JOURNAl~ OF
`
`\n Interdisciplinary Forum for Clinicians and Scientists
`
`VOLUME 6, NUMBER 2
`
`APRIL .. JUNE 1993
`
`ISSN 0891-9887
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2129 - 1/8
`
`

`
`JOURNAL OF
`
`Geriatric Psychiatry
`and
`eurology
`
`Editor
`Michael A. Jenike, MD
`Massachusetts General Hospital
`Boston, Massachusetts
`
`Editorial Assistant
`Mary T. Dickie
`
`Editorial Board
`Marilyn S. Albert, PhD
`Massachusetts General Hospital
`Boston, Massachusetts
`William H. Anderson, MD
`St. Elizabeth's Hospital
`Brighton, Massachusetts
`Lee Baer, PhD
`Massachusetts General Hospital
`Boston, Massachusetts
`D. Frank Benson, MD
`UCLA School of Medicine
`Los Angeles, California
`John P. Blass, MD, PhD
`Burke Rehabilitation Center
`White Plains, New York
`Dan G. Blazer, MD, PhD
`Duke University, Medical Center
`Durham, North Carolina
`Andrew W. Brotman, MD
`Freedom Trail Clinic
`Boston, Massachusetts
`Roger A. Brumback, MD
`University of Oklahoma
`College of Medicine
`Oklahoma City, Oklahoma
`Ewald W. Busse, MD
`Duke University Medical Center
`Durham, North Carolina
`Robert N. Butler, MD
`Mt. Sinai School of Medicine
`New York, New York
`Ned H. Cassem, MD
`Massachusetts General Hospital
`Boston, Massachusetts
`Bruce M. Cohen, MD, PhD
`McLean Hospital
`Belmont, Massachusetts
`Gene D. Cohen, MD, PhD
`National Institute of Mental Health
`Rockville, Maryland
`M. Cornelia Cremens, MD
`Abstract Editor
`Massachusetts General Hospital
`Boston, Massachusetts
`
`Jeffrey L. Cummings, MD
`Associate Editor for Behavioral Neurology
`West Los Angeles VA Medical Center
`Los Angeles, California
`
`Kenneth L. Davis, MD
`Huntington, New York
`David A. Drachman, MD
`University of Massachusetts Medical
`Center
`Worcester, Massachusetts
`Carl Eisdorfer, MD, PhD
`University of Miami School of Medicine
`Miami, Florida
`Barry Fogel, MD
`Rhode Island Hospital
`Providence, Rhode Island
`Marshal F. Folstein, MD
`Johns Hopkins University School of
`Medicine
`Baltimore, Maryland
`Alan J. Gelenberg, MD
`University of Arizona
`Tucson, Arizona
`Donald C. Goff, MD
`Massachusetts General Hospital
`Boston, Massachusetts
`C. G. Gottfries
`University of Gi:iteborg
`Hisings Backa, Sweden
`John Growdon, MD
`Associate Editor for Geriatric Neurology
`Massachusetts General Hospital
`Boston, Massachusetts
`Cyril I. Gryfe, MD, FRCPC
`Toronto, Canada
`Albert Heyman, MD
`Duke University Medical Center
`Durham, North Carolina
`Steven E. Hyman, MD
`Massachusetts General Hospital
`Boston, Massachusetts
`Lissy F. Jarvik, MD, PhD
`UCLA Neuropsychiatric Institute
`Los Angeles, California
`Hideyo Katsunuma, MD
`Tokyo Medical College Hospital
`Tokyo, Japan
`Jonathan D. Lief£, MD
`Hahnemann Hospital
`Brighton, Massachusetts
`
`Benjamin Liptzin, MD
`McLean Hospital
`Belmont, Massachusetts
`Charles A. Marotta, MD, PhD
`Associate Editor for Neuroscience
`Massachusetts General Hospital
`Boston, Massachusetts
`McLean Hospital
`Belmont, Massachusetts
`Joseph B. Martin, MD, PhD
`University of California
`San Francisco, California
`Marek-Marse! Mesulam, MD
`Beth Israel Hospital
`Boston, Massachusetts
`Gary D. Miner, PhD
`Associate Editor for Alzheimer's and Other
