3 months.

In another embodiment of the invention, biotinylated idrabiparin is administered for 6 months.

In another embodiment of the invention, the biotinylated idrabiparin is administered at a dose of 3.0 mg/week without severe renal insufficiency (creatinine clearance) 30 ml/min) of the patient.

In another embodiment of the invention, the biotinylated idrabiparin is administered at a dose of 1.8 mg/week with a severe renal insufficiency (creatinine clearance <30 ml/min) after an initial dose of 3.0 mg. Suffering.

According to the present invention, the efficacy and safety of biotinylated idrabiparin for the treatment of pulmonary embolism in patients with or without deep venous thrombosis and secondary prevention of venous thromboembolism in such patients Sex was assessed in comparison to a vitamin K antagonist (i.e., warfarin) as a standard antithrombotic therapy.

According to the invention, the venous thromboembolic disorder is selected from the group consisting of pulmonary embolism (fatal or non-fatal) and deep venous thrombosis.

In another embodiment of the invention, biotinylated idrabiparin is a vitamin K antagonist (ie, warfarin) compared to standard antithrombotic therapy in hemorrhage (defined as any clinically relevant bleeding), including major bleeding. Show increase Into the security. This effect is more pronounced 3 months after the start of treatment with biotinylated idrabiparin.

According to the invention, the term "bleeding" means any clinically relevant bleeding (i.e., major bleeding or clinically relevant non-major bleeding).

According to the invention, the term "major bleeding" means any of the following clinical conditions: ‧ bleeding associated with a decrease in hemoglobin of 2 g/dl or greater, ‧ resulting in the delivery of two or more units of compressed red blood cells or whole blood (will The red blood cell unit is defined as bleeding from approximately 500 ml of whole blood or corresponding to the red blood cell volume of approximately 500 ml of whole blood, and ‧ involves bleeding of key organs (intracranial, intraocular, intraspinal, retroperitoneal, or pericardial organs), Bleeding from death.

According to the present invention, the term "clinically related non-major bleeding" means any of the following clinical conditions: ‧ lowering hemodynamic bleeding, ‧ bleeding resulting from hospitalization, ‧ subcutaneously greater than 25 cm ² or 100 cm ² due to traumatic events Hematoma, ‧ intramuscular hematoma filed by ultrasound map, ‧ for more than 5 minutes, reproducible (ie, two or more non-handkerchief-like more extensive bleeding within 24 hours) or demand intervention ( For example, nasal bleeding with dressing or electrocoagulation, ‧ spontaneous (ie, not related to eating or brushing) or bleeding of gums lasting more than 5 minutes, ‧ visible to the naked eye and spontaneous or instrumental in the genitourinary tract (eg, Hematuria lasting more than 24 hours after catheter placement or surgery. ‧Mental positive gastrointestinal bleeding in the fecal occult blood test, including at least one of black feces or hematemesis, ‧more on toilet paper Spotted rectal blood loss, ‧ there are more than a few spots in the sputum and hemoptysis that does not occur in pulmonary embolism, ‧ is considered to have the following clinical consequences for the patient Blood type: - such as medical intervention, the need for irregular contact (visiting or telephone) with the physician or the temporary discontinuation of the study drug - or associated with daily behavioral pain or disorder.

As described above, biotinylated idrabiparin exhibits efficacy in the treatment of pulmonary embolism in patients with or without deep venous thrombosis and secondary prevention of venous thromboembolism in such patients. And enhance the security. Thus, another embodiment of the present invention is a modified benefit-to-risk ratio of biotinylated idrabiparin compared to a vitamin K antagonist (i.e., warfarin) as a standard antithrombotic therapy.

The improved benefit-to-risk ratio occurred 3 months after and 6 months after the weekly administration of biotinylated idrabiparin as described above.

In addition, biotinylated idrabiparin protects patients who have been on the drug for a long time.

Accordingly, the present invention is also directed to the treatment of pulmonary embolism for biotinylated idrabiparin in patients with or without deep venous thrombosis and secondary prevention of venous thromboembolism in such patients. , wherein the efficacy of biotinylated idrabiparin in such applications and its improved benefit-to-risk ratio is discontinued in treatment It continued to exist for up to 12 months after starting treatment with biotinylated idrabiparin.

More specifically, the present invention relates to biotinylated idrabiparl for use in veins after 6 months of initial treatment with biotinylated idrabiparin in patients with or without deep venous thrombosis Thrombotic embolism is further delayed for 6 months.

In the framework of the present invention, the term "prolonged prophylaxis" means protection against thromboembolic disorders (ie, pulmonary embolism and deep venous thrombosis) for a period of time after the cessation of biotinylated idrabiparin treatment, ie , the protection of the extension. The term "stop" means that the patient is permanently discontinued by biotinylated idrabiparin.

