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`On the I &th September 199& the Library received a copy of the journal "Alcoholism-
`Clinical and Experimental Research (publisher Williams & Wilkins) Volume 22, Number
`5, August 1998 containing the article Sustained-Release Naltrexonefor Alcoholism
`Treatment: A Preliminary Study (Henry R. Kranzler, Vania Modesto-Lowe, and Elie S.
`Nuwayser) on pages 1074-1079". It was to the best of my knowledge received intact and was
`assigned the Library Shelfinark: Document Supply 0786.789300. It was then catalogued on
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`" This is the exhibit marked "A" referred to in the statutory declaration of
`signed the dh of April2018
`before me
`Dolores Rice Notary Public"
`
`Seema Rampersad
`
`British Library Research Service
`Tel: +44 (0) 20 7412 7903 research@bl.uk
`
`AMN1011
`IPR of Patent No. 7,919,499
`
`

`

`3. And I make this solemn declaration conscientiously believing the same to be true and by
`virtue of the provisions of the Statutory Declarations Act 1835.
`
`Signature~~~
`s~4 1-pt.M. P~JI>JO
`
`Date /1/t- ~ /{)/!"
`
`DECLARED at
`This I i"
`
`day of April
`
`in the year 2018
`
`Before me
`
`Dolores Rice
`Notary Public
`
`3 Cedar Court
`6 Grosvenor Road
`Wan stead
`London
`Ell 2HQ
`
`Tel: 0208 530 3085
`
`British Library Research Service
`Tel: +44 (0) 20 7412 7903 research@bl.uk
`
`AMN1011
`IPR of Patent No. 7,919,499
`
`

`

`18-SEP-1998 BSDS ~~1~"
`ALCOHOLISM -HEW!:,VOilK THEN IAL.TII'IORE-
`*~
`
`0786 .. 719300
`J~
`. PB
`
`1/1
`
`AMN1011
`IPR of Patent No. 7,919,499
`
`

