>
`W1 253570
`l993
`No.2
`v.6
`C 01'-‘---‘-SEQ3 530062369
`TI: ZEITSCHRIFT FUR
`GERONTOPSYCHOLOGIE
`
`10/20/93
`
`Ueronto-
`
`
`
` Herausgegeben von ll. w U. usW'le, NUrnberg
`
`Siegfried Kanowski, Berlin
`
`
`
`Redaktion Ulrich M. Fleischmann, Niirnberg
`
`Activities-of—Daily—Living/ Befindlichkeit / Diagnostik /
`‘
`Demenzen / Depressive Syndrome / Evaluation von
`TherapiemaBnahmen / Fragebogen / Forschungsmethodik /
`Funktionelle Psychosen / Geriatrica / Gedachtnis /
`Klinische Skalen / Klinische Prijfungen / Leistungstests /
`Methodenentwicklung / Neurotisch-psychoreaktive Entwicklungen /
`Nootropica / Organische Psychosen / Psychometrie/
`Psychopharmakotherapie / Quer- und Langsschnitt-Studien /
`Ratingskalen / Selbstbeurteilungs-Skalen / Stimmung /
`Syndromkonfigurationen / Testverfahren
`
`,
`
`6. Jahrgang
`Heft 2
`Juni 1993
`
`4
`
`I'll : Verlag Hans Huber
`“j
`Bern Gottingen Toronto Seattle
`
`IPIC2015-00410
`
`Petitioners' EX. 1025
`
`Page 1
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`

`Wissenschaftlicher Beirat
`
`M. M. Baltes, Berlin, M Bergener, Koln; J. Bruder, Hamburg;
`S Hoyer, Heidelberg;W. Janke, Whrzburg;Chr. Kretschmar, Dfisseldorf; E Lang, Erlangen;
`H. Lauter, Mfinchen; U. Lehr, Heidelberg; P. Netter, GieBen; K. Oesterreich, Heidelberg;
`E. Olbrich, Erlangen; K. Pawlik, Hamburg; H. Radebold, Kassel; J. Rohmel, Berlin;
`R. Schmitz-Scherzer, Kassel; H.-D. Schneider, Fribourg; H. K. Schneider, Erlan gen;
`R.-M. Schfitz, Lfibeck; H. Thomae, Bonn; J. Wertheimer, Prilly/Lausanne
`
`Hinweise fiir Autoren
`
`In der Zeitschrift flir Gerontopsychologie und -psychiatr1'e
`werden empirische und theoretische Beitréige publiziert,
`die sich mit der Forschungsmethodik und der Methoden-
`entwicklung fiir den Bereich des hbheren Lebensalters
`sowie den daraus resultierenden Grundlagenergebnissen
`bzw. anwendungsorientierten Ergebnissen beschéiftigen.
`Im Mittelpunkt stehen deshalb u. a. die Psychometric und
`die Psychopathologie sowie klinische Prilfun gen von Arz—
`neimitteln bzw. die Bewertung von lnterventionsmaBnah-
`men all gemeinster Form im hoheren Lebensalter.
`
`Art und Umfang der Beitriige
`
`Die Zeitschrift far Gerontopsychologie und -psychiatrie
`publiziert deutsch- und englischsprachige Beitréige aus
`den oben genannten Bereichen:
`
`- Ubersichtsartikel und Sammelreferate als zusammen-
`fassende Darstellungen zu Forschungsmethoden, For-
`schungsergebnissen und Forschungsprojekten der
`Gerontopsychologie und —psychiatrie (Umfang bis zu
`50 Standard-Manuskriptseiten mit je 30 Zeilen 2'1 60
`Zeichen),
`- Methodische und empirische Originalarbeiten zu den
`genannten Themenbereichen (Umfang max. 40 Stan-
`dard-Manuskriptseiten),
`— Kurzbeitrdge, die in knapper Form kleinere Studien,
`Replikationen, Konzepte u. éi. darstellen oder iiber ge-
`plante Vorhaben berichten (Umfang ca. 12 Standard-
`seiten),
`- Nachrichten und Berichle fiber Aktivitéiten, Tagungen
`usw., soweit sie die Gerontopsychologie und -psychia-
`trie betreffen.
`
`Einsendung von Manuskripten
`
`Manuskripte fiir die Zeitschrift fir Gerontopsychologie
`und -psychiatrie sind in zweifacher Ausfertigung (ein-
`schlieBlich der Originale der Abbildungen und Tabellen)
`einzureichen. Sie Werden nach Publikation nicht zuriick-
`gesandt.
