- E 20119 E-
`
`ISSN 0004-4172
`
`HIIISIIIIIINII
`
`AHZNHMIHH
`
`Biotechnology in Drug Research 41- (II), 773—868, August 1991: 8- "
`
`Special Section
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`IPR2015-00410
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`Petitioners' EX. 1010
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`Page 1
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`IPR2015-00410
`Petitioners' Ex. 1010
`Page 1
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`

`

`ArzneimitteI—Forsch ung
`Drug Research
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`Special Section: Biotechnology in Drug Research
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`ISSN 0004-41 “1‘31
`
`8/199]
`Vol. 41 (It) - No. 8 . Fag. 773—868 (1.9.91)
`
`Inherit/Contents
`
`SE23 9]
`
`Hypnottka — Psynlloplmrmoka — Sodatfva — ZNS-flerapenttka
`CNSfletive Drugs 7 Hypnotic-s 7 Psyettofl'opies 7 Sednfires
`
`E
`Ditzler. K.
`Wirksan‘tkeit und Venrtigliehkeit von Memantin bei
`Patienten mit Demenz-Syndmthlazeho—kontrollierte
`Doppelhlindstudie
`Et’t'i'mr'y and Wei-ability of Memomioe in Patients will:
`Dementia Syndrome / A dortblP—iilind. placebo controlled
`trial
`
`Heerfl'etstauti'fliet-apeutika 7 fl’mtaka 7 Hmonr-Ihempwtflm
`Cardiac Drugs — Emitter: Stimulants 7 Coronary Drugs
`
`E
`Sakamoto. W. Fujie. K... Handa. H.
`Hemmung der Produklion von Prostaglandin E3 und
`Superoxid—Anion in peritonealen Makrophagen mn
`Raltcn clutch die Knlzium-Antagonisten Nifcdipin Lind
`Nisoldipin
`Inhibition ot‘Pr'osmglondt'n E3 and Slrperoxide :‘liiiori Pro7
`domino in Rat Peritoneal Macrophages by the Calcium
`.iiiitagooists Nifedipioe and Nisoliiipioe
`
`Kéltringer. P_. Langsteger. W.. Lind. F'.. Pierer. 6..
`Reisecker. F.. Eber. 0.
`Gallopami] und \-'eriinderungert der Adenosin-diplios-
`phat— und Kollagen—induzierten Thrombozyten-Aggre-
`gallon
`Gollopamil and Changes of .‘lt‘lr'll'flSitlF-diflilflfipilflflu-- and
`t‘ollagen—imlm‘erl Platelet .Ilggr‘egatiott
`
`[l
`
`Carlon. Re Cappelletti, F.. Zanehetta, M,
`Pedon. L.. Omello. R" Maiolino. P.. Vineenzi. M.
`Ventise GallopamiI-Langzeitinfusion bci Palienlen mit
`Ruheangina t Einfachblinde. selhslkontrollierte Studie
`versus Plazebo
`
`E
`
`Adirijnistrotlon of Gatloparw'l by Long—term Venous Infu-
`sion in Spontaneous Angina / .-'l single—blind. self—mn-
`trolled study versus pineal)”
`
`7?}
`
`78]
`
`7'86
`
`789
`
`Su-essaren
`Srreosors
`
`E
`Laviekfi. 3,, Raékovd. H.
`Verscltiedcne Stressoren und Lipidperonydation 1m
`Blot
`
`7'93
`
`E = Publication in English.
`
`G = Publication in German.
`
`Different Stressoi's and Blood Lipid Pero.\'id.'rtiou
`
`IPR2015-00410
`
`Petitioners' EX. 1010
`
`Page 2
`
`IPR2015-00410
`Petitioners' Ex. 1010
`Page 2
`
`

`

`Amman-aka — Mogan—flm—Thempeutikn 7 Urikosrrrmn
`Anflemen‘m — Gastrointestinal 13mg? — Britmurfr Drugs
`
`E
`Ungcthfim. W.
`Sludie LLIr chhsclwirkung mischcn Sucrali'al und Di—
`ciofcnacr’Piruxicum he-i gesundcn Probandcn
`Study on 1h." [Hm-mm”: henrpe’n Sunmdfinr and Diffu—
`anac/Pfruximm in Henfrhy l-Eu'unm-rs
`
`lipidserrker
`Lipid Reducers
`
`E
`Gcbhardt. R.
