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`Date: ApA_; J; 447 c2oot.f
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`Express Mail Label No.
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`EV 373377224 US
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`Inventor:
`Attorney's Docket No.:
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`Elliot Ehrich
`4000.3010 us
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`NAL TREXONE LONG ACTING FORMULATIONS AND METHODS OF USE
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`BACKGROUND OF THE INVENTION
`Alcohol dependence is a chronic disorder that results from a variety of genetic,
`psychological and environmental factors. Traditional treatment has consisted of two
`phases: detoxification and rehabilitation. Detoxification ameliorates the symptoms and
`signs of withdrawal; rehabilitation helps the patient avoid future problems with alcohol.
`In the past, most rehabilitative treatments have been psychosocial. With advances in
`neurobiology, there is increasing interest in drug therapy for alcohol dependence. For a
`discussion of the development of this field, see Swift, R., Drug Therapy for Alcohol
`Dependence, NEJM, May 13, 1999, 1482-1490. Yet, the successful treatment of
`alcoholism has many serious challenges and complications. Patient compliance is a
`serious problem.
`Accordingly, there is a need for improving naltrexone therapies.
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`SUMMARY OF THE INVENTION
`The inventions described herein arose from unexpected discoveries made during
`clinical trials with a long acting formulation of naltrexone. As such, the invention
`includes a method for treating an individual in need of naltrexone comprising the step of
`parenterally administering a long acting formulation comprising naltrexone to the
`individual wherein the serum AUC of naltrexone is at least about two times, preferably
`at least about three times, more preferably about 3.3 times greater than that achieved by
`50 mg/day oral administration.
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`The inventions also include a method of treating an individual in need of
`naltrexone comprising administering a long acting formulation in a dose comprising at
`least about 160 mg of naltrexone, preferably between about 160 mg and about 480 mg
`naltrexone, more preferably between about 160 and 240 mg of naltrexone or about 310
`to about 480 mg of naltrexone.
`The inventions also include a method of treating an individual in need of
`naltrexone comprising administering naltrexone, such as in a long acting formulation, in
`the absence of co-administering alcohol, to an individual who has not abstained from
`alcohol within three days, such as five days, prior to the naltrexone administration.
`The inventions include a method of increasing the days prior to occurrence of
`alcohol consumption in an individual in need of naltrexone comprising administering a
`long acting formulation comprising naltrexone, in the absence of co-administering
`alcohol, to an individual who has not abstained from alcohol within three days, such as
`five days, prior to the naltrexone administration.
`The inventions include a method of treating an individual in need of naltrexone
`comprising administering a long acting formulation comprising naltrexone in a dosage
`between about 160 mg to about 480 mg naltrexone every four weeks for a period of
`about 24 weeks or more wherein the individual has not used oral naltrexone within five
`days, such as within ten days, before said administration.
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`BRIEF SUMMARY OF THE ORA WINGS
`Figure lA-lC shows the cumulative mean event rate of heavy drinking during
`the study by treatment group and gender. As an example, at day 100, the mean number
`of cumulative heavy drinking days for the overall .study population was 22.3 for the
`long-acting naltrexone 380 mg patients, 27.3 for long-acting naltrexone 190 mg
`patients, and 30.0 for placebo patients.
`Figure 2 shows median heavy drinking days per month for each treatment group,
`overall and by gender.
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`DETAILED DESCRIPTION OF THE INVENTION
`The inventions relate to the administration of a naltrexone containing
`formulation, preferably a long acting naltrexone formulation, to patients in need thereof
`and to the use of naltrexone in the manufacture of medicaments for use in such
`5 methods.
`In one embodiment, the invention includes a method for treating an individual in
`need of naltrexone comprising the step of parenterally administering a long acting
`formulation comprising naltrexone to the individual wherein the serum AUC of
`naltrexone is at least about two times, preferably at least about three times, more
`preferably about 3.3 times greater than that achieved by 50 mg/day oral administration.