Accordingly, the present invention is also directed to biotinylated idrabiparin for preventing recurrence of a patient with or without deep venous thrombosis within 6 months after the initial 6-month treatment of biotinylated idrabiparin is stopped. Thrombotic embolism.

The invention also relates to a manufactured article comprising: - a packaging material, - a compound selected from the group consisting of biotinylated idrabiparin or a pharmaceutically acceptable salt thereof, and - a label or package insert contained in the packaging material, Indicates that the compound is effective as an antithrombotic therapy for the treatment of pulmonary embolism in patients with or without deep venous thrombosis and for venous thromboembolism in such patients Level prevention.

The invention also relates to a manufactured article comprising: - a packaging material, - a compound selected from the group consisting of biotinylated idrabiparin or a pharmaceutically acceptable salt thereof, and - a label or package insert contained in the packaging material indicating that the compound is safe for use as an antithrombotic therapy for the treatment of pulmonary embolism in patients with or without deep venous thrombosis and Secondary prevention of venous thromboembolism in these patients.

In another embodiment, the present invention is directed to a pharmaceutical composition comprising biotinylated idrabiparin for use in the treatment of pulmonary embolism in a patient with or without deep venous thrombosis and for use in Secondary prevention of venous thromboembolism in these patients. Preferably, the pharmaceutical composition comprises, for example, a 3.0 mg or 1.8 mg dose of biotinylated idrabiparin, and a pharmaceutically acceptable inert excipient. Such excipients are selected from the excipients known in the art, depending on the pharmaceutical formulation and mode of administration desired. Advantageous pharmaceutical compositions in accordance with the present invention are suitable for injectable formulations of the subcutaneous route.

In another embodiment, the invention relates to the treatment of biotinylated idrabiparin for the preparation of pulmonary embolism for patients with or without deep venous thrombosis and for the veins of such patients The use of a secondary prevention agent for thrombotic embolism, wherein the efficacy and safety of the use is clinically proven by Phase III clinical trials.

The invention will be more clearly understood from the following description of the invention.

The following abbreviations will be used: ALAT: alanine aminotransferase

aPTT: activation of partial coagulation-activated kinase time

ASAT: Aspartate Aminotransferase

AT: anticoagulant

B.i.d.: twice daily

CI: Confidence interval

CIAC: Central and Independent Adjudication Board

CT: Computerized tomography

CUS: compressed ultrasound map

DVT: deep vein thrombosis

INR: International Standardized Ratio

I.v.: intravenous

IVRS: Interactive Sound Response System

LMWH: Low molecular weight heparin

N: number of patients

PE: pulmonary embolism

PK: Pharmacokinetics

S.c.: under the skin

SRI: severe renal insufficiency

SSR126517E: Biotinylated idrabiparin in the form of a sodium salt

SSR29261: Avidin

UFH: undifferentiated heparin

ULN: upper limit of normal range

VKA: Vitamin K antagonist

VPLS: Ventilation/Perfusion Pulmonary Scintigraphy

VTE: Venous thromboembolism

CASSIOPEA (EFC6034) clinical trial

In the treatment of patients with symptomatic pulmonary embolism with or without symptomatic deep venous thrombosis, warfarin is adjusted relative to oral INR by SSR126517E (3.0 g subcutaneous route, once a week) International, multicenter, randomized, double-blind, double-simulated, parallel-group studies were performed for 3 or 6 months of treatment.

1. Purpose

Primary efficacy objective : To assess whether a 3- or 6-month treatment performed by a weekly SSR126517E sc injection is at least as effective as a 3- or 6-month treatment by INR-regulated warfarin Patients with symptomatic deep venous thrombosis (DVT) with symptomatic pulmonary embolism (PE) had recurrent venous thromboembolism (VTE) at 3 months.

Primary Secondary Efficacy Objective : To assess whether treatment for 6 months by SSR126517E sc injection once a week is at least as effective as treatment and prevention of DVT with or without DVT by INR-regulated warfarin for 6 months. Patients with symptomatic PE had a recurrence of VTE at 6 months.

2) Research design

Patients who have been diagnosed with symptomatic PE with or without acute symptomatic DVT may be enrolled in this trial. The treatment of any LMWH or UFH or fondaparinux therapeutic dose should not exceed 36 hours immediately before randomization. Randomization was performed immediately after diagnosis of PE (and DVT, if accompanied by suspected symptomatic DVT).

Treatment time was based on the baseline risk of DVT/PE recurrence, determined by the investigator to be 3 months or 6 months SSR126517E (or placebo), or INR to adjust warfarin (or placebo) prior to randomization.