`Hcmnmng dcr Choleslcrm-Biosymhesc in Primh’rkul-
`luren van Raltenhcpalozytcn dnrch ninety wéBrigen
`Knoblnuchcxtraki
`mum”; of Clmiesmmi BfusyrnhPs-fs by a I-i-htf‘risnlubk‘
`Gnr'h'r‘ Extra” in Pn'wan' Cultures of Rat Hepflmfj'lr‘fi
`
`Analgetikfl — Antiphlugia'flka — .flfirheumatika
`Analgesics —- Antmhlngistr‘rs — Anfirbeumaflc Dmgs
`
`K
`Graven. J
`Abschwfichung def Azuscmid-Wirkung in der chIC-
`schen Schlcifi: dcl' Raucnniere church nicht-stcroidalr
`Amirheumalika
`Attenuation of Azmmnnde'sAr-Ifnn in thr- Loop of Henle a!“
`Rat Kidney by Nuusremjda! Anfirinfimmnarmj- Drugs
`
`E
`Pinelli. A.._ Trivulzio. 5.. Man-exzi, L., Emma. L.
`Versi‘zirluc analgetische Wirkungcn \‘nn Tryplnphan
`dutch Mlopurino] bci Raltcn
`POIFntr‘an‘nn of me Analgesic Er‘l‘mrls of Trypwphan by
`Aanun'no} Eu Ems
`
`Muller. P.. Dnmmann. H.-G.. Bergdoh. H..
`Simon. B.
`EinfluB van Glycin auf die gastroduodenale Veflrtig-
`lichkcrl Von Acctylsalicylséiure r“ Eine endoskopmch
`kontrolliene Doppclhlindsludic an gcsundcn Prubam
`den
`
`G
`
`Influencp of Glycine on the Gasu‘arl‘uadfinaf This-rabfh'ly of
`x'lr'eryisah'r'yh‘c rlm'd/ An Pndosrrum'rrafly controlled double—
`blind study in healthy volunteers
`
`Immunmndulnromu 7 Immunsflmuhflm — Immuppmnsim
`fmmunomodadawrs - Innuunusfimufants - Immunosrrppmsauts
`
`E
`Schcffer, J.. Ounis. L. Kfinig. W.
`Wirkung cincs Immunsximulalors von Klebsmlla pneui
`moniae auf die Freismzung van Emzfindungsmedia-
`lnren ans humancn Granulozylen. Bascphilen und
`Thmmbo-zytcn
`Effect of an hmmnmsn'mm'marjr Subsranm of Kirabsl‘m'fd
`purwnoniae rm Inflammarm Response-:1 of’Hmuan Gran
`m'nryres. annpfu’ls and Plnmfms
`
`T9?
`
`80”
`
`305
`
`30';
`
`312
`
`Eli
`
`.inubfntika - Baklm‘xlde — Chemntbempeutfka — Zywstatika
`Antibncraflals — mummy —- Chemnihempenfits — Cytostalfcs
`
`E
`Zahncr. H.. Franz. M" Kiihler. P..Slriebe1.l—l. P.
`ln-\-'_Ilro—Wirksamkeil V011 E-len-Butyl-lgenzmhmm]-
`Denvalcn gcgcn adultc Lilomosoides carlnii
`.4n!{f?fariaf Effimr'y in vim] of 24w?~Bmfl-benznrhfnzu{r-
`Derivatives an Aduir Limmasuides um'im'i
`
`Lalitha. N.. Annapurna. 1,. lyengar. D 5..
`Bhalerao. U. T.
`
`32?
`
`E
`
`Untcrsnchung der baklenziden Aklivitm Yon ncuen
`9.6me;phcnyl-nprr0Tye!npropano—oxazolnncn und 2-
`ArylraIkyi)-4-ylinen-oxazol-S-oncn
`Smdir's on than rlnIHIflr‘rrlr'fa} Ann's!) 01' Nam"? gmrr-Uf—
`pthyI—s‘prm--rj'(.'fnpropano rnxnzufunes and Enqrflmikfl}
`4";de «nasal *5 ones
`
`Bancrnl‘cil'ld. A" Grimm. H.. Klielmann. W.
`Opt'crkuch. W. Werner. H.