`Es konnen grundséitzlich nur solche Arbeiten zur Publi-
`kation eingereicht Werden, die nicht gleichzeitig anderen
`Stellen zur Veriiffentlichung angeboten werden oder be-
`reits publiziert worden sind. Die eingereichten Arbeiten
`Werden durch die Mitglieder des wissenschaftlichen Bei—
`rats sowie ggf'. durch externe Beurteiler einem Review un—
`terzogen. Die formale Gestaltung der Artikel hat sich an
`den in diesem Heft enthaltenen Arbeiten zu orientieren.
`
`Manuskripte sind einzureichen bei:
`Prof. Dr. W. D. Oswald
`Institut ffir Psychologie II
`Redaktion Zeitschrift fi'lr Gerontopsychologie und
`-psychiatrie .
`Regensburger StraBe 160
`D-90478 Niirnberg
`
`Prof. Dr. S. Kanowski
`Freie Universitéit Berlin
`Institut fiir Gerontopsychiatrie
`ReichsstraBe 15
`D-14052 Berlin
`
`Anzeigenannahme: Verlag Hans Huber, LénggaB—StraBe 76, CPI-3000 Bern 9
`
`Erscheinungswcisc: vierteljéhrlich
`Jahresabonm'ment: (4 Hefte) SFr. 96.—/DM 104.—
`Porto und Versandgebfihren: SFr. 6.— (Schweiz), DM 9.— (BRD), SFr. lO.— (fibrige Lander)
`Einzelheft: SFr. 28.50/DM 30.- (Preise gelten fiir 1993)
`Abbestellungen spéitestens acht Wochen vor Ablauf des Abonnements
`Diese Zeitschrift wird regelméBig fiir die Literaturdatenbank PSYNDEX und den Referatedienst «Psychologischer In-
`dex» ausgewertet.
`
`Copyright 1993
`Verlag Hans Huber Bern Gottingen Toronto Seattle
`Gedruckt mit Unterstfitzun g der Deutschen Forschungsgemeinschaft
`Gesamtherstellung: Allgéiuer Zeitungsverlng GmbH, Kempten/Allgéiu
`ISSN 1011-6877
`
`IPR2015—00410
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`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Zeitschrift fiir Gerontopsychologie und -psychiatrie, 6, 1993, Heft 2, S. 103 — 117
`
`MARINA PANTEv*, R. RITTER, R. GORTELMEYER**
`
`* Merz + Co. Phanna GmbH & Co., Depts. Clinical Research/CNS* and Biometry“, Frankfurt/M., and Geriatric’s
`Practice, Freiburg i. Br., Germany
`
`Clinical‘and behavioural evaluation in long-term care patients
`with mild to moderate dementia under Memantine treatment
`
`Untersuchungen von Psychopathologie und Verhalten bei Altenpflegeheimpatiente’n
`mit leichter bis mittelschwerer Demenz unter Memantine
`
`Zusammenfassung: Die klinische Wirksamkeit und Ver-
`traglichkeit von Memantine (l-Arnino-3,5-Dimethylada-
`mantan hydrochlorid, Akatinol Memantine“, CAS
`41100-25-1) wurde in einer doppelblinden, placebokon—
`trollierten Studie bei 60 in Altenpfiegeheimen lebenden
`Patienten mit leichter bis mittelschwerer Demenz (SDAT,
`vaskularer und gemischter Typ) in einem Behandlungs-
`zeitraum von vier Wochen untersucht.
`Die konfinnatorische Statistik ergab fiir die Hauptziel-
`kriterien sowohl auf der psychopathologischen Ebene
`(SCAG, Globalurteil zur Wirksamkeit) 'als auch auf der
`Verhaltensebene (NOSIE-Index, BGP Subscore «Hilfs-
`bediirftigkeit») si'gnifikante Unterschiede zwischen Me-
`mantine und Placebo (p < (1* = 0.0125).
`Die klinische Relevanz der statistisch signifikanten Re-
`sultate wurde fiber eine Therapieresponder-Analyse nach
`dem Konzept der zufallskritischen Bewertung intraindivi-
`dueller Veranderungen ilberpriift.
`Unter Memantinebehandlung konnten in 70% der Pa-
`tienten klinisch relevante Verbesserungen fibereinstim-
`mend auf zwei unabhéingigen MeBebenen (SCAG Sum-
`menscore, NOSIE-Index) gefunden werden.
`Die in dieser Studie gefundene Therapieresponderrate ist
`deutlich hoher als die in Studien mit Nootropika.
