WO2008055092A2

WO2008055092A2 - Use of enoxaparin sodium for treating patients with acute ischemic stroke

Info

Publication number: WO2008055092A2
Application number: PCT/US2007/082788
Authority: WO
Inventors: Luis O. Toro-Figueroa
Original assignee: Aventis Pharma S.A.
Priority date: 2006-10-30
Filing date: 2007-10-29
Publication date: 2008-05-08
Also published as: WO2008055092A3; CL2007003121A1; TW200835509A; AR063530A1

Abstract

Methods for treating acute ischemic stroke in a patient in need thereof comprising administering an effective amount of enoxaparin sodium to the patient for a therapeutic dosing period are described. Also described are methods for preventing or treating thrombosis, such as thrombotic episodes, in a human patient with acute ischemic stroke by treating that patient with enoxaparin.

Description

ADMINISTRATION OF ENOXAPARIN SODIUM TO PATIENTS WITH ACUTE ISCHEMIC STROKE

[001] This invention relates to methods for treating a human patient with acute ischemic stroke. The methods comprise administering enoxaparin sodium (sometimes referred to herein as "enoxaparin") to the human patient. The invention also relates to methods for preventing or treating thrombosis, such as thrombotic episodes or venous thromboses, in a human patient with acute ischemic stroke.

[002] Enoxaparin sodium is available from sanofi-aventis under the trademark Lovenox® (Clexane® in some other countries). Known enoxaparin sodium dosage regimens include those shown below:

Dosage Regimen

Indication Standard Regimen Severe Renal Impairment

Prophylaxis in abdominal surgery 40 mg SC once daily 30 mg SC once daily

Prophylaxis in knee replacement 30 mg SC every 12 30 mg SC once daily surgery hours

Prophylaxis in hip replacement 30 mg SC every 12 30 mg SC once daily surgery hours or 40 mg SC once daily

Prophylaxis in medical patients 40 mg SC once daily 30 mg SC once daily

Inpatient treatment of acute DVT with 1 mg/kg SC every 1 mg/kg SC once or without pulmonary embolism 12 hours (with daily warfarin)

Outpatient treatment of acute DVT 1.5 mg/kg SC once 1 mg/kg SC once without pulmonary embolism daily (with warfarin) daily

Prophylaxis of ischemic 1 mg/kg SC every 1 mg/kg SC once daily complications of unstable angina and 12 hours (with non-Q-wave Ml aspirin)

Elderly: For treatment of acute Ml in elderly patients >=75 years of age, initiate dosing with 0.75 mg/kg SC every 12 hours

[003] Provided is a method for treating a human patient 65 years of age or older with acute ischemic stroke or a mean NIH stroke score of 10 or greater comprising administering to said patient at least one dose of 40 mg of enoxaparin sodium for a therapeutic dosing period. Also provided is a method for preventing or treating thrombosis, such as thrombotic episodes, in a human patient 65 years of age or older with acute ischemic stroke or a mean NIH stroke score of 10 or greater by treating that patient with enoxaparin.

[004] As used herein, "enoxaparin sodium" refers to the low molecular weight heparin (LMWH) approved by the U.S. Food and Drug Administration (FDA), or any other regulatory agency outside of the United States, as Lovenox^® (enoxaparin sodium injection), Clexane^® or Klexane^®, and any LMWH approved by the FDA, or any other regulatory agency outside of the United States, pursuant to an application citing Lovenox^® (enoxaparin sodium injection), Clexane^® or Klexane^® as the listed drug. Enoxaparin sodium is available from sanofi-aventis and sold in the United States in the form of enoxaparin sodium injection, under the trademark Lovenox^® (Clexane^® in some other countries). In general, enoxaparin sodium is obtained by alkaline degradation of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterized, for example, by a 2-0-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-0-disulfo-D-glucosamine at the reducing end of the chain. The average molecular weight is about 4500 daltons. The molecular weight distribution is:

<2000 daltons < 20%

2000 to 8000 daltons > 68%

>8000 daltons < 18%

[005] Enoxaparin sodium injection is a sterile aqueous solution containing enoxaparin sodium. Enoxaparin sodium injection is available from sanofi-aventis at 100 mg/ml in prefilled syringes (30 mg/0.3 mL pre-filled syringes, 40 mg/0.4 mL pre- filled syringes, 60 mg/0.6 mL pre-filled syringes, 80 mg/0.8 mL pre-filled syringes, and 100 mg/1.0 mL pre-filled syringes), graduated prefilled syringes, multiple-dose vials (300 mg/3.0 mL multi-dose vials), and ampoules (30 mg/0.3 mL). Enoxaparin sodium injection 100 mg/mL concentration contains 10 mg enoxaparin sodium (approximate anti-Factor Xa activity of 1000 IU [with reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard]) per 0.1 mL water for injection. Enoxaparin sodium injection is also available from sanofi-aventis at 150 mg/ml in graduated prefilled syringes (90 mg/0.6 mL pre-filled syringes, 120 mg/0.8 mL prefilled syringes, and 150 mg/1.0 mL pre-filled syringes). Enoxaparin sodium injection 150 mg/mL concentration contains 15 mg enoxaparin sodium (approximate anti- Factor Xa activity of 1500 IU [with reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard]) per 0.1 ml_ water for injection.

[006] The enoxapahn sodium injection prefilled syringes and graduated prefilled syringes are preservative-free and intended for use only as a single-dose injection. There are also multiple-dose vials and those contain 15 mg/1.0 ml_ benzyl alcohol as a preservative. The pH of the injection is 5.5 to 7.5. Enoxaparin sodium injection may also be administered in an arterial line for a hemodialysis indication.

[007] As used herein, reference to administration of enoxaparin sodium once daily means, for example, administration every twenty-four hours plus or minus four hours.

[008] The term "prevent," "preventing" and "prevention" refers to the administration of therapy an individual who may ultimately manifest at least one symptom of a disease or condition (e.g., thrombosis) but who has not yet done so, to reduce the chance that the individual will develop the symptom of a disease or condition over a given period of time. Such a reduction may be reflected, for example, in a delayed onset of the at least one symptom of a disease or condition in the patient.

[009] As used herein, the term "treat," "treating" or "treatment" refers to the administration of therapy to an individual who already manifests at least one symptom of a disease or condition {e.g., thrombosis), or who has previously manifested at least one symptom of a disease or condition.

[010] "Body weight" refers to the weight of a patient that is determined by actual weighing or by estimation prior to administration of enoxaparin sodium. In the event that the body weight of a patient is estimated prior to administration of the first dose of enoxaparin sodium, the body weight of the patient may be subsequently determined by actual weighing before any subsequent dose of enoxaparin, and the amount of enoxaparin administered to the patient with the next subsequent dose adjusted accordingly.

[011] "Kg" refers to body weight of the patient in kilograms.

[012] As used herein, "stroke" refers to the new onset of focal or global neurological deficit caused by ischemia or hemorrhage within or around the brain and lasting for more than 24 hours. Intracranial hemorrhage may be diagnosed by appropriate brain imaging, including, for example, a CT or MRI that shows the presence of an acute blood mass. Ischemic or bland infarction may be diagnosed, for example, by appropriate imaging which shows the presence of one or more of the following: hypodensity, edema, midline shift or ventricular effacement without evidence of hemorrhage. Hemorrhagic conversion of an ischemic infarction may be diagnosed by appropriate imaging that shows an ischemic infarction with localized petechial or confluent bleeding into necrotic tissue.

[013] As used herein, "acute ischemic stroke" refers to strokes caused by thrombosis or embolism.

[014] As used herein, "NIH Stroke Scale" refers to National Institutes of Health Stroke Scale (NIHSS), used to measure the severity of neurological dysfunction at the time of a stroke. The Stroke Scale typically is measured within 1 hour of an MRI or CT scan. A score greater than 25 indicates very severe neurological impairment; a score between 15 and 25 indicates severe impairment, while a score between 5 and 15 mild to moderately severe impairment, and a score less than 5 mild impairment.

[015] As used herein, "therapeutic dosing period" refers to the period of time beginning with the administration of a first dose of enoxapahn sodium and ending with the administration of the last dose of enoxaparin sodium on a continuing basis. For example, if enoxaparin sodium is administered approximately every twenty-four hours for a total of nine doses, the therapeutic dosing period is approximately 9 days (or approximately 216 hours), the time between the first dose and the ninth.