The Blind Central and Independent Adjudication Board (CIAC) evaluates all onset, clinically relevant bleeding, and death of PE (and DVT, where applicable), local confirmation, or suspected PE/DVT recurrence. The outcome of the award is the basis of the final analysis.

Patients in the 3-month class had an additional 13-week observation period after study treatment withdrawal. Patients in the 6-month class have an observation period of 13 weeks to 26 weeks.

3) Research population 3-1: Selection criteria

The following patients were enrolled in the study: patients with acute symptomatic PE with or without symptomatic DVT of the lower extremities.

3-2: Exclusion criteria

The following patients were excluded from the selected population of the study.

- Guidelines related to research methods:

1. The legal age limit (with country specificity).

2. Women who have fertility and have not taken appropriate contraceptive measures.

3. Those who have not obtained written consent for the test.

4. Other indications for anticoagulation but not for the current onset of PE.

5. Thrombosis, insertion of a cavity filter or the use of fibrinolytic agents to treat the current onset of PE.

6. Treatment of any LMWH or UFH or fondaparinux for up to 36 hours prior to randomization.

7. Life expectancy <6 months.

8. Participate in another drug treatment of a non-registered research product within the previous 30 days Treatment research.

- Guidelines related to warfarin or enoxaparin:

9. Pregnancy.

10. Threatened abortion.

11. Active bleeding.

12. bleeding tendency or bloody pain and pain.

13. Recently or expected to undergo a central nervous system, eye surgery, traumatic surgery leading to a large open surface.

14. Spinal puncture and other diagnostic or therapeutic options for the possibility of uncontrolled bleeding.

15. Malignant hypertension.

16. Unwell, alcohol-poisoned or unattended patients who are mentally ill or unable to cooperate.

17. It is known to be allergic to warfarin or any other component of this product.

18. Patients who are allergic to enoxaparin sodium, heparin or pork products.

19. List any other contraindications in the local warfarin or enoxaparin label.

- Guidelines related to SSR126517E:

20. Implement breastfeeding.

21. Creatinine clearance <10 ml/min or terminal renal failure.

22. Allergic to idrabiparin or SSR126517E.

- Guidelines related to avidin:

23. It is known to be allergic to biotin or egg protein.

4) Research products 4.1: Formulation

-SSR126517E: Sterile pyrogen-free isotonic solution containing sodium chloride and s.c. water for injection. This solution contains 6 mg SSR126517E per ml.

SSR126517E is supplied in a pre-filled syringe: ‧ contains 0.5 ml of this solution for administration of 3.0 mg dose to patients without severe renal insufficiency (SRI) (creatinine clearance > 30 ml/min) and for SRI (creatinine clearance The first injection was given to patients with 30 ml/min; • 0.3 ml (1.8 mg) of this solution was used for patients with SRI (injection after the first 3.0 mg injection).

- The placebo of SSR126517E is a sterile pyrogen-free isotonic solution containing sodium chloride and water for injection (s.c.). The placebo of SSR126517E is provided in a prefilled syringe: ‧ contains 0.5 ml of this solution for patients without SRI; ‧ contains 0.3 ml of this solution for patients with SRI

- Warfarin: 5 mg and 1 mg strength lozenges enclosed in capsules, and corresponding warfarin placebo.

-SSR29261 (Avidin): Sterile pyrogen-free lyophilized powder, provided in a clear glass stopper bottle containing 55 mg of avidin, rehydrated with 5.5 ml of water for injection or saline before administration. This gave a solution for iv injection at 10 mg/ml. Dilute 10 ml to 110 ml for 100 mg i.v. infusion.

-SSR29261 (avidin) placebo: provided in a clear glass stopper bottle containing 55 mg of sterile pyrogen-free lyophilized excipient powder, as The avidin powder has the same appearance and is rehydrated and administered in the same manner as described above for avidin.

- Enoxaparin: A pre-filled syringe sold locally, as registered locally, for b.i.d. (1.0 mg/kg/12 hours) for the treatment of venous thromboembolism.

4-2: Investment path

- Placebo for enoxaparin, SSR126517E and SSR126517E: subcutaneous (s.c.).

- Placebo for Warfarin and Warfarin: Oral.

- Placebo for SSR29261 or SSR29261: Intravenous (i.v.) infusion for 30 minutes.

5) Dosage regimen

The treatment of any LMWH or UFH or fondaparinux dose should not exceed 36 hours immediately before randomization.

After randomization, a dose of 1.0 mg/kg b.i.d. of enoxaparin was administered subcutaneously. If the local enoxaparin label indicates that it is for the treatment of PE, it should be hospitalized during this initial treatment phase. The number of platelets was monitored regularly during the treatment with enoxaparin.