`
`Keywords: Memantine, NMDA—antagonist, dementia
`study, therapy responder analysis '
`
`Summary: The clinical efficacy and tolerability of Me-
`mantine (1-amino-3,5-dimethyladamantane hydrochlo-
`ride, Akatinol Memantine“, CAS 41100-25-1) were inves-
`tigated in 60 patients suffering from dementia of mild to
`moderate degree living in long-term care facilities in a
`randomized, double-blind, placebo—controlled study.
`Memantine was given at a low initial doWO-mg/d on
`days 1 and 2, followed by 20 mg/d from day 3 to day 7
`and then 30 mg/d from day 8 to the end of the treatment
`after 28 days.
`The efficacy of Memantine was judged by means of end—
`point vs. baseline differences for the total score of the
`Sandoz Clinical Assessment Scale Geriatric (SCAG), the
`dimension «Need for help/care» of the Evaluation Scale
`for Geriatric Patients (BGP), and the Index of the Nurses
`Observation Scale for Inpatient Evaluation (NOSIE), as
`well as directly by the physicians global impression of
`clinical efficacy.
`The tolerability of Memantine was assessed on the basis
`of a global assessment and the documentation of adverse
`events; safety parameters were also monitored during the
`study. Only mild and transient side effects of Memantine
`were observed.
`..
`
`The clinical efficacy of Memantine was confirmed by the
`statistical significant differences between Memantine and
`placebo treatment (p < (1* = 0,0125) on independent
`assessment
`levels,
`i.e.
`the psychopathological (SCAG,
`global impression of efficacy) and the behavioural level
`(NOSIE Index, BGP subscore «need for help/care»).
`The clinical relevance of the observed drug effects is
`based on the improvement in daily functioning and social
`competence resulting in reduced need of help/care, as
`measured on two independent levels.
`Moreover clinical relevance of the observed improve-
`ments of clinical symptoms was confirmed by a therapy
`responder analysis using discriminant cut-off points for
`intraindividual change. Under Memantine a clinically rel-
`evant intraindividual improvement in two independent
`assessments (SCAG total score, NOSIE Index) was ob—
`served in 70% of the patients. The high therapy respon-
`der rate measured in this study differs from those known
`by other studies on nootropic drugs and indicates, that
`the NMDA-antagonist Memantine shows different pro-
`file in symptomatic treatment of dementia.
`
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`1. Introduction
`
`Dementing illnesses are a major contributor to
`disability in the elderly. Current diagnostic cri-
`teria for dementia include the presence of signif-
`icant impairment in social, occupational, and
`everyday
`functional
`abilities
`(DSM-III-R,
`1987). Up to now, there are unsolved problems
`and discrepancies between the diagnostic crite-
`ria of dementia and the criteria of evaluation of
`
`efficacy for clinical trials.
`The problems of evaluation of efficacy of an-
`tidementia drugs and of the clinical relevance of
`the measured therapeutic effects are reflected in
`published guidelines or
`in draft guidelines
`(AMADUCCI et al., 1990; KANOWSK] et al., 1990;
`Clinical Research Working Group of the Phar-
`maceutical Industry on Dementia, 1990; Bun-
`desgesundheitsamt
`[BGA],
`1991; Food and
`Drug Administration [FDA], 1989; European
`College of Neuropsychology [ECNP], 1991).
`A large number of instruments for assessing
`the mental state of elderly has become available.
`Many of the published methods focus on areas
`such as orientation, memory, and language and
`make use of mental performance tests, while
`only a few emphasize the importance of patients
`functioning in their habitual
`surroundings.
`However, assessment of functional abilities is
`
`essential to demonstrate drug-linked improve-
`ment in the patient’s everyday behaviour. There-
`fore, the documentation of changes in behav-
`ioural functions is a further important proof for
`the efficacy of an antidementia drug.
`Up to now, these criteria are not fullfilled in
`most studies with nootropic drugs (see WEYER,
`1992). For the NMDA (N-methyl-D-aspartate)
`antagonist Memantine however it was demon-
`strated in previous clinical studies that the drug
`not only improves vigilance (KUGLER, 1975;
`SCHULZ et al., 1992) and cognitive disturbances
`(DITZLER, 1991), but also drive, motivation,
`emotional conditions, motor functions in activi-
`ties of daily living, and social behaviour (DITz-
`LER, 1991; PARSONS & PANTEV, 1991; GORTEL-
`MEYER& ERBLER, 1992).
`The aim of the present study was to test the
`clinical efficacy and the tolerability of Meman-
`tine at doses of 20- 30 mg/day in patients with
`mild to moderate dementia, living in long-term
`care facilities. Evaluation of drug effects was
`
`104
`
`made on two independent assessment levels, the
`psychopathological and the behavioural level.