`Dementias
`Alzheimer's Foundation
`Tuls;~, Oklahoma
`George B. Murray, MD
`Massachusetts General Hospital
`Boston, Massachusetts
`Michael Otto, PhD
`Massachusetts General Hospital
`Boston, Massachusetts
`Eric A. Pfeiffer, MD
`University of South Florida College
`of Medicine
`Tampa, Florida
`Chester M. Pierce, MD
`Nichols House
`Cambridge, Massachusetts
`Derek M. Prins ley, MD
`University of Texas Medical Branch
`Galveston, Texas
`Peter V. Rabins, MD
`Johns Hopkins University School of
`Medicine
`Baltimore, Maryland
`MurJ:ay A. Raskind, MD
`VA Geriatric Research Education
`and Clinic Center
`Seattle, Washington
`Barry Reisberg, MD
`New York University Medical Center
`New York, New York
`E. P. Richardson, Jr, MD
`Associate Editor for Neuropathology
`Massachusetts General Hospital
`Boston, Massachusetts
`Paavo J. Riekkinen, MD
`University of Kupio
`Department of Neurology
`Kupio, Finland
`
`Jerrold F. Rosenbaum, MD
`Massachusetts General Hospital
`Boston, Massachusetts
`John Rowe, MD
`Mt. Sinai Medical Center
`New York, New York
`Carl Salzman, MD
`Massachusetts Mental Health Center
`Boston, Massachusetts
`Lon Schneider, MD
`University of Southern California
`Los Angeles, California
`Charles A. Shamoian, MD, PhD
`New York Hospital-Cornell Medical
`Center
`White Plains, New York
`James R. Slaughter, MD
`VA Medical Center
`Salt Lake City, Utah
`Gary W. Small, MD
`UCLA Neuropsychiatric Institute
`Los Angeles, California
`Theodore A. Stern, MD
`Massachusetts General Hospital
`Boston, Massachusetts
`Paul Summergrad, MD
`Massachusetts General Hospital
`Boston, Massachusetts
`Owen S. Surman, MD
`Massachusetts General Hospital
`Boston, Massachusetts
`Virginia E. Tay, RN, MSN
`Cambridge, Massachusetts
`Charles E. Wells, MD
`Vanderbilt University School of Medicine
`Nashville, Tennessee
`Linda Winter-Miner, PhD
`Alzheimer's Foundation
`Tulsa, Oklahoma
`William Yamanashi, PhD
`Tulsa, Oklahoma
`Jerome A. Yesavage, MD
`VA Medical Center
`Palo Alto, California
`
`Official publication of
`the Alzheimer's Foundation
`
`Q\
`~
`
`Copyright © 1993 Decker Periodicals Inc.
`journal of Geriatric Psychiatry and Neurology (lSSN 0891-9887) is published quarterly, january, April, july, and October, by Decker Periodicals Inc., One )ames
`Street South, P.O. Box 620, L.C.D. 1, Hamilton, Ontario, Canada L8N 3K7. The known office of publication is The Sheridan Press, Fame Avenue, Hanover, PA
`17331. Second Class postage paid at Hanover, PA, and additional offices.
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`L8N 3K7 or P.O. Box 785, Lewiston, NY, 14092-0785. Tel: (416) 522-7017; Fax: (416) 522-7839. ln Canada and the United States: (800) 568-7281. ln Japan,
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`L8N 3K7. Tel: (416) 522-7017; Fax: (416) 522-7839; in Canada and U.S.: (800) 568-7281.
`The journal of Geriatric Psychiatry and Neurology is indexed in Index Medicus, EM BASE the Excerpta Medica Database, Psychological Abstracts, and Neuroscience
`Citation Index and Research Alert. The journal is available in microform from University Microfilms International, 300 North Zeeb Road, Ann Arbor, Ml 48106.