`Zum Emflufl vnn Sulhaclam auf‘dic In—wlm-Akm‘ilfil
`\rnn Mezlociliin. Pipcracillm und Cefolaxim
`Impact nf‘Suflmr‘lam In! the HI-Ir‘fltfl'r’lf’rfi’ffy uf Jiiezfor‘ir—
`J'I'n. Piperailmfn‘ and (.‘Pfirlaxim
`
`(I
`
`Bal'kwcrlh. M. F.. Marigold. B.. Rchm. K. [1.
`Schmieder. (3.. Tfihcrich. H. Vinchenzo, .41... chcr. .l..
`Rfibartsch. (I
`Ermilllung dcr Bim-rri‘flgbarkeit von Cefudroxil bci
`glelchzciliger Gabe von N-Acetyicystein
`31's.? vaflabih'ry of fefndrmi.‘ Admnn'smrr-II Shmrhnnennsfir
`with N-.‘lr.'e'r}-'Jr:_1-'sfefne
`
`G
`
`831
`
`839
`
`f:
`Recs. F., Lukassck. 11.. Naher. K. G.. Cimbcckm‘. H.
`Vergleichende Unlersuchungcn zur Bjovnrfijgharkcn
`von C'cfuroximaxctil
`
`843
`
`Comparariw Int-em'garimis on fire Bium'm‘fabih'ry of Ce—
`fnmxfrm- r'rxrlrr‘.‘
`
`Amimykotika — Fungizide
`Amr'mymtr'cs — Fungicides
`
`5
`Dhmi. T.. Konakn. 5.. Uchlda. M" Yamaguchi. H.
`Antim) knlischc- Aklivilfit der neuen Substanz Lnloco~
`nazol an zwei Tinea-Modcllen
`
`8-1?
`
`flufffimgnl' Avril-'J'Ey m" the New .fiigt-HI anr'mra'znre if) Th‘n
`Tinea Mndnis
`
`Dematika
`Dematics
`
`G
`Parr. R. LL. Knrling. H, C.
`Bchnndlung des sebnrrhnischcn Ekzems mil Reloca-
`nazul
`im Verglcich zu ciner Wirkstofilfreien Pt‘iege-
`creme
`
`852
`
`Trearmem of Seburrhm‘it‘ Den-”anus 1m}: Kemennazufe as
`Cnmpar‘ed m a Bland Cream
`
`Bessndem firemen: MfllfldmgAfleh‘fflefll
`Special Themes: Mahdi-1:3 Resistance
`
`Pommerenke. E. W.. Maliem. J.. Traugou. l.J..
`Volm. M.
`Durch‘nrcchung der Multidrug-Resislcnz mil (Kr-Vera-
`pamil in vilm und in vivo
`Rnrm'szrf of Mrdridmgvrpsiswm- with {RJ-i-"r-mpmm'! in
`rim] and in rfro
`
`G
`
`855
`
`Biotechnology in Drug Research
`
`Czejka. M. J.. Jéiger. W..Scl1i.il1cr..l,. Fag]. U ..
`Schernthancr. Ci.
`Pharmaknkinmische Aspcku: dEr Komhinalinn mu In-
`tcrfcron-n-lb Lmd Folinsiiure mil Fluorouracil
`Pharmacnkinpm‘ r’lspm‘rs of er Cmnbmarinn of Infer—
`fm-anflii’h and Foh'." Arid win: FHmr-nnrarzf
`
`G
`
`.ukfindwungen I Annaum‘ements
`
`Buchbesprechungeu ,-' Honk Barrows
`
`860
`
`564
`
`8 {34
`
`L_____¥
`
`__-
`
`IPR2015-00410
`
`Petitioners' EX. 1010
`
`Page 3
`
`IPR2015-00410
`Petitioners' Ex. 1010
`Page 3
`
`

`

`Hypnotika - Psychopharmaka - Sedativa - ZNS-Therapeutika
`CNS-active Drugs - Hypnotics - Psychotropics - Sedatives
`
`Efficacy and Tolerability of Memantine in Patients
`with Dementia Syndrome
`A double-blind, placebo controlled trial
`
`K. Ditzler
`
`Summary
`The efficacy and tolerability of memantine (I -amino-3,5
`-dimethyl-adamantane hydrochloride, Akatinol Meman(cid:173)
`tine®; CAS 41100-52-1) was investigated in a double(cid:173)
`blind, randomized clinical study versus placebo in 66 pa(cid:173)
`tients aged between 65 and 80 years predominantly suf
`fering from mild to moderate vascular dementia. The tar(cid:173)
`get variables assessed were the baseline differences of the
`Sandoz Clinical Assessment Geriatric scale (SCAG) and
`Syndrom-Kurz-Test (SKT) total scores and the total time
`required in the subtests of Activity of Daily Living tests
`(ADL). Additional parameters assessed were the physi(cid:173)
`cian's global impression, the Mini Mental State Evalua(cid:173)
`tion (MMSE), the Tapping and Trace tests for fine motor
`rating and the quality in performing the ADL tests. Ad(cid:173)
`verse drug effects were recorded by DOTESITWIS. 59 of
`the 66 patients included in the study terminated the trial
`(29 in the placebo and 30 in the memantine group). For
`the baseline differences of the SCAG total score a statis(cid:173)
`tically significant improvement was observed already after
`14 days ofmemantine treatment as compared to placebo.