`On the behavioural assessment level the target
`efficacy criterion was focussed on the functional
`status as an decisive aspect in patients’ care.
`Emphasis was put on the clinical relevance of
`changes by using a therapy responder analysis.
`
`2. Methods
`
`2.1. Study Design, Sample and Procedure
`
`The study was designed as a prospective, ran-
`domized, placebo-controlled double-blind study
`with independent parallel groups of 30 patients
`each.
`
`The study was performed under guidance of
`Dr. Ritter, Freiburg/Brsg.
`All patients were investigated by the above-
`mentioned physician who was in charge of the
`long—term care facilities.
`The functional abilities and the behaviour in
`
`everyday life were rated by trained nurses.
`The study was supervised, conductet and
`monitored by the Clinical Research Dept. of
`Merz + Co., Frankfurt/Main.
`The blinding of the drugs was performed in
`the Dept. of Pharmaceutical Technology of the
`manufacturing company.
`
`2.1.1. Inclusion Criteria
`
`Male and female patients living in long-term
`care facilities, aged between 50 and 80 years suf-
`fering from primary degenerative and vascular
`dementia of mild to moderate degree were in-
`cluded.
`
`The diagnosis of dementia was established on
`clinical assessment according to the DSM-III-R
`criteria.
`
`The degree of dementia was assessed using
`the Lausanne scheme (LAUTER, 1973) and the
`Sandoz Clinical Assessment Geriatric, Scale
`
`(SHADER et al., 1974), cut-off:
`(SCAG)
`score of at least 80 points and more.
`CT—scan and laboratory assessments were
`used to exclude secondary dementias. Since Me-
`mantine as a NMDA—antagonist is supposed to
`be efficacious in all types of dementia of prima-
`
`total
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`differentiation of
`no
`origin,
`cerebral
`ry
`subgroups was performed in the present study.
`
`2.1.2. Exclusion Criteria
`
`Patients were excluded from the study by the
`following criterial:
`- participation in a study within the preceding
`four weeks
`
`- drug and/or alcohol abuse/dependence
`— known intolerance to the test product
`— severe chronic or terminal diseases
`
`— decompensated hypertension, haemodynam-
`ically relevant heart diseases, myocardial or
`cerebral infarction within the previous three
`months
`
`— impairment of liver function (elevation trans-
`aminases to more than the twice of normal
`
`level)
`— impairment of kidney function (serum cre-
`atinine level above 1.8 mg/dl)
`- secondary dementia
`— psychiatric disorders
`- Parkinson’s disease
`- Seizure disorders
`
`Concomitant Medication
`
`— Patients receiving concomitant psychotropic
`medication (tranquilizers, antidepressants,
`daytime sedatives, vasodilatators, or central
`nervous stimulants) were excluded from the
`study with the following exceptions:
`Occasional night sedation with chloral hy-
`drate and in exceptional cases (chronic users)
`a benzodiazepine with a short half—life.
`— Antihypertensive medications having psy-
`chotropic effects such as reserpine or pro-
`pranolol were not allowed during the study.
`- Anti—parkinson or anticonvulsant drugs were
`not permitted.
`— Other necessary medication (basic therapy of
`multimorbid patients) was permitted during
`the course of the study only with stable and
`constant doses.
`
`.w.
`
`At each visit of the patient, the identity, dos-
`age and frequency of administration of all con—
`comitant medications were recorded.
`
`The following wash-out periods were advised
`before the patients wererandomized to treat-
`ment:
`
`- Tricyclic antidepressants: one week, with the
`exception of fluoxetine requiring four weeks
`— Benzodiazepines: two weeks (with the excep-
`tion of an occasional bedtime hypnotic)
`— Antipsychotics: two weeks
`
`2.1.3. Medication
`
`The treatment phase lasted four weeks including
`a run—in period of ascending doses of seven days
`and was preceded by the wash-out phase de-
`pending on premedication, see 2.1.2.
`The test drugs were Memantine as tablets of
`10 mg Akatinol MemantineR (Batch No.
`9010]); manufacturer: Merz + Co., Frankfurt/
`Main, and placebo tablets of identical appear-
`ance. The tablets were to be taken at mealtimes
`
`(no special dietetic restrictions), the last tablet
`not later than 4.00 pm to avoid sleep disturb-
`ances.
`
`The dose regimen was: one tablet of Meman-
`tine/day on days 1 and 2, two tablets/day from
`day 3 to day 7, and three tablets/day through
`days 8-28. The dose was allowed to be reduced
`to two tablets per day in case of intolerance of
`30 mg/d.