[016] Provided is a method for treating a human patient 65 years of age or older with acute ischemic stroke or a mean NIH stroke score of 10 or greater comprising administering to said patient at least one dose of 40 mg of enoxaparin sodium for a therapeutic dosing period. Also provided is a method for preventing or treating thrombosis, such as thrombotic episodes, in a human patient 65 years of age or older with acute ischemic stroke or a mean NIH stroke score of 10 or greater by treating that patient with enoxaparin.

[017] In certain embodiments, prevention of thrombosis comprises prevention of subsequent thrombotic episodes. In certain embodiments, prevention of thrombosis comprises prevention of venous thrombosis. In certain embodiments, treatment of thrombosis comprises treatment of thrombotic episodes. In certain embodiments, treatment of thrombosis comprises treatment of venous thrombosis.

[018] Administration of enoxaparin sodium is, for example, by injection, and further for example, by subcutaneous injection.

[019] In certain embodiments, the therapeutic dosing period is, for example, at least 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or 15 days. In certain embodiments, the therapeutic dosing period is about 10 days.

[020] The dosage of enoxaparin sodium administered during the therapeutic dosing period is, for example, at least 20 mg, from more than 20 mg to less than 60 mg, from 22 mg to 58 mg, from 25 mg to 55 mg, from 27 mg to 52 mg, from 30 mg to 50 mg, from 32 mg to 47 mg, from 35 mg to 45 mg, from 37 mg to 43 mg, about 40 mg, or 40 mg. In certain embodiments, about 40 mg (or 40 mg) of enoxaparin sodium is administered. Typically, the enoxaparin sodium will be administered once daily.

[021] In certain embodiments, the therapeutic dosing period is initiated with 48 hours of onset of stroke symptoms. In certain embodiments, the patient undergoes a CT or MRI scan prior to administration of enoxaparin sodium to, e.g., confirm the diagnosis of acute ischemic stroke.

[022] In certain embodiments, the patient is unable to walk without assistance due to motor impairment of one or both legs. In certain embodiments, the motor impairment has lasted for at least 24 hours prior to administration of enoxaparin sodium.

[023] The patient receiving enoxparin sodium typically will be 65 years of age or greater. In certain embodiments, the patient is, for example, at least 70 years of age, at least 75 years of age, at least 80 years of age, at least 85 years of age, or at least 90 years of age.

[024] In certain embodiments, the patient exhibits a NIH stroke score of, for example, at least 10, at least 11 , at least 12, at least 13, at least 14, or at least 15. In certain embodiments, the NIH stroke score is between about 5 and 15. In certain embodiments, the NIH stroke score is about 11.

[025] In certain embodiments, enoxaparin is administered in an amount sufficient to reduce the primary end-point of symptomatic or asymptomatic deep-vein thrombosis (DVT), symptomatic pulmonary embolism (PE), or fatal PE, during treatment, as compared with an ACT-adjusted UFH regimen. DVT may be confirmed primarily by venography, or ultrasonography when venography was not practical. PE may be confirmed by VQ scan, CT scan, or angiography.

[026] In certain embodiments, administration of enoxapahn significantly reduced the incidence of the primary efficacy endpoint from by, for example, at least 30%, at least 35%, or at least 40%. In certain embodiments, the relative risk reduction was about 44%.

[027] In certain embodiments, the patient is administered at least one additional therapeutic agent. Such "co-therapy" (or "combination-therapy") may include the following examples: administration of each agent in a sequential manner in a regimen to provide beneficial effects of the drug combination; and/or co-administration of the aforementioned components in a substantially simultaneous manner (e.g., as in a single injection having a fixed ratio of these active agents or in multiple, separate injections for each agent, etc.).

[028] Thus, the methods described herein are not limited in the sequence of administration; the enoxaparin sodium may be administered either prior to, at the same time with or after administration of the other agent. In addition, enoxaparin sodium may be administered alone or in combination with other treatments, e.g., drug-eluting stent.