`

`CONTENTS
`
`(continued from cover one)
`
`LETTERS TO THE EDITOR
`Investigation into the Use of Alcohol at Thermal Spas: Can a Spa Represent a Place for Primary Prevention?
`Fabio Caputo, Giovanni Addolorato, Antonio Gaddi, Giovanni Gasbanini, Mauro Bernardi, and Giuseppe
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1072
`Francesco Stefanini
`
`RAPID COMMUNICATION
`Sustained-Release Naltrexone for Alcoholism Treatment: A Preliminary Study
`Hemy R. Kranzler, Vania Modesto-Lowe, and Elie S. Nuwayser
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1074
`
`RAPID COMMUNICATION
`A Family-Based Analysis of Whether the Functional Promoter Alleles of the Serotonin Transporter Gene HIT
`Affect the Risk for Alcohol Dependence
`Howard J. Edenberg, Jennifer Reynolds, Daniel L. Kolle1; Henri Begleitet; Kathleen K Bucholz, P. Michael
`Conneally, Raymond Crowe, Alison Coate, Victor Hesse/brock, T.-K. Li, John I. Nurnberger, Jr., Bernice Porjesz,
`. . . . . . . . . . . . . . . . . . . 1080
`Theodore Reich, John P. Rice, Marc Schuckit, Jay A. Tischfield, and Tatiana Foroud
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093
`
`PRECLINICAL
`Ethanol Acutely Decreases Calcium Transients in Cultured Human Myotubes
`Josep M. Nicolas, Emilia Antzlnez, Andrew P. Thomas, Joaquim Fernandez-Sola, Ester Tobias, Ramon Estruch,
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
`and Alvaro Urbana-Marquez
`Intravenous Self-administration of Ethanol in f3-Endorphin-Deficient Mice
`Nicholas J. Grahame, Malcolm J. Low, and Christopher L. Cunningham
`Confirmation of Quantitative Trait Loci for Alcohol Preference in Mice
`Lisa M. Tarantino, Gerald E. McClearn, Lawrence A. Rodriguez, and Robert Plomin
`. . . . . . . . . . . . . . . . . . . 1099
`The Reinforcing Effects of Ethanol Are Altered by the Endogenous Neurosteroid, Allopregnanolone
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1106
`Patricia H. Janak, .lane E. M. Redfern, and Herman H. Samson
`Role of Catalase in In Vitro Acetaldehyde Formation by Human Colonic Contents
`J. Tillonen, P. Kaihovaara, H. Jousimies-Some1; R. Heine, and M. Salaspuro
`. . . . . . . . . . . . . . . . . . . . . . . . . 1113
`In Vivo Induction of Tyrosylprotein Sulfotransferase by Ethanol: Role of Increased Enzyme Synthesis
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1120
`Patalapati Ramaprasad and Chinnaswamy Kasinathan
`Quantitation of the Mass of Fatty Acid Ethyl Esters Synthesized by Hep G2 Cells Incubated with Ethanol
`. . . . . . . . . . . . . . . . . . . . . . . . . . 1125
`Li Dan, Joanne E. Cluette-Brown, Ayman Kabakibi, and Michael Laposata
`Effects of Ethanol on Recombinant Glycine Receptors Expressed in Mammalian Cell Lines
`C. Fernando Valenzuela, Rita A. Cardoso, Marilee .J. Wick, Jeff' L. Weine1; Thomas V Dunwiddie, and R. Adron
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1132
`Hanis
`Electrophysiological Characterization of Cerebellar Neurons from Adult Rats Exposed to Ethanol during
`Development
`Cristina Backman, James R. West, Jolonda C. Mahoney, and Michael R. Palmer
`Taste Reactivity to Alcohol and Basic Tastes in Outbred Mice
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1146
`Stephen W Kieje1; Katherine G. Hill, and Helen J. Kaczmarek
`Effects of Chronic Ethanol Consumption and Aging on Proenkephalin and Neurotensin
`Nuzhath F. Tajuddin and Mmy J. Druse
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152
`continued on page ii
`
`. . . . . . . . . . . . . . . . . . . . . . 1137
`
`ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH (ISSN 0145-6008) is the official journal of The Research Society on Alcoholism and
`Intcma.tional Society for Biomedical Research on Alcoholism and is published nine times per year beginning in February by Williams & Wilkins, 351 West
`Camden Street, Baltimore, MD 21201-2436. Periodicals postage paid at Baltimore, MD and at additional mailing offices. POSTMASTER: Send address changes
`to. ALCOHOLISM! CLINICAL AND EXPERIMENTAL RESEARCH, 351 West Camden Street, Baltimore, MD 21201-2436. Subscription rates: RSA and
`[SlJBA Mllmbers: 1998 dues include a $95.00 subscription fee ($135.00 outside the U.S.); ASAM Members: $151.00 ($182.00 outside the U.S.) Nonmembers; U.S.:
`Persolitll $2t5.QO; Institutional $415.00; Single copy $71.00. Outside the U.S., except Japan: Pet:wnal $260.00; Institutional $470.00; Single copy $80.00; Special
`. Jn;.tl"lllnlng mte<li $1$0.00 ($175.00 outside the U.S.). Foreign prices exclude Japan. See Information for Subscribers for detailed instmctions. The GST Tax
`.l\lj!tn.l'iui for Canadian subscribers is 123394371. C.P.C. International Publication Mail #0059803. Country of origin USA. PRICES ARE SUBJECf TO
`· ·, ·cl#\NOE; ~fid!ll>~d ·by Index: MeiJicus, Curre/lt Contents, (Clinical Medicine, Life Sciences, Science Citation lnder, Neuroscience Citation Index, Rese(lrch Alert,
`· · .. t~l/l!ifJ.Mi.>((), 8-w:erpta Met!Jt}(J,, J?,efercnce Updale/Resetzrch hifomwtion Systems, Chemical Abstracts, and Biosciences Infonnation Service. Copyright c 1998 by The
`· , ~@Society onAieoft()lisro.
`
`.
`·
`
`AMN1011
`IPR of Patent No. 7,919,499
`
`