`
`2.1.4. Study Schedule
`
`The clinical and behavioural baseline examina-
`tion was carried out after the initial wash-out
`
`period. Three subsequent examinations fol-
`lowed in intervals of one and two weeks. All
`
`four examinations of each patient were carried
`out by the same physician and the same nurse
`staff.
`
`The schedule of the entire study is shown in
`Table 1.
`
`2.1.5. Efficacy Assessment
`
`As main target criteria for efficacy the following
`assessment scales were used:
`
`0 Global
`
`assessment
`
`of
`
`clinical
`
`efficacy
`
`(4 point scale) by the physician,
`0 the Sandoz Clinical Assessment Geriatric
`
`Scale SCAG (total score) (VENN, 1983; CIPS,
`1986), rated by the physician,
`
`105
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`Ybble 1: lnvestigational Schedule
`
`
`
`
`
`Investigations /
`Time (days)
`saw" IIIIIIII
`Assessmems
`
`
`Dose(imgIIIIII 20—30
`20-30
`2030
`
`
`Clinical status
`CT
`SCAG
`x IIIIIIII
`
`IIIIx III
`IBGIIIIIX III
`
`
`
`
`
`
`- of efficacy
`- of tolerability
`
`
`safety parameters IIIIIIIIII
`
`
`
`Global assessment
`
`0 the Evaluation Scale for Geriatric Patients 0 the Nurses Observation Scale for Inpatient
`(Beurteilungsskala fiir Geriatrische Patien—
`Evaluation, NOSIE-Index
`(HONIGFELD,
`ten, BGP), BGP (subscore «need of help/
`1974; CIPS, 1986),
`rated by the trained
`care») (KAM et al. 1971, CIPS 1986), rated by
`nurses of the care facilities.
`the physician,
`
`Ybble 2: Baseline data
`
`No. of patients
`
`I—M
`
`eanswm
`
`concomitant medication
`
`
`
`Max (years)
`
`Mean + SD((kg)
`
`60- 79
`
`70.3 + 3.3
`
`55-79
`
`Baseline severity
`
`SCAG total score
`SCAG item 19
`
`5 - mild to moderate
`
`6 ~ moderate
`
`7 - severe
`
`
`
`Duration of disease
`
`Mean i SD (month)
`
`50 2 + 12 7
`
`52. 7 + 23. 2
`
`Concomitant diseases
`
`Cardiopulmonary diseases
`Rheumatic diseases
`
`
`Hypertension
`Diabetes
`
`No. of patients receiving
`
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`2.1.5.1. Rsycliopathological Level
`
`- Physicians Global Assessment of Clinical Effi-
`cacy
`
`Global clinical efficacy was assessed by the
`physician in charge using a four point scale
`(see Table 3)
`- Sandoz Clinical Assessment Geriatric Scale
`
`(SCAG):
`The SCAG scale measures impairments and
`
`disturbances of cognitive, affective, social.
`and somantic functions and drive.
`The SCAG scale consists of 18 items and an
`
`overall impression, (item 19), all rated on a
`seven-point format; the scores of the individ-
`ual items are added together to give a total
`score (item 1— 18) or in five subscores (see Ta-
`ble 7) according to VENN (1983, 1986).
`Decreasing scores indicate clinical improve-
`ment.
`
`Table 3: Physicians Global Assessment of Clinical Efficacy after 4 weeks treatment
`
`
`
`
`placebo
`(n)
`
`* p < «1* = 0.0125, Mantel—Haenszel-xZ-test.
`
`2.1.5.2. Behavioural Level
`
`- Evaluation
`(BGP):
`The Evaluation Scale for Geriatric Patients
`
`for Geriatric Patients
`
`Scale
`
`(BGP) is a rating scale for functional disturb-
`ances in the elderly on the basis of behaviour
`observation.
`The BGP consists of four subscales for the
`
`rating of the following dimensions: 1.) need
`of help/care (summarizing 23 items), 2.) ag-
`gressiveness (5 items), 3.) physical (3 items),
`mental (4 items) disability and depressiveness
`(3 items), and 4.) inactivity (7 items).
`The use of a total score is not intended in the
`
`dutch original version. Reliability and validi—
`ty were highest for the subscore «need of
`help/care» (DIESFELDT, 1979, 1980, 1981).
`— Nurses Observation Scale for Inpatient Evalu-
`ation (NOSIE):
`The NOSIE is well established to assess be-
`
`havioural symptoms of psychiatric inpatients
`by staff personnel. The NOSIE consists of 30
`items of behaviour; the frequency of their
`occurrence is rated.