`
`POSTMASTER: Send address changes to journal of Geriatric Psychiatry and Neurology, Decker Periodicals Inc., P.O. Box 785, Lewiston, NY 14092-0785.
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2129 - 2/8
`
`

`
`JOURNAL OF
`
`Geriatric Psychiatry
`eurology Volume6,Number2
`and
`
`April-June 1993
`
`Contents
`
`Editorial
`
`65
`
`Alzheimer's Disease: Headlines, Confusion, and the Unknown
`Linda E. Nee, MSW
`
`Commentary
`66
`Acute Care of the African American Elder
`F.M. Baker, Risa Lavizzo-Mourey, and Billy E. Jones
`
`78
`
`84
`
`97
`
`Original Articles
`72
`Delayed Late Component of Visual Global Field Power in Probable Alzheimer's Disease
`Kerry L. Coburn, J. Wesson Ashford, and Marco A. Moreno
`The Nature and Time Course of Cognitive Side Effects During Electroconvulsive Therapy in the Elderly
`Eugene H. Rubin, Dorothy A. Kinscherf, Gary S. Figiel, and Charles F. Zorumski
`A Two-Year Longitudinal Study of Cognitive Function in Normal Aging and Alzheimer's Disease
`Charles Flicker, Steven H. Ferris, and Barry Reisberg
`Microanalysis of Senile Plaques Using Nuclear Microscopy
`Judith Landsberg, Brendan McDonald, Geoff Grime, and Frank Watt
`Memory Complaint, Memory Performance, and Psychiatric Diagnosis: A Community Study
`Susan Spear Bassett and Marshal F. Folstein
`
`105
`
`115
`
`Case Studies
`112
`Successful Treatment With Captopril of an Elderly Man With Polydipsia and Hyponatremia
`Michael J. Tueth and John Broderick-Cantwell
`Evaluation of Multiple Doses of Milacemide in the Treatment of Senile Dementia of the Alzheimer's Type
`Neal R. Cutler, T. Daniel Fakouhi, Ward T. Smith, Hugh C. Hendrie, Fumisuke Matsuo, John J. Sramek, and
`Robert L. Herting
`The Prevalence of Late-Onset Schizophrenia in a Psychogeriatric Population
`R. Yassa, D. Dastoor, C. Nastase, Y. Camille, and L. Belzile
`
`120
`
`Topics in Geriatrics
`126
`Dementia in a Population-Based Study
`12 7
`Mechanisms of Memory
`
`Departments
`111
`Notices
`128
`Abstracts
`130
`Instructions for Authors
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2129 - 3/8
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`

`
`Evaluation of Multiple Doses
`of Milacemide in the Treatment
`of Senile Dementia
`of the Alzheimer's Type
`
`Neal R. Cutler, MD; T. Daniel Fakouhi, PhD, MBA; Ward T. Smith, MD;
`Hugh C. Hendrie, MD; Fumisuke Matsuo, MD; John J. Sramek, PharmD;
`Robert L. Herting, MD, PhD .
`
`Abstract ------------------------------------------------------------------------------
`A multicenter, double-blind, placebo-controlled, parallel group study was conducted to assess the safety and efficacy of
`three doses of milacemide in the treatment of patients with senile dementia of the Alzheimer type of mild to moderate
`severity. Patients were randomly assigned to receive one of three dosages of milacemide (400, 800, or 1200 mglday) or
`placebo for 4 weeks followed by a single-blind 4-week placebo period. One hundred forty-eight men and women older
`than 50 years of age were enrolled, and 129 patients completed the study. The differences among treatment groups were
`not statistically different with respect to total scores on the Alzheimer's Disease Assessment Scale or any items and sub(cid:173)
`scales that were examined, nor were significant differences on the Clinical Global Impression Scale found. Clinically sig(cid:173)
`nificant increases in liver function tests, specifically aspartate aminotransferase and alanine aminotransferase (AST and
`ALT), were reported for five of the patients receiving milacemide, requiring their withdrawal from the study. U Geriatr
`Psychiatry Neurol1993;6:115-ll9).