`After 42 days this difference was still more pronounced
`and highly significant. Significant improvements after 14
`und 42 days of memantine treatment could also be dem(cid:173)
`onstrated for the SCAG subscales cognitive disturbances,
`lack of drive, emotional disturbances, social behaviour and
`somatic disturbances. Additionally, the efficacy of the drug
`could be confirmed by the SKT and ADL tests. Particularly
`striking in the ADL tests was the considerable improve(cid:173)
`ment achieved in the quality of performing the tasks under
`memantine treatment. In the physician's global impres(cid:173)
`sion the efficacy of memantine was confirmed with regard
`to dementia syndrome, general state of health and change
`in the symptomatology in the course of treatment. Me(cid:173)
`mantine was significantly superior to placebo from the
`14th day of treatment. A significant improvement in fine
`motor functions could be demonstrated in the Trace test.
`
`Neurological, Psychiatric and Psychotherapeutic Practice,
`Bad Krozingen (J?ed. Rep. of Germany)
`
`Arzneim.-Forsch./Drug Res. 41 (II), Nr. 8 (1991)
`Ditzler - Memantine
`
`Adverse drug effects recorded by DOTES for memantine
`were agitation/excitation, increased motor activity, sleep(cid:173)
`lessness and restlessness which, however, receded in the
`course of treatment. These adverse drug effects represent
`an excessive pharmacodynamic effect resulting from a too
`rapid dose increase. The present clinical study shows a
`clinically highly relevant decrease in dementia-related def
`icits under memantine. The patients' ability to care for
`themselves· and their social behaviour is considerably im(cid:173)
`proved. In contrast to so-called nootropics, the effect of
`memantine appears after only 14 days.
`
`Zusammenfassung
`Wirksamkeit und Vertri:iglichkeit von Memantin bei Pa(cid:173)
`tienten mit Demenz-Syndrom/Plazebo-kontrollierte Dop(cid:173)
`pelblindstudie
`Die Wirksamkeit und Vertri:iglichkeit von Memantin (l(cid:173)
`Amina- 3, 5 - dimethyladamantanhydrochlorid, Akatinol
`Memantine®; CAS 41100-52-1) wurde in einer doppel(cid:173)
`blinden, randomisierten ldinischen Studie gegen Plazebo
`an 66 Patienten im Alter von 65-80 Jahren mit Uber(cid:173)
`wiegend vaskuli:irer Demenz leichten bis mi:ij3igen Schwe(cid:173)
`regrades untersucht. Zielparameter waren die Ausgangs(cid:173)
`lagendifferenzen der Sandoz Clinical Assessment Geria(cid:173)
`tric Scale (SCAG)- und Syndrom-Kurztest(SKT)-Gesamt(cid:173)
`summen und der Gesamtbearbeitungszeit der Subtests der
`verwendeten Activity of Daily Living-Tests (ADL). Weitere
`Parameter waren das globale i:irztliche Urteil, der Mini
`Mental Status (MMSE), die Feinmotorik-Tests Tapping
`und Trace und die Qualitiit der Durchfiihrung der ADL(cid:173)
`Tests. UnerwUnschte Arzneimittelwirkungen wurden mit
`dem DOTES/TWIS-Verfahren erfaj3t. Von den 66 ein(cid:173)
`geschlossenen Patienten beendeten 59 die Studie (29 Pla(cid:173)
`zebo, 30 Memantin). Gemessen an den Ausgangslagen(cid:173)
`differenzen des SCAG-Gesamtscores ergab sich bereits
`nach 14 Tag en Behandlung mit M emantin eine statistisch
`signifikante Verbesserung gegenuber Plazebo. Nach 42 Ta(cid:173)
`gen war dieser Unterschied noch ausgepri:igter und hoch(cid:173)
`signifikant. Auchfiir die SCAG-Subskalen Kognitive Sto(cid:173)
`rungen, Antriebsarmut, Affektive Storungen, Soziales Ver(cid:173)
`halten und Somatische Starungen waren nach 14 und 42