`
`tardation, depression. Based on these seven
`subscores,
`the NOSIE index represents an
`evaluation of the patient’s condition from the
`caregivers’ viewpoint. Increasing values of
`the NOSIE index are regarded as an im-
`provement.
`
`2.1.6.
`
`Iblerability Assessment
`
`Tolerability of Memantine was assessed on the
`basis of the physician’s global rating of tolera-
`bility (4 points scale) after four weeks, and the
`monitoring of any adverse events either sponta-
`neously reported by the patient or observed by
`the investigator. For each adverse event, severity
`and duration as well as a judgement of the cau-
`sal relationship with the treatment were re-
`corded.
`
`2.1. 7. Laboratory Investigations
`
`The following laboratory parameters were
`measured before the start of the wash-out
`
`The NOSIE subscale scores (factors) are: so-
`cial competence,
`social
`interest, personal
`neatness, irritability, manifest psychosis, re-
`
`phase, at baseline and after four weeks; SGOT,
`SGPT, y-GT, serum creatinine, erythrocytes,
`platelets, and leucocytes.
`
`
`
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`As safety parameters, pulse rate and blood
`pressure were monitored in the supine position.
`
`2.1.8. Statistics
`
`With reference to the results of previous studies
`with Memantine, the decrease in the SCAG to-
`
`tal score after four (to six) weeks of treatment
`was supposed to be greater than 1.3 standard
`deviations or more. This parameter was used for
`the sample size estimation.
`The randomization was performed by means
`of RANCODE (IDV, Gauting) for n = 60
`patients.
`The hypotheses of different effects of Me-
`mantine compared to placebo were tested by the
`Mann-Whitney-U-Test
`(two-sided test on a
`global significance level a =' 0.05). Since the sta-
`tistical testing of the above-mentioned efficacy
`hypotheses necessitated repeated testing on the
`same material, a Bonferoni-Holm (I-COI'I'eCthIl
`
`was planed in the protocol; the nominal signif-
`icance level for each individual
`test
`is (1* 2
`0.0125.
`
`The confirmatory statistical analysis was per-
`formed on the basis of the intent-to-treat-sam-
`
`ple, including all patients as randomised.
`Additional analyses of variance with the
`NOSIE and the SCAG subscales were per-
`formed in the sense of exploratory data analy-
`sis; p-values given here are to be understood as
`descriptive significance.
`To evaluate the importance of statistically sig-
`nificant group differences of therapeutic effects
`fot the individual patient a responder analysis
`was performed to judge clinical relevance.
`The clinical relevance of the results relies on
`the concept of statistical relevant differences
`and is investigated by means of analysis of vari-
`ance to estimate the reliability of measurement
`(cf. WINER, 1974). The measurement of patient i
`with a measuring instrument, e. g. a psychiatric
`scale (like the SCAG) may be represented as:
`
`where
`
`Yij = “i + 3g;
`yij is the observed rating score
`rti is the true magnitude of the score, and
`8“- is the error of measurement.
`
`(1)
`
`Given that the rater is the same during the
`whole study, or different raters are trained prior
`
`108
`
`to the study in order to achieve a high interrater
`reliability, ni may be assumed to remain con-
`stant whereas eij is assumed to vary.
`’
`If 1ri remains constant for such measurement,
`the variance observed person within it is due to
`error of measurement.
`
`Under the assumption that iii and sij are un-
`correlated, the total variance 62 (y) is the sum of
`the true variance 0'2 (1c) and the error variance
`02 (a).
`The reliability (Q) of a measurement is defined
`by the variance due to true scores divided by the
`total variance:
`
`2
`9 = ‘Tifloz—
`6 (it) + (S (a)
`
`(2)
`
`From (2) follows the standard error of measure-
`ment (0(3)) equals:
`
`6(8) = 0(y) - V (1‘9)
`
`(3)
`
`For the estimation of the reliability of measure-
`ment of change ((1) the standard error (c(d)) is
`defined as:
`
`6(d) = 6(Y) . [2 0‘9)?”
`
`(4)
`
`On the basis of this concept it is possible to de-
`fine a critical difference at a specified (l-leVel.
`The score must exceed or fall below the critical
`
`difference to indicate a relevant change in a spe-
`cified characteristic, e. g. a syndrom.
`
`dcrlt(ll) = Zu . 0(Y) - [2 0—9)]1/2
`
`(5)
`
`The definition of these critical cut-off points,
`which separate irrelevant from clincial relevant
`changes in scores, is performed by means of var-
`iance component analysis which is in detail ex-
`plained by WEYER (1992). The estimation of var-
`iance components is performed in several steps
`on the basis of the results of an ANOVA with
`
`repeated measurements on time (random effects
`model) which is performed with the data of five
`examination days under placebo treatment
`(days 0, 7, 14, 21 and 28). The reliability coeffi-
`cient Q, the standard error 0(d) and the critical
`difference on the 5% level for each scale (SCAG
`total score, NOSIE Index) will be used for defi-
`nition of therapy responders.