`
`Senile dementia of the Alzheimer type (SDAT)
`
`is a progressive condition that is principally
`manifested by memory deficits and loss of other in(cid:173)
`tellectual abilities of sufficient severity to interfere
`5
`with social or occupational functioning. 1
`-
`Neurochemical studies have identified several
`neurotransmitter systems that are known to have an
`impact on memory processes, primarily the cholin(cid:173)
`ergic system, as evidenced by loss of cholinergic
`neurons in the nucleus basalis in Alzheimer's pa(cid:173)
`tients, as well as
`the adrenergic-dopaminergic,
`-y-aminobutyric acid (GABA)-ergic, and glutamater-
`
`Received Jan 12, 1992. Received revised Feb 25, 1992. Ac(cid:173)
`cepted for publication March 20, 1992.
`From California Clinical Trials (Drs Cutler and Sramek), Bev(cid:173)
`erly Hills, CA, Searle Research and Development (Drs Fakouhi
`and Herting), Skokie, IL, the Pacific Northwest Clinical Research
`Center (Dr Smith), Portland, OR, the Indiana University Medical
`Center (Dr Hendrie), Indianapolis, IN, and the University of Utah
`School of Medicine (Dr Matsuo), Salt Lake City, UT.
`Address correspondence to Dr N.R. Cutler, California Clini(cid:173)
`cal Trials, 8500 Wilshire Boulevard, 7th Floor, Beverly Hills, CA
`90211.
`
`11 In several studies glutamate bind(cid:173)
`gic systems. 6
`-
`ing to N-methyl-o-aspartate (NMDA) receptor sites
`was significantly reduced in Alzheimer's disease
`patients,I2
`14 although negative studies also demon(cid:173)
`-
`strated no reduction in NMDA receptor sites despite
`apparent reduction of glutamate uptake. 15
`17 Marked
`-
`decreases in glutamate levels were also found in a dis(cid:173)
`section of the perforant pathway zone. 18 Coupling in
`the glycine recognition site in the NMDA-receptor
`may also be impaired. 19
`It has been reported that activation of the
`NMDA subtype of glutamate receptors leads to
`long-term potentiation in the postsynaptic neurons
`when stimulated by either NMDA or the natural ag(cid:173)
`onist, the excitatory amino acid glutamate. 20
`21 Be(cid:173)
`'
`cause long-term potentiation has been suggested as
`a mechanism for memory formation, positive modu(cid:173)
`lation of NMDA-receptors should lead to memory
`and learning enhancement.
`Milacemide (2-n-pentylaminoacetamide hydro(cid:173)
`chloride), a monoamine oxidase-B inhibitor and a
`prodrug for glycine, has been shown to have a
`
`Journal of Geriatric Psychiatry and Neurology I Vol. 6 I April-June 1993
`
`115
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2129 - 4/8
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`

`
`Cutler et al
`
`unique action in several tests that evaluate short(cid:173)
`term memory. Milacemide was able to reverse mem(cid:173)
`ory impairment induced by electroshock in the
`passive avoidance task in rats, as well as memory
`loss by scopolamine and diazepam in the spontane(cid:173)
`ous alternation test in mice. 22 It also facilitated mem(cid:173)
`ory consolidation in the passive avoidance model in
`rats. 23 These results in animal studies indicate that
`milacemide may have beneficial effects on cognition.