The time of treatment with enoxaparin was at least 5 days (including enoxaparin provided at a 1.0 mg/kg bid dose for the treatment of VTE before randomization) when feasible. Enoxaparin (recommended for 4 to 5 days in combination with warfarin (or placebo for warfarin)) 2 consecutive INR continuous values at intervals of at least 24 hours (true value of warfarin group, SSR126517E group) Analog value) Stop after 2.0.

Warfarin (or placebo) should be administered within 24 hours of randomization and a baseline risk factor for recurrence of VTE should be administered for 3 or 6 months. Adjust the dose of warfarin (or placebo) to maintain (true or simulated) centralized INR within the therapeutic range (target 2.5, range 2.0-3.0). The INR should be checked at least once a month. If the normal threshold of the INR value at which vitamin K should be administered is reached, it is not necessary to break the blindness, but the condition is (i) only if the patient does not have an absolute need to understand the anticoagulant it receives. At the time of the relevant bleeding, and (ii) the vitamin K provided is administered orally, or if it is not administered orally, it can only be administered via the subcutaneous route. If the patient develops symptoms and the condition is absolutely necessary to know the anticoagulant it receives, or if vitamin K must be administered via the intravenous route, blindness should be broken.

SSR126517E (or placebo) was started at 12 hours after enoxaparin administration after the last randomization. SSR126517E (or placebo) was administered s.c. once a week for 3 or 6 months. All patients received the first 0.5 ml injection (3.0 mg in the SSR126517E group). Subsequent injections were also 0.5 ml, but did not include patients with severe renal insufficiency (defined as creatinine clearance <30 ml/min), which was reduced to 0.3 ml (1.8 mg in the SSR126517E group).

In the case of severe bleeding, or in the case of an emergency invasive procedure with uncontrolled bleeding, or in the case of overdose, if possible and appropriate, after the blindness is broken, the SSR126517E patient may be given an open label infusion. The method was administered with 110 ml of avidin solution (ie, 100 mg of avidin extract).

Invasive surgery for the possibility of uncontrolled bleeding Next, 110 ml of avidin or avidin placebo can be administered i.v. infusion prior to the procedure and 4 days after the study capsule is deactivated, without the need to break the blindness.

Avidin (open label or double blind) can be administered during the weekly injection treatment and during the next 2 weeks of the last weekly injection.

6) primary prognosis and primary secondary outcome 6-1: Performance

In 99 days, one-stage efficacy prognosis for patients at both levels (3- and 6-month treatment) was symptomatic recurrent PE/DVT (fatal or non-fatal) when validated by CIAC.

Within 190 days, the secondary efficacy prognosis for 6-month-level patients was symptomatic recurrent PE/DVT when verified by CIAC.

There are two additional efficacy prognoses: - the time to reach the first symptomatic recurrent PE/DVT (fatal or non-fatal) during the patient's treatment, ie, a combined analysis of 3- and 6-month-level patients; The composition of the prognosis of 99 days (all patients) and the efficacy prognosis within 190 days (only 6-month class patients).

The definition of suspected symptomatic onset of recurrent PE/DVT is as follows: 1-PE: One of the following phenomena:

• A new intraluminal filling defect was found in the (sub)segment or more proximal branches when spiral CT scans.

‧ With a pulmonary angiogram, a new intraluminal filling defect or an extension of an existing defect or a new sudden cut of a blood vessel larger than 2.5 mm in diameter was found.

‧At least 75% of the segments were found by pulmonary ventilation/perfusion imaging (VPLS) New perfusion defects without matching ventilation defects (high probability).

‧ Confirmation of non-deterministic spiral CT, pulmonary angiography or pulmonary scintigraphy of lower extremity DVT by compression ultrasound or venography.

Or 2-lower limb DVT: One of the following phenomena: If DVT examination is not performed in advance: ‧ Uncompressed ultrasound (CUS), ‧ Intraluminal filling defect found on venography

If a DVT has been performed at the time of screening, then: ‧ where the compression has turned into a normal abnormal CUS, or if it is not compressible during screening, the thrombus diameter is significantly increased during full compression (4 mm or more), ‧ cavity The filling defect is expanded, or a new intraluminal filling defect is found, or a non-visual expansion of the vein is present in the case of a sudden severance on the venogram.

Or 3- Objectively filed fatal PE.

Or 4-cannot be attributed to an archival cause or the death of DVT/PE cannot be ruled out.

Perfusion/ventilation lung scan, spiral computed tomography (CT) scan, pulmonary angiography alone or in combination, and compression ultrasound imaging (CUS) for PE in non-deterministic lung scans or spiral CT scans An exclusive diagnosis of recurrence.