`This invention arose from the unexpected discovery that substantially improved serum
`levels of naltrexone can be achieved by administering long acting formulations of
`naltrexone, such as the Alkermes, Inc. formulation, Vivitrex® injectable suspension,
`made employing its Medisorb® delivery system. Indeed, it was not expected that serum
`levels of about 3.3 times that achieved by a 50 mg/day oral dose could be achieved by a
`single IM administration of Vivitrex®.
`The inventions also include a method of treating an individual in need of
`naltrexone comprising administering naltrexone, such as in a long acting formulation, in
`the absence of co-administering alcohol, to an individual who has not abstained from
`alcohol within three days, such as five days, prior to the naltrexone administration. In
`this embodiment, it was unexpectedly discovered that good to excellent results could be
`achieved without either requiring alcohol abstinence or requiring alcohol consumption
`during therapy, as taught by Sinclair, United States Patent No. 4,882,335. Further, good
`to excellent results were achieved in patients that did not receive oral. naltrexone in
`advance of the long acting formulation administration, contrary to the clinical protocols
`as taught by Drug Abuse Sciences. Thus, the inventions also include administering a
`long acting formulation to individuals who did not receive a prior oral dose of
`naltrexone, for example, within 3, such as within about 5 days or about 10 days of
`commencing therapy.
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`As such, the inventions also include a method of treating an individual in need
`of naltrexone comprising administering a long acting formulation in a dose comprising
`between about 160 mg and 240 mg of naltrexone or about 310 mg to about 480 mg of
`naltrexone and formulations for use in the methods described herein .. Preferred
`formulations are administered in a dose comprising about 190 mg or about 380 mg
`naltrexone.
`The naltrexone can be in any form, including anhydrous, hydrate, solvate or salt
`forms or combinations thereof. It can be crystalline or non-crystalline or combinations
`thereof. A preferred naltrexone form comprises a naltrexone ethanolate, such as that
`described in United States Patent Application No. 60/475,863, filed on June 4, 2003,
`which is incorporated herein by reference and/or anhydrous naltrexone. A particularly
`preferred naltrexone form is that produced by the encapsulation process described in
`United States Patent No. 6,264,987, by Wright et al., which is incorporated herein by
`reference.
`The naltrexone can be combined with any of the well-known biodegradable and
`bioerodible carriers, such as polylactides, poly(lactic acids) and poly-lactide-co-
`glycolides and collagen formulations. A particularly preferred polymer is a polylactide-
`co-glycolide polymer which possesses a molecular weight of at least 100,000 daltons,
`such as those described below in the exemplification. Such materials may be in the
`form of solid implants, sponges, and the like.
`As stated above, the naltrexone is preferably in a long acting formulation. Long
`acting (also referred to as extended, sustained, or controlled release) preparations may
`be achieved through the use of polymers (preferably poly-lactide or poly-lactide-co-
`glycolide polymers) to entrap or encapsulate the naltrexone described herein. Extended
`release formulations can be made by spray drying polymer-drug mixtures, emulsion-
`based technologies, coacervation based technologies, film casting, extrusion based
`technologies and other processes to manufacture polymer-drug microparticles
`possessing an extended release profile. Examples of suitable extended release
`technologies that can be used to incorporate the novel naltrexone forms described herein
`include, without limitation, the MEDISORB® technology, as described in, for example,
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`US Patent Nos. 6,264,987 to Wright, 5,654,008 and/or 5,792,477, for example; the
`PROLEASE® technology, as described, for example in US Patent 6,358,443 to Herbert;
`the technologies described by Southern Research Institute, as described for example in
`US Patents 6,306,425 and 5,407,609; and "Method of Preparing Sustained Release
`5 Microparticles," U.S. Application No. 60/441,946, filed January 23, 2003, and the
`technologies described by Alza Corp., including the ALZAMER® Depot injection
`technology. The contents of these patents are incorporated herein by reference in their
`entirety.
`In a preferred embodiment, the long acting formulation delivers therapeutically
`beneficial amounts of naltrexone to the patient for a period of at least one week,
`preferably at least about two weeks, more preferably at least about 3 or about 4 or more
`weeks. A four week delivery is often referred to as a monthly delivery.