`They are consistent with the hypothesis that milace(cid:173)
`mide exerts stimulatory effects through the newly dis(cid:173)
`covered supraspinal glycine receptors associated
`allosterically with NMDA-receptors. 24
`26 Glycine
`-
`does not readily cross the blood-brain barrier, but mil(cid:173)
`acemide does and is then metabolized to glycina(cid:173)
`mide and glycine. 27 Because this biotransformation
`results in a marked increase in glycine concentration
`in the central nervous system, milacemide may be
`considered a prodrug for glycine. Thus, milacemide
`was identified as one of the first drugs modulating
`these supraspinal glycine receptors positively, with
`the consequence of offering benefit in the treatment of
`memory impairment and, possibly, learning deficien(cid:173)
`cies. Because of these properties, it seemed justified to
`objectively evaluate the efficacy and safety of milace(cid:173)
`mide in the treatment of the cognitive and memory
`disorders that occur in patients suffering from SDAT.
`
`Methods
`Men and women, aged 50 years or older, with
`Alzheimer's disease were enrolled into the study at
`10 sites. The presence of SDAT was determined by
`clinical evaluation supported by NINCDS criteria, a
`Mini-Mental State Examination score between 10
`and 27, a Dementia Rating Scale score less than 20,
`a Global Deterioration Scale score of 3 to 5, a
`Hachinski Cerebral Ischemia Scale score of 4 or less,
`and a history of progressive worsening of memory
`and other cognitive functions documented for at
`least 1 year before enrollment. A computed tomo(cid:173)
`graphic or magnetic resonance imaging scan within
`1 year of enrollment must have been compatible
`with a diagnosis of SDAT. Patients were excluded if
`they had evidence of cerebral ischemia or other
`brain disorders; neurologic, substance abuse, or
`psychiatric disorders (other than SDAT); or signifi(cid:173)
`cant cardiovascular, thyroid, hepatic, renal, pulmo(cid:173)
`nary, gastrointestinal, or other clinically significant
`medical conditions as determined by physical ex(cid:173)
`amination, electrocardiogram, and laboratory tests
`(including triiodothyronine, thyroxine, folic acid,
`and vitamin B12 determinations). Patients who had
`
`participated in an investigational drug trial within
`the last 30 days before entering this study were
`also excluded. Concomitant psychoactive medica(cid:173)
`tion was prohibited unless prescribed by the physi(cid:173)
`cian or investigator on a prn basis. Calcium channel
`blockers, angiotensin-converting enzyme inhibitors,
`~-blockers, and anticholinergic drugs were also pro(cid:173)
`hibited.
`
`Study Design
`This was a multicenter, randomized, double-blind,
`parallel group, dose-response study of milacemide
`in patients with SDAT. After screening determina'"
`tion of eligibility, patients received milacemide in
`single oral doses of 400, 800, or 1200 mg/day or
`matching placebo for 4 weeks during the double(cid:173)
`blind treatment period, which was followed by a
`4-week placebo washout period. All patients (or
`their family member or legal guardian) provided oral
`and written signed consent.
`Efficacy was assessed by the subject's perfor(cid:173)
`mance using the Alzheimer's Disease Assessment
`Scale (ADAS), 28 the Clinical Global Impression Scale
`(CGI), the Patient Global Improvement Rating, 29 the
`Physical Self-Maintenance Scale, and the Instrumen(cid:173)
`tal Activities of Daily Living Scale (IADL). 30 Efficacy
`measures were evaluated at the screening visit (visit
`1) and biweekly during the double-blind period (at
`visits 3 and 5) and during the placebo washout pe(cid:173)
`riod (at visits 7 and 9). A 17-item Hamilton Depres(cid:173)
`sion Scale was administered at baseline and at the
`end of the double-blind drug administration period
`to rule out any major depressive state. Safety mea(cid:173)
`sures, including electrocardiogram, hematology and
`biochemistry screens, and urinalysis were per(cid:173)
`formed weekly.