`

`CONTENTS
`
`(continued from page i)
`
`Inhibition of Intracolonic Acetaldehyde Production and Alcoholic Fermentation in Rats by Ciprofloxacin
`J.-P. Vzsapiiii, K Jokelainen, T. Nosova, and M Salaspuro .... , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1161
`Microsomal Acetaldehyde Oxidation is Negligible in the Presence of Ethanol
`Yue-Sheng Wu, Katja S. Salmela, and Charles S. Lieber
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1165
`The Alcohol Deprivation Effect in the Alcohol-Preferring P Rat under Free-Drinking and Operant Access
`Conditions
`D. L. McKinzie, K L. Nowak, L. Y01ger, W. J. McBride, J. M Murphy, L. Lumeng, and T.-K Li
`
`. . . . . . . . . 1170
`
`RAPID COMMUNICATION
`Defective Intracellular Processing of Lactase-Phlorizin Hydrolase Protein in Rats Prenatally Exposed to
`Ethanol
`Gemma Estrada, Stephen D. Krasinski, Richard J. Grand, and M. Dolores Lopez-Tejera
`
`. . . . . . . . . . . . . . . . 1177
`
`ANNOUNCEMENT
`
`Jellinek Memorial Award..................................................................... 1183
`
`ON lOAN FROM BlDS BOSTON SPA.
`
`i
`I·
`1
`r
`
`j,
`j
`
`I .
`
`FOR USE AT THE BRITISH LIBRARY
`ST. PANCRAS READING ROOM ONLY
`
`CRNDAIT L
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`2 L
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`J
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`Spa,
`1net:JnLt:,tlt....n. ... , ..... , ___
`Wetherby, West Yorkshire, United Kingdom L:::.<:.:> to.::;)
`
`D55·2a I 01/11
`
`AMN1011
`IPR of Patent No. 7,919,499
`
`

`

`0145-6008/98/2205-1074$03.00/0
`ALcoHoLisM: CLINICAL AND EXPERIMENTAL RESEARCH
`
`Vol. 22,No.5
`August 1998
`
`RAPID COMMUNICATION
`
`Sustained-Release Naltrexone for Alcoholism
`Treatment: A Preliminary Study
`
`Henry R. Kranzler, Vania Modesto-Lowe, and Elie S. Nuwayser
`
`This 12-week study examined the bioavailability, tolerability, and po-
`tential efficacy of an injectable sustained-release preparation (SRP}
`of naltrexone (NTX). Twenty alcohol-dependent subjects took NTX
`50 mg po daily for 2 weeks, followed by a 2-week, no-medication
`Washout Period, a 4-week Injection Period, and a 4-week Follow-up
`Period. Fifteen subjects (75%} received a single subcutaneous injec-
`tion of 206 mg of sustained-release NTX, and five subjects (25%}
`received a placebo injection. All subjects also received eight weekly
`coping skills sessions· during the Oral NTX, and the Washout and
`Injection Periods. Results: After injection, NTX plasma concentra-
`tions exceeded a mean of 1 ng/ml for 21 days. Adverse effects pro-
`duced by the SRP of NTX were comparable with those resulting from
`oral NTX therapy. Compared with placebo, the SRP of NTX signifi-
`cantly reduced the frequency of heavy drinking days during the In-
`jection and Follow-up Periods. Conclusions: The results of this pre-
`liminary study support the potential clinical utility of the SRP of NTX
`for treatment of alcohol dependence.
`Key Words: Naltrexone, Sustained-Release Preparation, Alcohol-
`ism, Alcohol Dependence, Pharmacotherapy.
`
`N ALTREXONE (NTX), an opioid antagonist, reduces
`
`in alcohol-dependent pa-
`alcohol consumption
`tients. 1•2 Despite these early results, more recent findings
`indicate that, as in opioid addicts,3 the effectiveness of
`NTX in alcoholics is limited by problems with compliance.
`Recent studies by Chick4 and Volpicelli et al.5 failed to