`In one preferred embodiment, the naltrexone is present in the extended release
`device or formulation in an amount of at least about 5% by weight, preferably at least
`about I 0% by weight, more preferably at least about 30% by weight, such as about 35%
`by weight naltrexone of the total weight of the device, or formulation.
`Alternatively, instead of incorporating naltrexone into polymeric particles, it is
`possible to entrap these materials in microparticles prepared, for example, by
`coacervation techniques or by interfacial polymerization (for ex~mple,
`hydroxymethylcellulose or gelatine-microcapsules and poly-(methylmethacrylate)
`microcapsules, respectively), in colloidal drug delivery systems (for example,
`liposomes, albumin, microparticles, microemulsions, nanoparticles, and nanocapsules),
`or in macroemulsions.
`When the composition is to be used as an injectable material, including but not
`limited to needle-less injection, it can be formulated into a conventional injectable
`carrier. Suitable carriers include biocompatible and pharmaceutically_ acceptable
`solutions. The injection can be intramuscular or subcutaneous.
`While the formulation may contain additional excipients, as is well known in the
`art, the present invention can achieve an excellen~ release profile with the simple
`formulation described herein. Such additional excipients can increase or decrease the
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`rate of release of the agent. Ingredients which can substantially increase the rate of
`release include pore forming agents and excipients which facilitate polymer
`degradation. For example, the rate of polymer hydrolysis is increased in non-neutral pH.
`Therefore, an acidic or a basic excipient such as an inorganic acid or inorganic base can
`be added to the polymer solution, used to form the microparticles, to alter the polymer
`erosion rate.
`A preferred embodiment of the described sustained release formulations consists
`essentially of the biocompatible polymer and naltrexone. By "consists essentially of' is
`meant the absence of ingredients which substantially increase the rate of release of the
`active agent from the formulation. Examples of additional excipients which would not
`be expected to substantially increase or decrease the rate of release of the agent include
`additional active agents and inert ingredients.
`In yet another embodiment, the formulation consists of the biocompatible
`polymer and naltrexone. By "consists of' is meant the absence of components or
`ingredients other than those listed and residual levels of starting materials, solvents, etc.
`from the process.
`As stated above, the formulation preferably releases naltrexone over a period of
`at least about one, two, three or four weeks. As such, the formulation can be
`administered using a dosing schedule which achieves the desired therapeutic levels for
`the desired period oftime. For example, the formulation can be administered and,
`optionally, the patient monitored until levels of the drug being delivered return to
`baseline. Following an actual or projected return to baseline, the formulation can be
`administered again. Alternatively, the subsequent administration of the formulation can
`occur prior to achieving baseline levels in the patient. As such, the formulation can be
`advantageously administered weekly, with a one week release formulation, biweekly.
`with a two week release formulation, or monthly with a four week release formulation.
`Vivitrex is a four week release formulation with a monthly (e.g., every four weeks)
`administration. The therapy can end after a single dose or can be maintained for longer
`periods oftime. In one embodiment, the therapy can maintained for at least about 4, 8,
`12, 16, 20 and 24 weeks or more. Where more than one administration is given, the
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`second administration can be given at least about 7 days, preferably at least about 14
`days, more preferably at least about 21 days, such as about 28 days, after the first
`administration and combinations thereof. In this context "about" preferably means
`within three days of the targeted date.
`Particularly good results were achieved upon administering the same
`formulation and same dose with each administration. Thus, where a 380 mg dose was
`given in the first administration, good to excellent results were achieved when the
`second and subsequent doses were about 380 mg. Surprisingly, good to excellent
`results were also obtained when each dose administered contained 190 mg naltrexone,
`particularly in men and women who were abstinent from alcohol in the three or five
`days prior to commencing treatment. As such, in one embodiment of the invention, the
`doses and/or formulations administered in each subsequent administration were similar
`or the same. As stated above, the formulation is preferably a microsphere formulation
`and is administered by IM injection. Administration to the buttock in a volume of up to
`about 4 mL in an injectable diluent was performed in the trials leading up to these
`inventions.