`
`Statistical Methods
`Treatment groups were compared with respect to
`age by a two-way analysis of variance (ANOV A) us(cid:173)
`ing study site and treatment group as factors in the
`model. A power calculation yielded sample groups
`of 30 patients (total 120) based on a standard devia(cid:173)
`tion of 15 and a 5-point drop in the ADAS from
`baseline with an a of .05 and power slightly greater
`than . 90. Treatment groups were compared with re(cid:173)
`spect to sex and race using the Cochran-Mantel-Haen(cid:173)
`szel test. At the screening visit, eligibility for
`enrollment in the study was assessed with the Mini(cid:173)
`Mental State Examination, the Dementia Rating Scale,
`the Global Deterioration Scale, and the Hachinski Ce(cid:173)
`rebral Ischemia Scale. Treatment groups were com(cid:173)
`pared with respect to total scores on these scales by
`
`116
`
`Journal of Geriatric Psychiatry and Neurology I Vol. 6 I April-June 1993
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2129 - 5/8
`
`

`
`Evaluation of Milacemide for Senile Dementia
`
`nine patients completed the study. Nineteen pa(cid:173)
`tients withdrew or were withdrawn before the end
`of the study because of adverse events (n = 10),
`treatment failure (n = 7), or noncompliance (n = 2).
`Treatment groups were not statistically different
`with respect to age, sex, height, and weight. How(cid:173)
`ever, of a total of five black patients randomized,
`four were randomized to the 1200 mg group; the
`other was in the placebo group. All other patients
`were white (n = 143).
`
`Efficacy Analysis
`At visit 1, the treatment groups did not differ signif- ·
`icantly with respect to total score or with respect to
`noncognitive behavior score, word recognition,
`word recall, or orientation subsection scores. Study
`sites differed with respect to baseline total scores
`and subscale scores; however, study site-treatment
`interaction on the baseline scores was not signifi(cid:173)
`cant. The total ADAS scores are summarized in Ta(cid:173)
`ble 1. No significant changes from baseline were
`observed between treatments for total or subsection
`scores of the ADAS (total ADAS, P = .97; cognitive
`behavior, P = . 93, noncognitive behavior, P = .57;
`word recognition, P = .61; word recall, P
`.59; and
`orientation, P = .93).
`As a group, the placebo patients tended to be
`less severely ill (Table 2). The CGI severity of illness
`ratings showed no differences between treatments
`in the proportion of patients showing improvement
`(P = .39). A greater proportion of patients on mil(cid:173)
`acemide had improved scores at the end of the treat(cid:173)
`ment (10% to 13% on milacemide versus 3% on
`
`two-way ANOV A using study site and treatment
`group as factors.
`The primary measure used in determining effi(cid:173)
`cacy was the cognitive behavior score of the ADAS,
`which consists of 21 items. Eleven of these items
`combine to form a cognitive behavior subscale, and
`the other 10 form a noncognitive behavior subscale.
`Two items that form part of the cognitive subscale
`are also intended to be analyzed separately. These
`are the word recall score and the word recognition
`score. The primary measure used in statistical tests
`of efficacy is the sum of the cognitive behavior item
`scores. Tests were also done ·on the word recall
`score, the word recognition score, the orientation
`score, and the sum of noncognitive behavior item
`scores. Means and standard deviations of the total
`ADAS score and each subscale were calculated by
`treatment group and visit. ADAS scores taken at the
`screening visit were submitted
`to a
`two-way
`ANOV A with investigator and dose level as factors
`in the model to establish baseline comparability of
`treatment groups. To ensure the validity of the
`ANOV A, ADAS scores were examined for heteroge(cid:173)
`neity of variance among treatment groups, using the
`F max -test. 24 Where significant heterogeneity of vari(cid:173)
`ance was found, the Kruskal-Wallis test was used to
`verify the results of the ANOVA.