`show an overall advantage for NTX. In these studies, the
`active medication was superior to placebo (PLA) in redl!-c-
`ing alcohol consumption only among highly compliant sub-
`jects. Although compliance with a variety of medications is
`often problematic,6 the importance of these findings is
`underscored by the fact that alcoholics show particularly
`8
`low rates of medication compliance.7
`•
`One approach to ensuring medication compliance is the
`
`use of a sustained-release preparation (SRP), which may
`also increase the likelihood of a therapeutic response by
`yielding a more predictable and constant plasma concen-
`tration than oral drug administration.9 A parenterally ad-
`ministered SRP may also result in a higher brain concen-
`tration of the parent compound by bypassing hepatic
`metabolism. 9
`Chiang et al. 10 administered a 63-mg, sustained-release
`NTX bead preparation to three healthy male volunteers.
`Concentrations of NTX were highest on the first day after
`subcutaneous administration and then fell to 0.2 to 0.4
`ng/ml from day 2 until the end of the experiment (23 to 32
`days after implantation). Local irritation occurred in two of
`the subjects. In a subsequent study, Chiang et al. 11 found
`relatively constant plasma concentrations of NTX (0.30 to
`0.46 ng/ml) and 6-{3-naltrexol (0.64 to 1.07 ng/ml) for 2 to 4
`weeks after implantation, concentrations that partially or
`completely blocked the effects of intravenous challenges
`with 15 mg of morphine.
`More recently, an SRP of NTX that uses biodegradable,
`injectable microcapsules was administered to four healthy
`volunteers with no reported adverse effects.12 Alim et a1. 13
`administered the same microcapsule preparation subcuta~
`neously to 8 cocaine-dependent subjects: 2 received a PLA
`injection, 3 received 103 mg of NTX, and 3 received 206 mg
`of NTX. Patients in the NTX and PLA groups reported
`mild pain during the first few days after injection, with
`erythema and induration occurring commonly. The ,.""''"'""t;
`study examined the bioavailability, tolerability,
`poten~
`tial efficacy of this microcapsule SRP of NTX (produced
`BIOTEK, Inc., Woburn, MA) in alcohol-dependent S\lb~
`jects.
`·
`
`From the Alcohol Research Center, Department of Psychiatl}' (H.R.K.,
`V.M.-L), University of Connecticut Health Center, Fannington, Connecticut;
`and BIOTEK, Inc. (E.S.N.), Woburn, Massachusetts.
`Received for publication January 28, 1998; accepted April 6, 1998
`This study was supp01ted by the National Institutes of Health Grants
`AA03510, AA07290, AA00239, and RR06192 (General Clinical Research
`Center).
`Rep1int requests: Hemy R. Kranzle1~ M.D., Department of Psychiatry,
`MC2103, University of Connecticut Health Cente1~ Fmmington, CT 06030-
`2103.
`Copyright © 1998 by The Research Society on Alcoholism.
`1074
`
`METHODS
`
`Procedures
`Twenty alcohol-dependent subjects participated in this 12-week stud~.
`After a minimum of 3 days of abstinence from alcohol, all
`underwent 2 weeks of treatment with 50 mg/day of oral NTX (Oral
`Period) to identify those individuals who could not tolerate the
`tion. Subjects then entered a 2-week, medication-free Washout
`followed by random assignment to receive one injection of either uvp·..,•·.,,c~i,1
`NTX (15 subjects, 75%) or placebo (5 subjects, 25% ), which was ex~1ectel!'
`Alcohol Clin Exp Res, Vol 22, No 5, 1998: pp
`
`AMN1011
`IPR of Patent No. 7,919,499
`
`