`The methods of the inventions achieved good to excellent results in women and,
`in particular, men. Good to excellent results were achieved in young individuals
`(defined as less than 50 years of age), particularly men. Individuals afflicted by alcohol
`dependency, such as a heavy drinker achieved good to excellent results. A heavy
`drinker is understood in the art to include women who consume four or more alcoholic
`beverages in a day and men who consume five or more alcoholic beverages in a day.
`In yet another embodiment, the inventions include a method of increasing the
`days prior to occurrence of alcohol consumption in an individual in need of naltrexone
`comprising administering a long acting formulation comprising naltrexone in
`accordance with the protocols and/or dosing regimens described herein. In one
`embodiment, the increase in days prior to occurrence of alcohol consumption can
`include the consumption of a single alcoholic beverage or it can include consumption of
`four or five alcoholic beverages, such as the number of drinks characterizing an episode
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`of "heavy drinking," above. In general, the greater the number of days that transpire
`prior to alcohol consumption indicates a more successful therapy.
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`EXEMPLIFICATION
`5 Method for Manufacturing Vivitrex® Long Acting Formulations
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`The invention includes a preferred method for manufacturing ·extended release
`devices, wherein the resulting device contains a mixture of the described polymorphic
`forms.
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`Polymer solution can be formed by dissolving a poly(lactide )-co-glycolide
`polymer, such as a 75:25 DL PLGA (poly(lactide)-co-glycolide) in a polymer solvent,
`such as ethyl acetate (EtAc), to form a solution. Preferred PLGA polymers are high
`molecular weight polymers, such as polymers possessing a molecular weight of at least
`about 100,000 daltons. A naltrexone solution can be formed by dissolving naltrexone
`base in a suitable solvent, such as benzyl alcohol (BA), to form a solution. The polymer
`solution and the naltrexone solution are preferably mixed together to form a
`drug/polymer solution that will be the "organic" or "oil" phase of the. emulsion.
`The "aqueous" or "continuous" phase of the emulsion (emulsifying solution) is
`prepared. The aqueous phase preferably contains poly(vinyl alcohol) (PVA) and
`polymer solvent, such .as EtAc. The organic phase and the aqueous phase can be
`conveniently combined in a first static mixer to form an oil-in-water emulsion.
`In an optional partial extraction step, the emulsion flows out of the first static
`mixer and into a second static mixer where the emulsion can be combined with a
`primary extraction solution which enters the second static mixer. The primary
`extraction solution (such as can be formed by an EtAc aqueous solution) can initiate
`solvent extraction from the microdroplets of the emulsion during the partial primary
`extraction step in the second static mixer.
`The outflow of the first or second static mixer can flow into ah extraction vessel
`containing primary extraction solution. The solvents (BA and EtAc) are substantially
`extracted from the organic phase of the emulsion in this primary solvent extraction step,
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`resulting in nascent microparticles comprised mainly of polymer and drug. The primary
`solvent extraction step lasts for approximately six hours.
`The microparticles can be collected, and vacuum dried, optionally with a
`nitrogen bleed using a customized vibratory sieve. After collection and prior to drying,
`the microparticles are rinsed with a 25% ethanol solution that removes the emulsifying
`agent (PVA), and enhances yield by aiding in the transfer of the microparticles to the
`cold dryer. This step is conducted, preferably at cold temperatures, until the desired
`level of dryness is achieved. As can be seen in the examples below, the degree of
`dryness (as measured, for example, by a humidity probe), impacts upon the degree of
`crystallinity achieved in the final product. For example, it can be advantageous to select
`a drying time of at least about 8, 16, 24 or 40 hours of drying. For example, it can be
`advantageous to select a drying time of at least about 8, 16, 24 or 40 hours where drying
`is 40%, 70%, 95% or 100% complete respectively. Drying is considered complete when
`the absolute humidity of the effluent gas reaches approximately 0 g/m3•
`The microparticles can then be resuspended in a second extraction solution. The
`second solution can contain the solvent desired to form the polymorphic form, such as
`ethanol. For example, a solution comprising at least about 10% by volume, preferably
`at least about 20% ethanol, can be used. This can be conveniently called the reslurry
`and secondary solvent extraction steps. The solvent, such as ethanol, can facilitate
`further extraction of BA and EtAc. Further, the crystallinity of the drug increases
`during the step. The secondary solvent extraction step is carried out in an extraction
`vessel for approximately two, three, four or more hours. This step can be conveniently
`completed at room temperature. However, other temperatures can be selected as well.