`To examine the effect of withdrawal from mil(cid:173)
`acemide, changes in total ADAS score and in cogni(cid:173)
`tive behavior score from the last available double(cid:173)
`blind
`treatment period
`total score
`to
`the
`last
`available washout period score were submitted to
`an ANOV A using treatment and study site as fac(cid:173)
`tors in the model. The Cochran-Mantel-Haenszel
`test was used in comparing the proportion of pa(cid:173)
`tients in the milacemide groups showing at least a
`one-point improvement on the ·Severity of Illness
`scale to the proportion in the placebo group, con(cid:173)
`trolled for effects of study sites. The IADL Scale
`consists of ratings on 10 everyday activities. Individ(cid:173)
`ual ratings are on a scale of 1 to 3, 1 to 4, or 1 to 5,
`with lower numbers representing greater disability.
`Differences from baseline for each scale were sub(cid:173)
`mitted to ANOV A as described under methods for
`the ADAS.
`
`Results
`One hundred forty-eight patients (75 men and 73
`women; mean age, 71.5 years; age range, 52 to 91
`years) were randomized to treatment with milace(cid:173)
`40), 800 mg (n = 38), 1200 mg
`mide, 400 mg (n
`33), or placebo (n = 37). One hundred twenty-
`(n
`
`Placebo
`Screening (visit 1)
`Mean
`30.0
`SD
`14.2
`n
`37
`Day 14 (visit 3)
`Mean
`27.3
`SD
`14.3
`37
`n
`Day 28 (visit 5)
`Mean
`28.3
`SD
`13.4
`33
`n
`Washout
`Mean
`SD
`n
`
`28.8
`16.2
`35
`
`TABLE 1
`Alzheimer's Disease Assessment Score: Total Scores
`Milacemide
`800 mg
`
`400 mg
`
`1200 mg
`
`33.8
`10.8
`40
`
`33.6
`13.4
`39
`
`32.6
`12.4
`38
`
`34.7
`15.1
`37
`
`29.4
`13.0
`36
`
`26.9
`13.0
`35
`
`26.4
`11.5
`31
`
`25.8
`11.3
`32
`
`28.6
`13.0
`32
`
`29.8
`16.3
`31
`
`26.9
`14.0
`30
`
`26.9
`15.6
`28
`
`Journal of Geriatric Psychiatry and Neurology I Vol. 6 I April-June 1993
`
`117
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2129 - 6/8
`
`

`
`TABLE 2
`Clinical Global Impression Severity of Illness Rating
`Milacemide
`800 mg
`
`400 mg
`
`1200 mg
`
`4.10
`0.71
`40
`
`4.07
`0.73
`40
`
`4.05
`0.71
`40
`
`4.10
`0.79
`39
`
`3.76
`0.75
`38
`
`3.75
`0.73
`36
`
`3.68
`0.68
`34
`
`3.80
`0.76
`35
`
`3.85
`0.79
`33
`
`3.84
`0.77
`32
`
`3.41
`0.81
`32
`
`3.72
`0.92
`29
`
`Placebo
`Baseline (visit 1)
`Mean
`3.57
`SD
`0.69
`3.7
`11
`Day 14 (visit 3)
`3.62
`Mean
`0.64
`SD
`37
`11
`Day 28 (visit 5)
`Mean
`3.69
`0.68
`SD
`35
`11
`Washout
`Mean
`SD
`n
`
`3.78
`0.72
`36
`
`Cutler et al .
`
`Clinical Laboratory Values
`Clinically significant increases in liver function tests,
`specifically aspartate aminotransferase and alanine
`aminotransferase (AST and ALT), were reported for
`five patients receiving milacemide. In three of the
`five patients, elevations were judged to be severe
`(one patient receiving 1200 mg/d and two patients
`taking 400 mg/d); however, all liver function test el(cid:173)
`evations were reversible on drug discontinuation.
`With the exception of the abnormalities in liver func(cid:173)
`tion tests and a single patient with blood in urine,
`none of the clinical laboratory values constituted an
`adverse event.
`
`Discussion
`None of the milacemide groups showed a statisti(cid:173)
`cally significant increase in efficacy ratings over pla(cid:173)
`cebo. The results of this placebo-controlled double(cid:173)
`blind trial are in contrast to those reported by
`Schwartz et al, 31 who found that milacemide had a
`significant effect on the speed and accuracy of verbal
`retrieval in normally functioning young and elderly
`volunteers. Cognitive behavior values were highly
`nonsignificant (P = .93).