`

`SUSTAINED-RELEASE NTX FOR ALCOHOLISM TREATMENT
`
`Week 0
`
`2
`
`4
`
`8
`
`12
`
`Injection Period
`
`Followup Period
`
`Weekly Coping Skills Sessions
`(Treatment Phase)
`Fig. 1. Timeline of study periods.
`
`to deliver medication for 4 weeks (Injection Period). The first 8 weeks of
`the study (which included the 2-week Oral NTX Period, the 2-week
`Washout Period, and the 4-week Injection Period) were designated as the
`Treatment Phase, because during this time all subjects also received
`weekly, individual coping skills psychotherapy. 14•15 After the 8-week
`Treatment Phase, all subjects underwent two research assessments over a
`4-week Follow-up Period. Figure 1 shows a timeline of each subject's
`participation.
`
`Assessments
`The Michigan Alcoholism Screening Test, 16 Addiction Severity In-
`dex/7 and Alcohol Dependence Scale18 were administered at study entry
`to evaluate alcoholism severity and alcohol treatment history. The Time-
`Line Follow-Back Assessment method 19 was used to quantify drinking
`days, heavy drinking days (;;:,:4 drinks in a day for females and ;;:,:5 drinks
`in a day for males), and total alcohol consumption during the 4-week
`Pretreatment Period and for each period of the 12-week study.
`y-Glutamyltranspeptidase (GGTP) levels were obtained at the same in-
`tervals to validate reported alcohol consumption.
`Three assessments were repeated weekly during the 8-week Treatment
`Phase: breath alcohol testing, the Systematic Assessment for Treatment
`Emergent Events20 to monitor adverse events, and the Beck Depression
`Inventory21 to measure recent depressive symptoms.
`
`Subjects
`Subjects were recruited through advertisements. All subjects gave writ-
`ten, informed consent to participate. After screening, subjects were eval-
`uated using the Structured Clinical Interview for DSM-IV,22 clinical lab-
`oratory tests (CBC, urinalysis, blood chemistries, and, for women, a serum
`pregnancy test), and a physical examination. Inclusion criteria were age 18
`to 60 years, ability to read English, and a current DSM-IV diagnosis of
`Alcohol Dependence.23 Exclusion criteria were a current DSM-IV diag-
`nosis of drug dependence (other than nicotine), a lifetime diagnosis of
`opioid dependence, psychoactive drug use in the preceding month, no
`stable residence, evidence of a major psychiatric or medical illness, preg-
`nancy, or lack of birth control. As shown in Table 1, there were no
`significant between-group differences on any demographic or clinical
`variables. All subjects were Caucasian,
`
`Treatment
`Prior to injection, the microcapsule preparation was reconstituted in a
`suspending medium, to a total volume of 2.4 mi. The preparation was
`administered subcutaneously as a single injection in the gluteal region.
`The active SRP contained 206 mg of NTX, the maximal dose previously
`administered to humans. 13 The PLA preparation contained vehicle and
`microcapsules, but no NTX. A research pharmacist randomly assigned
`subjects to a medication group, with double-blind conditions maintained
`throughout the study.
`
`Laboratory Analysis
`Blood was collected nine times over the course of the 8 weeks after
`injection (i.e., during the Injection and Follow-up Periods). Solid-phase
`
`Table 1. Pretreatment Demographic and Clinical Features by
`Medication Group
`NTX
`(n = 15)