DVT diagnosis is better by bilateral lower extremity venography or CUS (including measurement of the tibia, femoral and three bifurcation veins before and after compression) Path) implementation. In the case of randomized diagnosis of acute symptomatic DVT, or detection of deep veins in the leg to determine the diagnosis of the initial PE, a check of the same type as the user of the randomized group is performed to confirm or rule out DVT recurrence.

6-2: Security

When classified by CIAC, the basic safety prognosis is any clinically relevant bleeding (ie, major bleeding and other clinically relevant non-major bleeding).

7) Evaluation plan 7-1: Screening stage

The screening phase was performed within 48 hours prior to randomization.

Patients with acute symptomatic PE may be eligible for this study only if the following laboratory tests are performed prior to randomization: perfusion/ventilation lung scan, spiral CT scan, pulmonary angiography, and if Need, bilateral venography of the lower extremities or compression of the ultrasound and measurement of the depth of the deep vein.

The diagnosis of PE is based on any of the following phenomena: ‧ Intraluminal filling defects are found in (sub) or more proximal branches during spiral CT scans, ‧ intraluminal filling defects are found by pulmonary angiography Or sudden severance of blood vessels larger than 2.5 mm in diameter, ‧ by VPLS, at least 75% of the segments showed perfusion defects without matching ventilatory defects (high probability), ‧ confirmed by lowering DVT by compression ultrasound or venography Non-deterministic spiral CT, pulmonary angiography or pulmonary scintigraphy.

If suspected acute symptomatic DVT is present, the diagnosis should be confirmed by bilateral venography or CUS prior to randomization, including measurement compression. The diameter of the tibia, femoral head, hernia, and the three bifurcation veins before and after the lower extremities.

The diagnosis of DVT is based on any of the following phenomena: • Incompressible veins are found in the three bifurcations of the calf vein and/or the more proximal vein CUS, and in the venography, the three points in the calf vein Intraluminal filling defects are found in the fork and/or the proximal vein.

7-2: After random grouping

After randomization, contact (hospital/clinical visit or telephone) was performed at week 2 (D8 ± 1 sky window), week 3 (D15 ± 1 sky window), and week 4 (D22 ± 1 sky window). A mandatory visit was made at week 7 (D43 ± 3 skylights) to provide warfarin or its placebo. For SRI patients, hospitalization/clinical visits were mandatory only after the first injection of SSR126517E or its placebo and at D15 ± 1 skylight.

All patients underwent hospitalization/clinical visits at randomized distances of 3 months (D99 [+7 skylights]) and 6 months (D190 [+7 skylights]).

The platelet count, ASAT, ALAT, creatine blood, and pregnancy test were measured at the end of the study treatment.

‧ The number of platelets is monitored regularly during the treatment with enoxaparin.

‧ Creatine blood is systemically examined in the presence of kidney disease or an extrarenal disorder that may affect renal function.

Measurement of ALAT and total bilirubin (and, if total bilirubin > × 2 ULN, conjugated bilirubin) in the following cases: ‧ in the 3 month hierarchy in D99 [+7 skylight], and in 6 In the monthly hierarchy D99 [+7 skylight] and D190 [+7 skylight], or systemic measurements within 2 weeks after discontinuation of long-term study drug, depending on what happens first; ‧ when clinical signs of liver damage appear.

The long-term study drug was discontinued when it was observed that the total bilirubin of the ×3 ULN and the total bilirubin of x2 ULN (mainly conjugated bilirubin) increased simultaneously and was confirmed by the second test performed within 48 hours. These tests are reviewed on the last 7 days thereafter and continue to be performed until normal or stable conditions are restored.

VTE recurrence was assessed by the above laboratory examination until the end of the study.

The anti-coagulation process can be reversed with open-labeled avidin (SSR29261) when needed in the following situations: in case of life-threatening bleeding, emergency invasive surgery with the possibility of uncontrolled bleeding or overdose under. Double-blind administration of avidin or its placebo was performed prior to implantation of an invasive procedure with the possibility of uncontrolled bleeding, and after the fourth day of discontinuation of the study capsule. If the placebo for biotinylated idrabiparin/biotinylated idrabiparin is reinstated after a previous double-blind administration of avidin or its placebo, this can be repeated in the same environment.

8) Statistical considerations - group analysis

A performance analysis was performed on the All Random Groups group (patients with the number of patients recorded in the IVRS database and assigned treatments).

A first-level efficacy prognosis analysis (secondary efficacy analysis) was also conducted for the “Compliant Program” group.

A bleeding analysis was also performed on the All Random Groups group. For all governance The treatment group implemented other safety analyses.

- sample size

Assuming that the standard treatment group had a 2.4% VTE incidence at 3 months and a pre-specified non-inferiority margin of 2.0 for odds ratios, the sample size of each group of 1600 patients necessarily showed biotinylated Ai Heparin is at least 85% more effective than warfarin and has a one-sided Type I error of 0.025.