`In the collection/final dry step, the microparticles are collected, and vacuum dried with
`a nitrogen bleed using a customized vibratory sieve.
`In the final harvest step, the microparticles can be transferred into a sterile
`container and stored, for example, in a freezer at -20°C, until filling into vials.
`Preferably, the stored microparticles are sieved through a 150 micro.n screen to remove
`any oversized material prior to filling into vials.
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`Example 1
`The naltrexone base microparticles were produced using a co~solvent extraction
`process. The theoretical batch size was 15 to 20 grams. The polymer (MEDISORB®
`7525 DL polymer, MEDISORB® 8515 DL polymer and MEDISORB® 6536 DL
`polymer, all available from Alkermes, Inc., Blue Ash, Ohio.) was dissolved in ethyl
`acetate to produce a 16. 7% w/w polymer solution. The naltrexone base anhydrous was
`dissolved in benzyl alcohol to produce a 30.0% w/w solution. In various batches, the
`amount of drug and polymer used was varied to produce microparticles with different
`theoretical drug loading ranging from 30%-75%. The ambient polymer and drug
`solutions were mixed together until a single homogeneous solution (organic phase) was
`produced. The aqueous phase was at ambient conditions and contained I% w/w
`polyvinyl alcohol and a saturating amount of ethyl acetate. These two solutions were
`pumped via positive displacement pumps at a ratio of 3: 1 (aqueous: organic) through a
`114" in-line mixer to form an emulsion. The emulsion was transferred to a stirring
`solvent extraction solution consisting of 2.5% w/w of ethyl acetate dissolved in distilled
`water at 5-10° C, at a volume of 0.5L of extraction solution per theoretical gram of
`microparticles. Both the polymer and drug solvents were extracted into the extraction
`solution from the emulsion droplets to produce microparticles. The initial extraction
`process ranged from two to four hours. The microparticles were collected on a 25 µm
`sieve and rinsed with a cold ( <5°C) 25% w/w ethanol solution. The microparticles were
`dried cold overnight (approximately 17 hours) using nitrogen. The microparticles were
`then transferred to the reslurry solution, which consisted of a vigorously stirring 25%
`w/w ethanol solution at 5-10°C After a short mixing time (five to fifteen minutes), the
`reslurry solution and the microparticles were transferred to a stirring 25% w/w ethanol
`~econdary extraction solution (approximately 25°C at a volume of0.2 L of secondary
`extraction solution per theoretical gram of microparticles ). The microparticles stirred
`for six hours enabling additional solvent removal from the microparticles to take place.
`The microparticles were then collected on a 25 µm sieve and rinsed 'Yith a 25% w/w
`ethanol solution at ambient temperature. These microparticles dried in a hood under
`ambient conditions overnight (approximately 17 hours), were sieved to remove
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`agglomerated microparticles and then placed into a freezer for storage.
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`Example 2
`A 1 kg batch of naltrexone microspheres was prepared as follows. Polymer
`solution was formed by dissolving 75:25 DL PLGA (poly(lactide)-co-glycolide) in ethyl
`acetate (EtAc) to form a solution of 16.7% polymer and 83.3% EtAc. A naltrexone
`solution was formed by dissolving naltrexone base in benzyl alcohol (BA) to form a
`solution of 30% naltrexone base anhydrous and 70% BA. The polyrrier solution and the
`naltrexone solution were mixed together to form a drug/polymer solution that was the
`"organic" or "oil" phase of the emulsion.