[029] In certain embodiments, the at least one additional therapeutic agent is chosen from thrombolytic agents, fibrinolytic agents, neuroprotective agents, and antiplatelet agents. In certain embodiments, the at least one additional therapeutic agent is a thrombolytic agent chosen from alteplase, anistreplase, reteplase, urokinase and streptokinase. In certain embodiments, the at least one additional therapeutic agent is a neuroprotective agent chosen from caspase inhibitors, glutamate antagonists, calcium antagonists, opiate antagonists, GABA-A agonists, calpain inhibitors, NMDA receptor antagonists, K.sup.÷ channel modulators, PDH kinase inhibitors, and antioxidants. In certain embodiments, the at least one additional therapeutic agent is an antiplatelet agent chosen from aspirin, clopidogrel, ticlopidine, abciximab, eptifibatide, tirofiban and dipyridamole.

[030] In certain embodiments, the at least one additional therapeutic agent is a GP llb/llla inhibitor. In certain embodiments, the GP llb/llla inhibitors include abciximab (marketed as ReoPro^®), tirofiban (marketed as Aggrastat^®), and eptifibatide (marketed as Integrelin^®). In certain embodiments, the at least one additional therapeutic agent is tissue plasminogen activator. In certain embodiments, the at least one additional therapeutic agent is dipyridamole, such as extended release dipyridamole. I

[031] In certain embodiments, prevention of thrombosis comprises prevention of thrombotic episodes. In certain embodiments, treatment of thrombosis comprises treatment of thrombotic episodes.

[032] In providing enoxaparin sodium dosage regimens, the dosage regimen for administration of enoxaparin sodium is based on the particular indication. For each indication, methods are provided herein that include methods for preventing and/or treating acute ischemic stroke in a human patient.

[033] It will be readily apparent to one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the methods and applications described herein are suitable and may be made without departing from the scope of the invention or any embodiment thereof. Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples of the invention, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention.

EXAMPLE 1 : Prevail Study

[034] Patients with an acute ischemic stroke, confirmed by CT scan, and unable to walk without assistance due to motor impairment of the leg were enrolled in a prospective, open-label, parallel group, multicenter study. Patients were randomized within 48 hours of stroke symptoms to receive enoxaparin 40 mg SC o.d. or unfractionated heparin (UFH) 5000 IU SC q12h, for 10±4 days. The primary efficacy endpoint was the composite of symptomatic or asymptomatic deep-vein thrombosis (DVT), symptomatic pulmonary embolism (PE), or fatal PE, during treatment. DVT was confirmed primarily by venography, or ultrasonography when venography was not practical. PE was confirmed by VQ scan, CT scan, or angiography. Primary safety endpoints included clinically significant intracranial bleeding and major extracranial bleeding.

[035] 1762 acute ischemic stroke patients from 15 countries were randomized. Baseline characteristics were similar between groups. The mean age was 66.0 ± 12.9 years and the mean NIH stroke score was 11.3. In the efficacy population (enoxaparin, n=666; UFH, n=669), the mean duration of prophylaxis was 10.5 days for both enoxaparin and UFH. Compared with UFH, enoxaparin significantly reduced the incidence of the primary efficacy endpoint from 18.1 % (121/669) to 10.2% (68/666), corresponding to a 44% relative risk reduction (p=0.0001 , adjusted for NIH stroke score stratification). The combined incidence of clinically significant intracranial and major extracranial bleeding was small and similar between groups (1.3% enoxaparin vs 0.7% UFH, p=0.2275).

[036] Among other things, the results of the Prevail Study indicate that enoxaparin 40 mg o.d. is significantly more effective than UFH q12h for preventing VTE in acute ischemic stroke patients, with similar safety.

EXAMPLE 2: Treatment of a Stroke Patient

[037] A patient who has suffered an acute ischemic stroke is identified. The patient is 66 years old and the NIH stroke score of the patient is determined to be 11.3. Enoxaparin is administered to the patient at a dose of 40 mg by subcutaneous injection once a day for ten days. During the ten days of treatment the patient does not suffer from any of symptomatic or asymptomatic deep-vein thrombosis (DVT), symptomatic pulmonary embolism (PE), or fatal PE, during treatment. The patient also does not suffer clinically significant intracranial bleeding or major extracranial bleeding during the ten days of treatment.