- Performance analysis

If the upper limit of the 95% confidence interval for the warfarin advantage ratio of SSR126517E for the first-line efficacy prognosis (recurrence of VTE within 99 days) over the expected duration of treatment (Mantel-Haenszel χ ² analysis) is less than 2.0, then the organism Avidin is considered to be at least as effective as warfarin.

The secondary efficacy prognosis for 6-month-level patients (recurrence of VTE within 190 days) was performed using the same method and applying the same non-inferiority cut-off value analysis.

The time to reach the first symptomatic recurrent PE/DVT during the patient study treatment period was analyzed by Cox's proportional hazard model analysis and stratified over the expected duration of treatment.

- Security analysis

The clinically relevant bleeding ratios at 3 months (99 days) and 6 months (190 days) of each treatment group were calculated and compared between treatment groups using Mantel-Haenszel(R) ² stratified over the expected duration of treatment. The cumulative incidence of clinically relevant bleeding during the 3 month and 6 month period of the combination and up to the end of the study in the treatment group was described using the Kaplan-Mill method.

9) Duration of the study period (per patient)

The duration of treatment pre-specified by the investigator is 3 or 6 months (depending on recurrence) The PE/DVT assessment risk factor is followed by an additional observation period of 13 weeks (3 months) or 13 to 26 weeks (6 months).

10) Results

A total of 3202 patients were randomized, 1599 were in the biotinylated idrabiparin group and 1603 were in the warfarin group.

The statistical characteristics of randomized patients in the two treatment groups were similar.

79% of patients were included in the 6-month class in the biotinylated idrabiparin and warfarin groups.

10-1: Performance results - Level 1 analysis

In all randomized cohorts, biotinylated idrabiparin was at least as effective as warfarin to reduce the risk of symptomatic recurrent PE/DVT until day 99 (p < 0.0001 for non-inferiority testing). The upper limit of 95% CI is 1.25, which is lower than the pre-specified 2.0 non-inferiority threshold.

Note: The odds ratio, 95% CI and p-value are from the Mantel-Haenszel test. Determined to stratify on the expected duration of treatment (3 or 6 months of hierarchy).

^{The a} p-value is used to test the non-inferiority hypothesis (non-inferiority margin: 2.0) at an effective value of 0.025.

- Different components of symptomatic recurrent PE/DVT within 3 months

The incidence of symptomatic recurrent fatal or non-fatal PE was similar in the two treatment groups up to day 99, but for patients with DVT, biotinylated idrabiparin (0.3%) was higher than the warfarin group (1.1 %)less.

- Symptomatic recurrent PE/DVT within 6 months

Biotinylated idrabiparin is at least as effective as warfarin in reducing the risk of symptomatic recurrent PE/DVT in a randomized population of 6 months of class Until day 190 (p=0.0001 for non-inferiority testing). The upper limit of 95% CI is 1.31, which is lower than the pre-specified 2.0 non-inferiority threshold.

Among the randomized patients in the 6-month class, the incidence of symptomatic recurrent fatal or non-fatal PE was similar in the two treatment groups up to day 190, but in patients with DVT, biotinylation The idrate group (0.6%) was less than the warfarin group (1.3%).

- Symptomatic recurrent PE/DVT during the 3 months and 6 months of the combination

The cumulative incidence of symptomatic recurrent PE/DVT at day 99 was 2.2% (biotinylated idrabiparin group) by combining 3 months and 6 months and using event time to analyze the limit data. And 2.7% (warfarer group). On day 190, these cumulative rates were 2.6% and 3.4%, respectively. The hazard ratio was 0.77 (95% CI: 0.51 to 1.17).

The Kaplan-Mill cumulative incidence curve (Figure 1) shows that until about day 50, the incidence of PE/DVT was similar between the two groups, and then began to differentiate, with fewer events occurring in the biotinylated idrabiparin group. .

- Symptomatic recurrent PE/DVT until the end of the study

The cumulative incidence of symptomatic recurrent PE/DVT was 3.1% on day 360, taking into account all events that occurred during the treatment period or during the post-treatment follow-up period of 3 to 6 months (biotinylated Aiqu) Heparin group) and 7.2% (warfarin group). The hazard ratio was 0.49 in 95% CI (0.35 to 0.70), a 51% reduction in the risk of developing symptomatic recurrent PE/DVT, and demonstrated the efficacy of biotinylated idrabiparin compared to warfarin at 12 months. Advantage.

The Kaplan-Mill cumulative incidence curve (Figure 2) shows that after 190 days, the incidence of PE/DVT in the warfarin group tends to increase, whereas in the biotinylated idrabiparin group, this incidence is maintained. stable.