`The "aqueous" or "continuous" phase of the emulsion (emulsifying solution)
`was prepared by dissolving poly( vinyl alcohol) (PV A) and EtAc in water-for-injection
`(WFI). The organic phase and the aqueous phase were combined in a first static mixer
`to form an oil-in-water emulsion. The droplet size of the emulsion was determined by
`controlling the flow rates of the two phases through the first static mixer.
`In a partial primary extraction step, the emulsion flowed out of the first static
`mixer and into a second static mixer where the emulsion was combined with a Primary
`extraction solution which enters the second static mixer. The primary extraction
`solution (2.5% EtAc and 97 .5% WFI at approximately 6°C) initiated solvent extraction
`from the microdroplets of the emulsion during the partial primary extraction step in the
`second static mixer.
`The outflow of the second static mixer (combined flow stream of the emulsion
`and the primary extraction solution) flowed into an extraction vessel containing primary
`extraction solution. The solvents (BA and EtAc) were further extracted from the
`organic phase of the emulsion in this primary solvent extraction step, resulting in
`nascent microparticles comprised mainly of polymer and drug. The primary solvent
`extraction step lasted for approximately six hours.
`The microparticles were collected, and vacuum dried with a nitrogen bleed using
`a customized vibratory sieve. After collection and prior to drying, the microparticles
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`were rinsed with a 25% ethanol solution that removes the emulsifying agent (PV A), and
`enhances yield by aiding in the transfer of the microparticles to the dryer.
`To further reduce the solvent levels the microparticles were resuspended in a
`second extraction solution of 25% ethanol and 75% WFI in the reslurry and secondary
`solvent extraction steps. The ethanol facilitated further extraction of BA and EtAc. The
`secondary solvent extraction step was carried out in an extraction vessel for
`approximately four hours. In the collection/final dry step, the microparticles were
`collected, and vacuum dried with a nitrogen bleed using a second customized vibratory
`sieve.
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`In the final harvest step, the microparticles were transferred into a sterile
`container and stored in a freezer at -20°C until filling into vials. Preferably, the stored
`microparticles were sieved through a 150 micron screen to remove any oversized
`material prior to filling into vials.
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`Example 3
`Screening and Eligibility Criteria
`Participants were male or nonpregnant, nonlactating female outpatients ~ 18
`years old with a current diagnosis of alcohol dependence. Patients had a minimum of
`two episodes of heavy drinking (~5 alcoholic drinks/day for men and.~4 drinks/day for
`women) per week during the 30 days prior to screening.
`Exclusion criteria included evidence of liver failure; alanine aminotransferase
`(ALT) or aspartate aminotransferase (AST) levels greater than three times the upper
`limit of normal; history of pancreatitis; major depression with suicidal ideation,
`psychosis, or bipolar disorder (patients with treated depression and stable
`pharmacotherapy for at least 8 weeks were not excluded); dependence within the past
`year on benzodiazepines, opiates, or cocaine; more than 7 days of inpatient treatment
`for substance abuse during the month prior to screening; or use of opiates, oral
`naltrexone, or disulfiram during the two weeks prior to screening.
`Detoxification prior to randomization was performed only if indicated by
`investigator judgment and had to be completed seven days before initiation of study
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`therapy. Use of benzodiazepines was prohibited during the week prior to the first dose
`of study medication.
`Randomization procedures
`Patients were randomized to one of three treatment groups: long-acting
`injectable naltrexone 380 mg, long-acting injectable naltrexone 190 mg, or matching
`volumes of placebo (one-half of the placebo patients received an injection volume
`corresponding to 380 mg and the other halfreceived an injection volume
`corresponding to 190 mg). The study used a dynamic randomization procedure to
`balance allocation on gender, patient-specified goal of total abstinence, self-reported
`abstinence for the 7-day period prior to first injection, and study site.