`
`PLA
`(n = 5)
`
`Test
`
`1075
`
`p
`
`80.0
`80.0
`40.0
`48.2 (4.3)
`15.0 (4.1)
`
`1.00
`1.00
`0.13
`0.77
`0.96
`
`0.63
`0.63
`0.69
`0.49
`0.51
`0.30
`
`73.3
`66.7
`80.0
`47.0 (9.0)
`14.9 (2.8)
`
`FET
`FET
`FET
`F = 0.08
`F = 0.00
`F = 0.24
`1.7 (2.5)
`1.0 (1.7)
`4.9 (1.0)
`F= 0.24
`5.2 (1.3)
`24.0 (14.0) F = 0.17
`21.9 (8.4)
`F = 0.49
`13.1
`(3.1)
`15.2 (8.2)
`F = 0.44
`19.8 (10.6) . 23.2 (7.2)
`0.80 (0.45) F = 1.15
`0.47 (0.64)
`
`Demographics
`Gender (% male)
`Employment (% full time)
`Marital status (% married)
`Age (years)
`Education (years)
`Clinical Features
`BDI* score
`DSM-IVt criteria
`MAST:!: score
`ADS§ score
`Years of heavy drinking#
`Prior treatments for
`alcoholism#
`• BDl. Beck Depression Inventory (Becket al., 1961).
`t Alcohol Dependence Criteria (American Psychiatric Association, 1994).
`:j: MAST, Michigan Alcohol Screening Test (Selzer, 1971).
`§ADS, Alcohol Dependence Scale (Skinner and Allen, 1982).
`#From the Addiction Severity Index (Mclellan et al., 1988).
`
`extraction and derivitization, followed by gas chromatography-negative
`ion chemical ionization-mass spectrometry, were used to measure plasma
`concentrations of NTX and 6-{3-naltrexol. 24 The precision and accuracy of
`this procedure have previously been demonstrated.24
`
`Data Analysis
`A two-tailed criterion of p < 0.05 was used to define statistical signif-
`icance. One-way analysis of variance (ANOV A) was used to compare
`groups on continuous measures and Fisher's Exact Test (FET) was used
`for categorical measures. Paired t tests were used to compare mean weekly
`adverse effects during the Oral NTX Period with those occurring during
`the Injection and Follow-up Periods. The Pearson correlation coefficient
`was used to examine the degree of association between changes in GGTP
`level and changes in total alcohol consumption during the Oral/Washout,
`Injection, and Follow-up Periods and to examine the association between
`adverse effects and changes in alcohol consumption.
`Hierarchical multiple regression was used to examine the effect of the
`SRP (i.e., NTX versus PLA) on adverse effects and drinking outcomes,
`after controlling for the respective measures during the Oral NTX and
`Washout Periods. Measures from these periods were entered into the
`analyses prior to medication group to examine change from the time of
`random assignment through the end of the study (i.e., the only time over
`which the injection could have exerted its effects). Because drinking
`measures from the Pretreatment Period did not contribute significantly to
`the variance in drinking outcomes during the study, they were not included
`in the regression equations. Regression analyses were conducted sepa-
`rately for the Injection and Follow-up Periods. Based on prior reports, 1•2
`we hypothesized that the SRP of NTX would exert its greatest effects on
`the percentage of heavy drinking days.
`
`RESULTS
`
`Plasma Concentrations
`Plasma concentrations of NTX and 6-J3-naltrexol were
`obtained after the Washout Period (i.e., immediately prior
`to the depot injection), and then a mean of 1, 3, 8, 13, 20,
`27, 34, 42, and 64 days after the injection. As can be seen in
`Fig. 2, the mean plasma NTX concentration exceeded 1
`nglml, the concentration thought to produce opioid antag-
`
`r!
`
`1:
`
`AMN1011
`IPR of Patent No. 7,919,499
`
`