[038] While the administration of enoxaparin sodium has been described in connection with certain embodiments, it is not intended to limit the invention to the particular forms set forth, but on the contrary, it is intended to cover such alternatives, modifications and equivalents as may be included within the spirit and scope of the invention as defined by the following claims.

Claims

What is claimed is:

1. A method for treating a human patient 65 years of age or older with acute ischemic stroke or a mean NIH stroke score of 10 or greater comprising administering to said patient at least one dose of 40 mg of enoxaparin sodium for a therapeutic dosing period.

2. The method of claim 1 wherein enoxaparin sodium is administered by injection.

3. The method of claim 2 wherein enoxaparin sodium is administered by subcutaneous injection.

4. The method of claim 1 wherein the therapeutic dosing period is at least 6 days.

5. The method of claim 4 wherein the therapeutic dosing period is about 10 days.

6. The method of claim 1 wherein enoxaparin sodium is administered at a dosage of at least 20 mg once daily.

7. The method of claim 6 wherein enoxaparin sodium is administered at a dosage of about 40 mg once daily.

8. The method of claim 7 wherein enoxaparin sodium is administered at a dosage of 40 mg once daily.

9. The method of claim 1 wherein the therapeutic dosing period is initiated with 48 hours of onset of stroke symptoms.

10. The method of claim 1 wherein the patient undergoes a CT scan prior to administration of enoxaparin sodium.

11. The method of claim 1 wherein the patient is unable to walk without assistance due to motor impairment of one or both legs.

12. The method of claim 11 wherein the motor impairment has lasted for at least 24 hours prior to administration of enoxaparin sodium.

13. The method of claim 1 wherein enoxaparin sodum is administered in an amount sufficient to reduce the primary end-point of symptomatic or asymptomatic deep-vein thrombosis (DVT), symptomatic pulmonary embolism (PE), or fatal PE, during treatment, as compared with an ACT-adjusted UFH regimen.

14. The method of claim 1 wherein the patient is administered at least one additional therapeutic agent.

15. The method of claim 14 wherein the at least one additional therapeutic agent is chosen from thrombolytic agents, fibrinolytic agents, neuroprotective agents, and antiplatelet agents.

16. A method for preventing or treating thrombosis comprising administering to a human patient 65 years of age or older with acute ischemic stroke or a mean NIH stroke score of 10 or greater at least one dose of 40 mg of enoxaparin sodium for a therapeutic dosing period.

17. The method of claim 16 wherein enoxaparin sodium is administered by injection.

18. The method of claim 17 wherein enoxaparin sodium is administered by subcutaneous injection.

19. The method of claim 18 wherein the therapeutic dosing period is at least 6 days.

20. The method of claim 19 wherein the therapeutic dosing period is about 10 days.

21. The method of claim 16 wherein enoxaparin sodium is administered at a dosage of at least 20 mg once daily.

22. The method of claim 21 wherein enoxaparin sodium is administered at a dosage of about 40 mg once daily.

23. The method of claim 22 wherein enoxaparin sodium is administered at a dosage of 40 mg once daily.

24. The method of claim 16 wherein the therapeutic dosing period is initiated within 48 hours of onset of stroke symptoms.

25. The method of claim 16 wherein the patient undergoes a CT scan prior to administration of enoxaparin sodium.

26. The method of claim 16 wherein the patient is unable to walk without assistance due to motor impairment of one or both legs.

27. The method of claim 26 wherein the motor impairment has lasted for at least 24 hours prior to administration of enoxaparin sodium.

28. The method of claim 16 wherein enoxaparin sodum is administered in an amount sufficient to reduce the primary end-point of symptomatic or asymptomatic deep-vein thrombosis (DVT), symptomatic pulmonary embolism (PE), or fatal PE, during treatment, as compared with an ACT-adjusted UFH regimen.

29. The method of claim 16 wherein the patient is administered at least one additional therapeutic agent.

0. The method of claim 29 wherein the at least one additional therapeutic agent is chosen from thrombolytic agents, fibrinolytic agents, neuroprotective agents, and antiplatelet agents.