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`Study Procedures and Outcome Definitions
`Patients received an injection of study medication at 4-week intervals over 24
`weeks, alternating between the left and right gluteus maximus. Injections were
`prepared and administered by individuals who were not involved in any of the safety
`or efficacy assessments, and treatment assignment was blinded to all study personnel.
`All patients received standardized supportive therapy (12 sessions) using the
`BRENDA model (Volpicelli JR, Pettinati HM, McLellan AT, O'Brien CP. Combining
`medication and psychosocial. treatments for addictions: the BRENDA approach. New
`20 York: The Guilford Press; 2001), a six-stage low-intensity intervention designed to
`facilitate direct feedback with respect to addiction-related consequences. During this
`trial, BRENDA sessions were administered by study site personnel including
`psychologists, nurses, therapists, counselors, and physicians.
`The number of standard drinks consumed per day was recorded using the
`Timeline Follow Back (TLFB) method (Sobell LC, Sobell MB. Timeline Followback:
`a technique for assessing self-reported ethanol consumption. In: Allen J, Litten RZ,
`eds. Measuring alcohol consumption: psychosocial and biological methods. Totowa,
`NJ: Humana Press, 1992:41-72). Breath alcohol levels of ~0.02 gm/dL were required
`before self-report data were collected. Patients who discontinued study drug treatment
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`prematurely were allowed to remain in the study, continue to follow the established
`visit and procedure schedule, and receive BRENDA treatment.
`
`Study Formulation: Naltrexone long-acting injection (Vivitrex®) consists of
`5 microspheres (approximately 100 µM) composed of naltrexone and polylactide-co-
`glycolide polymeric matrix (Medisorb®), a common biodegradable medical polymer
`with an extensive history of human use in absorbable sutures and extended-release
`pharmaceuticals. Following injection, naltrexone on the surface of the microspheres is
`released, yielding peak concentrations within three days. Thereafter, by a combination
`of diffusion and erosion, naltrexone is further released for greater than 30 days.
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`10
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`Definition of Outcomes. The primary efficacy endpoint was the event rate of
`heavy drinking over the 24 weeks of treatment. The definition of heavy drinking (~5
`drinks per day for men and ~4 drinks per day for women) is consistent with that used
`in previous trials of oral naltrexone. Secondary endpoints included the event rate of
`"risky" drinking (>2 drinks per day for men and> 1 drink per day for women)
`specified by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) (U.S.
`Department of Agriculture/U.S. Department of Health and Human Services. Home
`and Garden Bulletin no. 232. Nutrition and yo.ur health: dietary guidelines for
`20 Americans. 3rd ed. Washington, DC: Supt. of Docs., U.S. Government. Printing
`Office, 1990) and the event rate of any drinking days. Exploratory endpoints included
`serum gamma-glutamyl transferase (GGT) changes over time, and time to patient
`discontinuation. Adverse events were coded using the MedDRA dictionary of
`preferred terms.
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`Statistical Methods
`The primary analysis for the primary and secondary endpoints was performed
`on an intention-to-treat population (i.e., all randomized patients who received at least
`one dose of study medication). The primary objective was to determine whether
`treatment with long-acting naltrexone (at either 190 mg or 380 mg) decreased the
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`event rate of heavy drinking relative to treatment with placebo injection. Statistical
`methods to analyze multiple drinking episodes in alcoholism treatment clinical trials
`have been described by Wang et al., Short of complete abstinence: an analysis
`exploration of multiple drinking episodes in alcoholism treatment trials. Alcohol Clin
`Exp Res. 2002;26: 1803-9. The primary analysis for the primary endp.oint was
`performed using a stratified recurrent event Andersen-Gill like model with robust
`variance estimation (Lin DY, Wei LJ, Yang I, and Ying Z. Semiparametric regression
`for the mean and rate functions of recurrent events. J Royal Stat Soc (B) 2000;62:
`711-30; SAS/STAT user's guide. Version 8. Cary, NC: SAS Institute, 1999:2596).
`The p