`

`1076
`
`KRANZLER ET />J...
`
`10~------------------------------------,
`
`Table 2. Means for Drinking Measures by Study Period and Medication Group
`Prior to Depot Injection
`NTX
`(n = 15)
`
`PLA
`(n = 5)
`
`p Value*
`
`Pretreatment Period (4 weeks)
`% drinking days
`% heavy drinking days
`Average drinks/day
`Oral NTX Period (2 weeks)
`% drinking days
`% heavy drinking days
`Average drinks/day
`Washout Period (2 weeks)
`% drinking days
`% heavy drinking days
`Average drinks/day
`
`• Using ANOVA.
`
`68.1 (19.1)
`50.2 (30.0)
`4.9(3.6)
`
`11.4 (14.9)
`2.9(9.3)
`0.3 (0.5)
`
`21.0 (24.3)
`7.3 (13.6)
`0.8 (1.1)
`
`71.3 (16.1)
`64.7 (29.0)
`6.1 (4.0)
`
`5.8 (7.4)
`0
`0.1 (0.2)
`
`19.1 (19.4)
`0
`0.5(0.6)
`
`0.73
`0.36
`0.61
`
`0.44
`0.51
`0.37
`
`0.88
`0.26
`0.57
`
`5
`
`10
`
`15
`
`30
`25
`20
`Days Following Injection
`Fig. 2. Naltrexone and 6-f3-naltrexol plasma concentrations after a single
`depot injection in 15 alcoholics. Values are mean (SEM) for days on which multiple
`measurements were taken.
`
`45
`
`50
`
`55
`
`onist effects, 10•25 for 21 days after the active SRP was
`administered.
`
`Medication Tolerance
`Seven subjects [5 NTX (33.3%) and 2 PLA (40%)] com-
`plained of a burning sensation at the time of the injection
`(FET = 0.59). In three of these cases (2 NTX and 1 PLA),
`soreness at the injection site persisted over the week after
`injection. An area of induration was evident at the injection
`site among 13 subjects [11 NTX (73%) and 2 PLA ( 40%)
`(FET = 0.29)], with the size of the induration ranging from
`0.5 em (NTX subject) to 4.0 em (PLA subject) in diameter.
`The induration resolved completely to palpation over a
`period of 2.8 (SD = 1.3) weeks (range = 1 to 5 weeks).
`Nine subjects [2 PLA (40%) and 7 NTX (46.7%)] re-
`ported other adverse effects during the Injection Period
`(FET = 0.60). The mean number of weekly complaints
`during this period was 0.40 (SD = 0.54) for the PLA group
`and 1.33 (SD = 1.95) for the NTX group. Adverse effects
`reported after depot NTX were comparable in frequency to
`those reported during the Oral NTX Period (mean = 1.80,
`SD = 1.82, paired t14 = 1.07, p = 0.30). Although the
`number of adverse effects during the Oral NTX Period
`predicted the number of adverse effects during the Injec-
`tion Period [f3 = 0.457, F(1,18) = 4.74, p = 0.043], the
`depot NTX and PLA groups did not differ significantly on
`this measure [13 = 0.257, F(1,16) = 1.59, p = 0.23].
`Of the adverse effects reported during the Injection Pe-
`riod, fatigue was most common (n = 3: no PLA subjects
`and 20% of NTX subjects), followed by complaints of
`mood changes (n = 2: no PLA subjects and 13.3% of NTX
`subjects). Rash, palpitations, headache, nausea, vertigo,
`and insomnia were each reported by one NTX subject. No
`complaints of a severe nature were reported during the
`Injection Period. All adverse effects resolved spontane-
`ously.
`During the Follow-up Period, eight NTX subjects ( 40%)
`and no PLA subjects reported adverse effects (FET =
`0.051). The mean number of weekly complaints by NTX
`subjects during this period was 1.27 (SD = 1.67), which
`
`does not differ statistically from the comparable measure
`during the Oral NTX Period (paired t 14 = 0.81, p = 0.43).
`There was a trend for the number of complaints reported
`during the Follow-up Period to be correlated with both the
`number of complaints during the Oral NTX Period [13 =
`0.455, F(1,18) = 4.22, p = 0.055] and with the medication
`group [13 = 0.402, F(1,16) = 4.16, p = 0.059]. During the
`Follow-up Period, 1 NTX subject reported severe vomiting,
`which resolved spontaneously.
`
`Validation of Self-Reported Drinking
`NTX subjects' GGTP levels (n = 15) declined from 40.9
`units/liter (SD = 28.9) at baseline to 29.4 units/liter (SD =
`21.3) for the Injection Period and 30.1 units/liter (SD =
`21.4) for the Follow-up Period. PLA subjects' levels (n = 4;
`one subject failed to provide one specimen) declined from
`43.0 units/liter (SD = 19.9) at baseline to 33.5 units/liter
`(SD = 16.4) for the Injection Period and 38.5 units/liter
`(SD = 7.1) for the Follow-up Period. Between-group com-
`parisons of GGTP levels were nonsignificant (p's all >
`0.10). However, change in GGTP level was significantly
`correlated with change in total alcohol consumption during
`the Oral and Washout Periods combined [r = 0.48, p =
`0.017] and during the Injection Period [r = 0.4 7, p = 0.021 ].
`There was also a trend for an association between the
`change in these measures during the Follow-up Period [r =
`0.33, p = 0.084].
`
`Drinking Measures
`Table 2 shows drinking measures for the three study
`periods preceding the depot injection. ANOVA revealed
`no between-group differences on these measures (p's all
`>0.10).
`Table 3 shows drinking measures for the Injection and
`Follow-up Periods. These comparisons control for the cor-
`responding measures during the Oral NTX and Washout
`Periods.
`Injection Period. During the Injection Period, the per-
`centage of drinking days was predicted by the comparable
`
`AMN1011
`IPR of Patent No. 7,919,499
`
`