`Reasons for lack of efficacy in this trial may be a
`relative nonresponsiveness of NMDA-receptor acti(cid:173)
`vation in the population itself, or the time period of
`active drug administration ( 4 weeks) may be too
`brief to begin to see acute changes or improvements.
`Also, given the slow progression of the disease,
`some clinical trials in SDAT patients are conducted
`for 6 months or longer to evaluate for changes in
`disease progression over time. 32 Although milace(cid:173)
`mide administration was associated with a tendency
`(P
`.10) toward improvement of CGI severity
`scores, no clear dose-response relationship between
`tendencies for improvement and milacemide dos(cid:173)
`ages used in this study was found. Nonetheless, it is
`unlikely that future long-term trials with milacemide
`will be planned because of the effects on hepatic en(cid:173)
`zymes seen in our study and in a previous milace(cid:173)
`mide (1200 mg/d) study in SDAT (Dysken et al, in
`preparation). Enzyme elevations requiring drug dis(cid:173)
`continuation were observed in our study at low (400
`mg/d) and at high dosages (1200 mg/d).
`stimulat(cid:173)
`Other promising approaches
`for
`ing NMDA receptors in SDAT patients include par(cid:173)
`tial agonists for the glycine-B site, such as D-cyclo(cid:173)
`serine, which can stimulate NMDA-receptors in a
`low-glycine environment while blocking excess stim(cid:173)
`ulation in a high-glycine environment. 33 The latter is
`important because excessive stimulation of NMDA-
`
`placebo), but the difference was not statistically sig(cid:173)
`nificant (P
`.10).
`No significant differences between treatments
`were found on the Patient Global Improvement Rat(cid:173)
`ing, the Physical Self-Maintenance Scale, or the
`IADL, either by visit or at endpoint. Although the
`Hamilton Depression Scale scores of the study sites
`differed with respect to baseline, the differences
`with respect to change from baseline were not statis-
`tically significant.
`·
`Of the 148 enrolled patients, seven were with(cid:173)
`drawn from the study because of treatment failure.
`All were on active drug. Three were receiving 400
`mg/day, and two each received 800 mg/day and 1200
`mg/day. These patients were judged to range from
`"minimally worse" to "much worse" on the CGI.
`Two patients were also withdrawn because of non(cid:173)
`compliance, and 10 withdrew because of adverse
`events.
`
`Adverse Events
`A total of 255 adverse events rated as mild (160), mod(cid:173)
`erate (84), and severe (11) for milacemide and 74
`events of mild (57) and moderate (17) severity for pla(cid:173)
`cebo were reported during the study. The overall fre(cid:173)
`quency of adverse events was similar between
`milacemide (43.5%) and placebo (50.0% ); however, a
`pattern differentiating milacemide from placebo could
`be seen. The most frequent drug-related treatment(cid:173)
`emergent adverse events were fatigue, headache, diz(cid:173)
`ziness, and nausea, whereas the most frequent
`placebo-related events were headache, rhinitis, dizzi(cid:173)
`ness, back pain, diarrhea, and nervousness.
`
`118
`
`Journal of Geriatric Psychiatry and Neurology I Vol. 6 I April-June 1993
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2129 - 7/8
`
`

`
`Evaluation of Milacemide for Senile Dementia
`
`receptors can potentially
`and/or neurotoxicity.
`
`lead
`
`to
`
`tachyphylaxis
`
`Acknowledgments
`We wish to thank the following for their participation in the
`study: Rodman Shankle, MD; John E. Crowder, MD; Jacob H.
`Fox, MD; Christopher M. Clark, MD; N.P.V. Nair, MD; Leonard
`F. Rozek, PhD; and Denise Yee. We also thank Holland Trotman
`for her assistance in preparation of the manuscript.
`
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