`The main statistical analysis of the data was
`performed by Pharma, Management Organiza—
`tion Marketing GmbH, Kronberg/Ts. Descrip—
`
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`tive analyses and retest-reliability calculations
`were performed by the Biometrical Dept. at
`Merz + Co., Frankfurt/M.
`
`2.1.9. Premature Discontinuation of Treatment
`
`Patients whose clinical picture worsened during
`therapy and whose continued participation in
`the study was ethically and medically no longer
`justifiable had to be excluded from further
`treatment. Other reasons for premature discon-
`tinuation were the withdrawal of consent to par—
`
`ticipate and the necessity of concomitant medi-
`cation not permitted in the study protocol.
`Patients who dropped out in the first two weeks
`of treatment and patients who discontinued
`treatment prematurely because of adverse events
`which were not related to the test drugs could be
`replaced. Dropouts had to be documented.
`
`2.1.10. Ethical Aspects
`
`The study followed the ethical guidelines as for-
`mulated in the Helsinki declaration of 1964
`
`(amended 1975, 1983 and 1989) and was carried
`out in accordance with the German guidelines
`on the proper performance of clinical
`trials
`(Bundesanzeiger, 1987). The investigator was
`experienced in conducting psychopharmacolog-
`ical trials in accordance with § 40 (1) of the sec-
`
`ond German Drug Law of August 16, 1986. The
`study was approved by the Ethics Committee of
`Freiburg/Brsg.
`Informed Consent to participate as required
`by the Declaration of Helsinki
`(1989) was
`obtained prior to entering the study.
`
`3. Results
`
`3.1. Patients
`
`60 Patients (45 female, 15 male) participated
`and fulfilled the protocol of the study. The base-
`line data of the sample (Table 2) indicate that
`the parallel groups were comparable with re—
`spect to age, weight, height, duration of disease,
`SCAG total score and SCAG item 19, and con-
`comitant diseases.
`
`The most frequently recorded concomitant
`diseases were: cardiopulmonary diseases (pre-
`sent in 90% of the patients), rheumatic diseases
`(47%), hypertension (37%), and diabetes (5%).
`Concomitant medication was allowed only,
`when in a steady state and was documented in
`full detail.
`
`86% of the patients received cardiac glyco-
`sides, 10% nitrates, 3% antihypertensives, 31%
`antirheumatics; 2% antilipidemic and 2% uri-
`cosuric agents and 2% other medication. There
`were no protocol violations by concomitant
`medications.
`
`thle 4: SCAG item 19: Clinical Global Impression of Disturbances (absolute frequency)
`
`
`
`
`
`109
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`3.2. Assessments of Therapeutic Eflicacy
`3.2.1. Global Ratings
`
`3.2.2. Comprehensive Assessments
`
`3.2.2.1. Psychopathological Level
`
`A) Physicians Global Assessment of Clinical
`Efficacy
`Physicians global assessment of efficacy at
`the end of the study is presented in Table 3.
`
`B) Global Impression ofDisturbances
`(SCAG item 19)
`
`Table 4 shows the frequency distribution of
`SCAG item 19 (global impression of disturb—
`ances) depending on medication and time of
`assessment. The table shows that on Me—
`
`mantine there was a clear improvement re-
`sulting in a shift from «severe» and «moder-
`ate» to «milder» stage of disturbances,
`whereas patients on placebo deteriorated
`partly from «mild to moderate» to «moder-
`ate» and practically no change was observed
`in stage «severe» in this group.
`
`Tab. 5a shows the improvement (absolute) dif-
`ferences: (endpoint vs. baseline) of the SCAG
`total
`score. The average improvement was
`-15.2 points (18% of the baseline value) under
`Memantine treatment and —5.3 points (6% of
`the baseline value) under placebo; the difference
`being statistically significant (p S 0.001 < (1*,
`Mann-Whitney U—test).
`
`3.2.2.2. Behavioural Level
`
`A) BGP Subscore «Need of Help/ Care»
`There was a statistical decrease (improve-
`ment) in the BGP Subscore «Need of Help/
`Care» by Memantine as compared to place-
`bo as shown in Table 5b. The mean of the
`
`Table 55 Differences (endpoint vs. baseline) on the psychopathological and the behavioural level
`
`a) Psychopathological level (physicians rating)
`
`total score
`
`25
`
`
`"mm--Mll
`Winn—mn—
`n—m——-
`
`
`
`75
`
`* p_< 0.001 < ¢" (MannWhitney--U——test)
`
`b) Behavioural level (physicians rating)
`
`BGP subscore
`
`Percentlle
`
`Percentlle
`
`
`
`.need at help- m---m—
`mun“
`m...