Until the end of the study, the incidence of fatal PE was similar between the two treatment groups, but for patients with non-fatal PE (1.0% vs 2.6%) or DVT (0.6% vs. 1.9%), biotinylated idrabiparin Less group.

Note: In the worst case, the patient is only counted once.

^a or not due to the cause of filing or the death of PE.

- Symptomatic recurrent PE/DVT based on replacement with VKA until the end of the study

In a randomized cohort, other efficacy analyses were performed on patients who were treated with or without warfarin after initial 3 months (D99) or 6 months (D190) treatment with biotinylated idrabi.

As shown in Table 6, patients who did not receive warfarin after biotinylated idrabiparin had a warfarin treatment at 12 months and after initial treatment with biotinylated idrabiparin A similar incidence of recurrent thromboembolic disease confirms the protective effect of biotinylated idrabiparin after treatment with biotinylated idrabiparin.

Table 7 shows the incidence of thrombotic embolism during the period after biotinylated idrabiparin discontinuation (from D100/D191 to the end of the study).

Note: Patients who were not evaluated for recurrent PE/DVT after D100/D191 were excluded from the analysis.

Table 8 shows the results of patients who were initially treated with biotinylated idrabiparin for 6 months, i.e., the majority (80%) of randomized patients.

10-2: Security results - bleeding within 3 months

In the biotinylated idrabis group, there was a statistically significant decrease in the incidence of clinically relevant bleeding (ie, major bleeding or clinically relevant non-major bleeding) up to day 99. The incidence of clinically relevant bleeding in the biotinylated idrabis group was 4.5% vs. 6.6% for the warfarin group (p=0.0098 for test excellence).

Up to day 99, in the case of patients with major bleeding, the biotinylated idrabis group (1.3%) was less than the warfarin group (2.4%), with an odds ratio of 0.51 (95% CI from 0.30 to 0.88). The incidence of intracranial hemorrhage and fatal bleeding was similar between the two groups.

Table 10 - Major bleeding - random groupings occurring within 99 days from randomization

Note: The odds ratio, 95% CI, and p-value were determined by the Mantel-Haenszel test and stratified over the expected duration of treatment (3 or 6 months of stratum).

- bleeding within 6 months

In the 6-month randomized group, the biotinylated idrabis group had less clinically relevant bleeding up to day 190 compared to the warfarin group: 6.6% versus 8.1%. This difference was not statistically significant (p=0.1675), but showed a dominant trend in biotinylated idrabiparin.

^{The a} p-value is tested at the significance level of 0.05 (both sides) to test the advantage hypothesis.

Until day 190, the biotinylated idrabiparin group (1.9%) was less than the warfarin group (2.8%) in patients with major bleeding. The incidence of intracranial hemorrhage and fatal bleeding was similar between the two groups.

- Bleeding during the 3 months and 6 months of the combination

By combining the 3 month and 6 month periods and using the time of occurrence analysis to determine the limit data, the cumulative incidence of clinically relevant bleeding at day 99 was 4.6% (biotinylated idrabiparin group) and 6.7% ( Warfaring Group). On day 190, these cumulative rates were 6.6% and 9.1%, respectively. The hazard ratio was 0.70 (95% CI: 0.54 to 0.91).

The Kaplan-Mill cumulative incidence curve (Figure 3) shows that until the 8th day, the incidence of bleeding was similar between the two groups, and then began to differentiate, where biotin Fewer events occurred in the levothatin group.

- bleeding until the end of the study

By considering all bleeding that occurred during the treatment period or after 3 to 6 months of post-treatment follow-up, the cumulative incidence of clinically relevant bleeding on day 360 was 8.3% (biotinylated idrabiparin) and 10.0% (warfarin) Group) (see Figure 4). The hazard ratio was 0.79 in 95% CI (0.62 to 1.00).

- death

Overall, the number of patients who died in the study was similar in the two treatment groups (biotinylated idrabiparin 5.9% vs. Chinese statin group 5.3%).

10-3: Benefit-risk assessment

Tables 13 and 14 show pulmonary embolism in a randomized population at the treatment stage (treated by biotinylated idrabiparin for 3 months or 6 months) and up to the end of the study (evaluated at 12 months), The incidence of deep vein thrombosis or major bleeding (complex endpoint). These results confirm the improved benefit-risk ratio of biotinylated idrabiparin to warfarin during and after treatment (up to 12 months).

Note: Hazard ratios, 95% CI, and p-values were determined using the Cox proportional hazards model and stratified over the expected duration of treatment (3 or 6 months of stratum).

Note: Hazard ratios, 95% CI, and p-values were determined using the Cox proportional hazards model and stratified over the expected duration of treatment (3 or 6 months of stratum).