`

`I I
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`
`SUSTAINED-RELEASE NTX FOR ALCOHOLISM TREATMENT
`
`Table 3. Means for Drinking Measures by Study Period and Medication Group
`after Depot Injection
`
`Injection Period (4 wee~s)
`% drinking days
`% heavy drinking days
`Average drinks/day
`Follow-up Period (4 weeks)
`% drinking days
`% heavy drinking days
`Average drinks/day
`
`NTX
`(n = 15)
`
`PLA
`(n = 5)
`
`p Value*
`
`21.0 (25.5)
`3.7 (10.7)
`0.7(0.6)
`
`28.2 (35.8)
`7.8 (18.2)
`1.1 (1.7)
`
`28.4 (34.5)
`5.3 (8.4)
`0.9 (1.2)
`
`44.6 (31.4)
`23.0 (32.8)
`1.9 (1.7)
`
`0.42
`0.03
`0.08
`
`0.58
`0.04
`0.04
`
`• Using linear regression, controlling for the corresponding measures during
`the Oral NTX and Washout Periods.
`
`measure during the Oral NTX [f3 = 0.72, F(1,18) = 19.25,
`p < 0.001} and Washout [13 = 1.31, F(1,17) = 27.80, p <
`0.001 J Periods. The medication group did not affect this
`measure [f3 = -0.09, F(1,16) = 0.70, p = 0.42].
`The percentage of heavy drinking days during the Injec-
`tion Period was predicted by the comparable measure dur-
`ing the Oral NTX Period [/3 = 0.84, F(1,18) = 40.54, p <
`0.001 ], but not by heavy drinking days during the Washout
`Period [f3 = 0.47, F(1,17) = 3.85,p = 0.067]. However, as
`hypothesized, the SRP of NTX produced a significantly
`lower percentage of heavy drinking days during the Injec-
`tion Period [f3 = -0.26, F(1,16) = 5.46, p = 0.034], an
`effect (f) = 0.269.26
`Mean drinks/day during the Injection Period was pre-
`dicted by the comparable measure during both the Oral
`NTX Period [f3 = 0.70, F(1,18) = 17.63,p = 0.001] and the
`Washout Period [f3 = 0.74, F(1,17) = 13.45, p = 0.002].
`There was a trend [f3 = -0.23, F(1,16) = 3.4,p < 0.083] for
`the SRP of NTX to reduce the mean number of drinks/day
`during the Injection Period .
`Follow-up Period. During the Follow-up Period, there
`was a trend for the percentage of drinking days to be
`predicted by the comparable measure during the Oral NTX
`Period [f3 = 0.45, F(1,18) = 4.45, p = 0.05]. The compa-
`rable measure during the Washout Period was a significant
`predictor [/3 = 1.65, F(1,17) = 24.72,p < 0.001]. However,
`there was no effect of the SRP of NTX on the percentage
`of drinking days during the Follow-up Period [/3 = -0.09,
`F(1,16) = 0.32, p = 0.58].
`The percentage of heavy di"inking dttyli during the
`Follow-up Period was predicted by the comparable mea-
`sure during the Oral NTX Period [f3 = 0.56, F(1,18) = 8.25,
`p = 0.010], but not by heavy drinking days during the
`Washout Period [f3 = 0.05, F(1,17) = 0.02, p = 0.88].
`Again, as hypothesized, individuals receiving the SRP of
`NTX had significantly fewer heavy drinking days during the
`Follow-up Period [f3 = -0.43, F(1,16) = 5.18, p = 0.037),
`an effect (f) = 0.245.26
`The mean number of drinks/day during the Follow-up
`Period was predicted by the comparable measure during
`both the Oral NTX Period [/3 = 0.55, F(1,18) = 7.71,p =
`0.012] and the Washout Period [f3 = 0.71, F(1,17) = 7.12,
`· p = 0.016]. A significant advantage for the SRP of NTX on
`
`70
`
`60
`
`&1 Depot Placebo (N=5)
`0 Depot Naltrexone (N'"'15)
`
`50
`
`... t:
`e40
`., a.
`
`30
`
`1077
`
`*
`
`20
`
`10
`
`*
`
`0
`Pretreatment Oral NTX
`Washout
`Injection
`Follow-up
`Fig. a. Percent (mean + SEM) heavy drinking days by medication group and
`study period. *p < 0.05, after controlling for heavy drinking days during the Oral
`NTX and Washout Periods. "No heavy drinking by placebo subjects during the
`Oral NTX and Washout Periods.
`
`this outcome measure emerged during the Follow-up Pe-
`riod [/3 = -0.35, F(1,16) = 5.01, p = 0.040], an effect (f)
`= 0.239.Z6
`
`Relations Between Adverse Events and Changes in
`Alcohol Consumption
`When correlations between the number of adverse
`events reported and the change in each of the three drink-
`ing measures were examined separately for the Injection
`and Follow-up Periods, all were found to be nonsignificant
`(r's all <0.34, p's all >0.10).
`
`Integrity of the Double Blind
`When subjects were asked to judge which medication
`they received, the majority (12, or 60%) guessed incor-
`rectly. One PLA subject (20%) and 7 NTX subjects
`( 46.7%) correctly identified their medication assignment
`(FET = 0.60).
`
`DISCUSSION
`This study provides preliminary evidence for the bio-
`availability, tolerability, and efficacy of an SRP ot NTX for
`the treatment of alcohol dependence. A clinically signifi-
`cant effect of NTX on the frequency of heavy drinking was
`evident during the 4-week Injection Period. This effect
`persisted during the 4-week Follow-up Period (Fig. 3). An
`effect of similar magnitude was observed on the mean
`number of drinks per day, but only during the Follow-up
`Period. GGTP level did not differ by treatment group,
`which may be due to the fact that GGTP levels are a
`relatively insensitive measure of alcohol consumption,27
`and they were only modestly elevated in this subject sample
`at baseline. However, correlations with GGTP level ob-
`served herein support the validity of self-reported alcohol
`consumption. Because participants were no better able to
`
`AMN1011
`IPR of Patent No. 7,919,499
`
`

`

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`··."'.·-
`
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`:,
`,., ;.
`
`1078
`
`KRANZLER ET Al.
`
`identify the medication they received and there was no
`correlation between adverse events and changes in self-
`reported drinking, it appears that there was a direct phar-
`macological effect of the SRP of NTX on alcohol consump-
`tion.
`Olsen and Kincl28 listed the following criteria for an ideal
`NTX sustained-delivery system: ease of administration, ab-
`sence of an adverse tissue reaction, a relatively constant
`release of the drug for at least 30 days, and biodegradation
`within a short time after that. Using these criteria, the
`microcapsule formulation described herein, although
`promising, is not ideal. The volume of fluid that was in-
`jected produced discomfort. Although