`+3
`—|— “I. -_
`
`" p g 0.001 < ¢" (Mann-Whitney-U-test)
`
`c) Behavioural level (nurses’ rating)
`
`
`
`
`
`WW-MWM-
`
`75
`
`25
`
`m_
`
`I-_--Ml
`
`
`
`
`
`
`* p g 0.001 < a‘ (Mann-Whitney-U-test)
`
`110
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`differences was -8.3 points (38% of the
`baseline value)
`in the Memantine group
`(range from —21 to +1 points) and -1 point
`(5% of the baseline value) in the placebo
`group (range from -4 to +3 points). This
`difference was statistically significant (p <
`(1*, Mann-Whitney U-tcst).
`
`13)
`
`NOSIE Index
`
`Whereas the changes in the placebo group of
`the NOSIE index mean values from 135.8 to
`
`135.2 were marginal (difference -0.6 points,
`0.4% of the baseline value), the mean index
`values in the Memantine group increased
`from 130 to 152.7 (difference +22.7 points,
`17% of the baseline value). The group differ-
`ence being statistically significant after four
`weeks treatment (p < (1*, Mann-Whitney
`U-test for the baseline differences, Table 5c).
`
`3.2.3. Subscore Analysis
`
`.
`
`A) The SCAG subscores (Table 6) were calcu-
`lated to provide a better description of the
`profile of effectiveness of Memantine. Anal-
`ysis of variance showed an interaction of
`
`medication x time for all subscores (0.001 s
`p 5 0.004) except «somatic disturbances».
`Table 6 shows the course of the mean scores
`
`and the p—vaiues for group differences at the
`individual times of measurement.
`
`Starting from comparable initial values,
`the
`subscore
`«cognitive
`disturbances»
`showed a significant decrease (improvement)
`in the Memantine group after four weeks.
`With regard to the subscore «social behav-
`iour» there was no change in the mean val-
`ues in the placebo group. In contrast the sub-
`score of the Memantine group showed a sig-
`nificant decrease
`(improvement) at
`the
`second and the fourth week.
`
`In comparison to placebo the subscore
`«lack of drive» showed a stronger decrease
`(improvement)
`in the Memantine group,
`which was also significant at the second and
`fourth week.
`In the subscore «affective disturbances»
`
`there was a significant difference between
`the baseline values of the placebo and Me-
`mantine group.
`Whereas the placebo group showed no
`change in the time course, however under
`Memantine a distinct decrease of the dis-
`turbances could be observed.
`
`Table 6: SCAG total score and subscore (mean), separately for time of measurement and medication group
`(M = Memantine, p = placebo)
`
`Time (days)
`
`Subscores
`
`
`
`Cognitive disturbances
`
`Disturbances in social behaviour
`
`Lack of drive
`
`Affective disturbances
`
`Somatic disturbances
`
`9,4
`
`16.8
`17.8
`
`23. 3
`24.5
`
`13. 4
`11 9
`
`24. 8
`25. 9
`
`13.9
`11.6
`
`t
`
`162
`17.9
`
`21. o
`23.9] *
`
`12.5
`11.5
`
`90
`9.8
`
`8.6 1*
`9.8
`
`8.3 J *
`
`14.9
`17.2
`
`19.0
`23.2
`
`11.9
`11.4
`
`78
`
`
`
`* p_< 0 05 (descriptive significance for group difference)
`
`ill
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`In the subscore «somatic disturbances»
`there was at baseline a lower value in the
`
`provement in the Memantine group after
`four weeks.
`
`Memantine group. Under Memantine treat-
`ment a stronger decrease of somatic disturb—
`ances (p 3 0.015) could be observed.
`
`An examination of the NOSIE subscores
`
`B)
`
`shows that the increase (improvement) in the
`index after four weeks of treatment is due to
`
`an improvement rated in all subscales.
`Exploratory multivariant testing for medi—
`cation and time effects yielded significant in-
`teractions (medication x time) in most of the
`NOSIE subscores (p S 0.05). Table 7 shows
`the course of the mean scores and the
`
`p—values for group differences et each time
`of measurement.
`
`Starting from comparable initial values,
`the subscore «social competence» showed a
`significant improvement in the Memantine
`group starting after two weeks.
`In the subscore «social interest» there was
`
`no change in the mea