11) Conclusion

In this trial, it has been demonstrated that biotinylated idrabiparin is associated with the treatment of PE and the prevention of recurrent venous thromboembolic disease in patients with and without or with DVT compared to warfarin Inferiority. In addition, biotinylated idrabiparin has been shown to be superior to warfarin for safety endpoints (specifically clinically relevant bleeding).

Biotinylated idrabiparin has a better and significantly net clinical benefit within 3 and 6 months of initiation of treatment, with protection up to 12 months without increasing the risk of bleeding.

Analysis at 12th month showed that biotinylated idrabiparin compared to hua The decree has better efficacy (lower recurrent symptomatic DVT/PE risk) and better safety (lower bleeding risk).

Figure 1 shows the Kaplan-Meier cumulative incidence of PE/DVT (fatal or non-fatal) within 3 months and 6 months of the combination (random population).

Figure 2 shows the cumulative incidence of Kaplan-Mill in PE/DVT (fatal or non-fatal) up to the end of the study (random population).

Figure 3 shows the cumulative incidence of Kaplan-Mill in clinically relevant bleeding within a combined 3 month and 6 month period (random population).

Figure 4 shows the cumulative incidence of Kaplan-Mill clinically relevant bleeding up to the end of the study (random population).

Claims (16)

A biotinylated idrabiotaparinux for the treatment of pulmonary embolism in patients with or without deep venous thrombosis and secondary prevention of venous thromboembolism in such patients, The efficacy and safety of this use is clinically proven by Phase III clinical trials. The biotinylated idrabiparin used in claim 1 wherein the clinical trial recruited 3202 patients. Biotinylated idrabiparin as claimed in claim 1 or 2, wherein the clinical trial comprises a patient identified as having acute symptomatic pulmonary embolism with or without deep venous thrombosis of the lower extremity. The biotinylated idrabiparin used in any one of claims 1 to 3, wherein the biotinylated idrabiparin is administered for 3 or 6 months. The biotinylated idrabiparin used in any one of claims 1 to 4, wherein the biotinylated idrabiparin is administered once a week at a dose of 3.0 mg to a patient who does not have severe renal insufficiency; Or once a dose of 1.8 mg is administered once after the initial 3.0 mg dose is administered to patients with severe renal insufficiency. The biotinylated idrabiparin used in any one of claims 1 to 5, wherein the efficacy and safety of such uses are evaluated in comparison to a vitamin K antagonist as a standard antithrombotic therapy. The biotinylated idrabiparin used in any one of claims 1 to 6, wherein the venous thromboembolic disorder is selected from the group consisting of a fatal or non-fatal pulmonary embolism and a deep venous thrombosis. Biotinylated idrabiparin as used in any one of claims 1 to 7, The biotinylated idrabiparin exhibits enhanced safety in terms of bleeding compared to vitamin K antagonists as standard antithrombotic therapies. The biotinylated idrabiparin used in claim 8 wherein the biotinylated idrabiparin exhibits enhanced safety in terms of major bleeding. The biotinylated idrabiparin used in any one of claims 1 to 9, wherein the biotinylated idrabiparin exhibits an improved benefit-risk ratio compared to a vitamin K antagonist as a standard antithrombotic therapy . Biotinylated idrabiparin as used in any one of claims 6, 8 or 10, wherein the vitamin K antagonist is warfarin. The biotinylated idrabiparin used in any one of claims 1 to 11, wherein the efficacy of the biotinylated idrabiparin in such use and its improved benefit-to-risk ratio persists after treatment interruption until Beginning 12 months after treatment with this biotinylated idrabiparin. Biotinylated idrabiparin as claimed in claim 12, wherein the biotinylated idrabiparin is compared to VKA when evaluated at 12 months after 3 to 6 months of treatment with the biotinylated idrabiparin The risk of symptomatic pulmonary embolism and deep venous thrombosis was reduced by 51%. A biotinylated idrabiparin for providing an additional 6 additional patients with or without deep venous thrombosis after an initial 6-month treatment interruption with the biotinylated idrabiparin Prolonged prevention of venous thromboembolic disease in the month. A manufactured article comprising: a packaging material selected from the group consisting of biotinylated idrabiparin or a pharmaceutically acceptable salt thereof And a label or package insert contained in the packaging material, indicating that the compound is effective as an antithrombotic therapy for pulmonary embolism in patients with or without deep venous thrombosis Treatment and secondary prevention of venous thromboembolism in these patients. A manufactured article comprising: a packaging material, a compound selected from the group consisting of biotinylated idrabiparin or a pharmaceutically acceptable salt thereof, and a label or package insert contained in the packaging material, indicating that the compound is safe as an antithrombotic Therapeutic method is used for the treatment of pulmonary embolism in patients with or without deep venous thrombosis and secondary prevention for venous thromboembolism in such patients.