`Tag en Behandlung signifikante Verbesserungen zugunsten
`von Memantin nachweisbar. Die Wirksamkeit liej3 sich
`auch im SKT und im ADL-Test bestatigen, wobei bei den
`ADL-Tests insbesondere die erhebliche Verbesserung der
`
`773
`
`IPR2015-00410
`Petitioners' Ex. 1010
`Page 4
`
`

`

`Qualitiit der DurchjUhrung der Aufgaben unter M emantin
`auffiel. Im globalen arztlichen Urteil in bezug auf das
`dementielle Syndrom, den allgemeinen Gesundheitszu(cid:173)
`stand und die Zustandsveranderung im Verlauf der The(cid:173)
`rapie bestatigte sich die Wirksamkeit von Memantin. Im
`globalen arztlichen Urteil erwies sich Memantin ab dem
`14. Tag Plazebo signijikant iiberlegen. Im Trace-Test liej3
`sich eine signijikante Verbesserung der Feinmotorik nach(cid:173)
`weisen. An unerwiinschten Wirkungen wurden im DO(cid:173)
`TES im Vergleich zu Plazebo unter Jvfemantin vermehrt
`Agitiertheit/Erregung, gesteigerte motorische Aktivitat,
`
`Schlajlosigkeit und Bewegungsruhe erfaj3t, die sich im Ver(cid:173)
`lauf der Therapie jedoch zuriickbilden. Die aufgetretenen
`unerwiinschten Wirkungen sind Ausdruck eines Zuviel an
`pharmakodynamischer Wirkung und Folge einer zu ra(cid:173)
`schen Dosissteigerung. Die vorliegende klinische Studie
`belegt eine klinisch hochrelevante Abnahme demenzbe(cid:173)
`dingter Dejizite unter Memantin. Die Selbstversorgungs(cid:173)
`fiihigkeit und soziale Kompetenz der Patienten wird we(cid:173)
`sentlich verbessert. Im Gegensatz zu sogenannten Noo(cid:173)
`tropika tritt die Wirkung von Memantin bereits naGh 14
`Tagen ein.
`
`Key words:
`
`Akatinol Memantinf!i' · CAS 41100-52-1 · Dementia syndrome · Memantine, clinical study
`
`1. Introduction
`Causal therapy of dementia, which basically amounts to
`prophylaxis of factors causing the dementia, is not in
`sight. Treatment concentrates on the mobilization of the
`cerebral reserves still present in the clinical condition
`while preventing further progress of the disease. The aim
`is to optimize the patients' remaining autonomy and to
`maintain as long as possible an independent life in the
`environment to which they are accustomed, to restore
`their independence, or at least to improve their ability to
`care for themselves.
`Recent therapeutic studies with a cholinomimetic
`showed certain improvements in symptoms in some Alz(cid:173)
`heimer patients, but the treatment was associated with
`considerable adverse reactions. Alongside the acetylcho(cid:173)
`line hypothesis, based on an acetylcholine deficit due to
`loss of cerebral neurons, the glutamate hypothesis is gain(cid:173)
`ing in importance. According to this hypothesis there is
`a loss of glutamatergic neurons in the cortex, whereby the
`degree of dementia correlates strongly with the destruc(cid:173)
`tion of cortical neurons which have intense synaptic in(cid:173)
`terlinking under physiological conditions, their principal
`neurotransmitter being glutamate. There has been world(cid:173)
`wide research on the subject of glutamatergic neurotrans(cid:173)
`mission and influences exerted on it, and new drugs have
`been sought.
`In the search for potential agents active on dementia, ev(cid:173)
`idence has emerged that the adamantane derivative me(cid:173)
`mantine (1-amino-3,5-dimethyladamantane hydrochlo(cid:173)
`ride, CAS 41100-52-1) may be effective: in studies by
`Ambrozy and Danielczyk [l] and by Tempel [2] meman-
`. tine was found to exert positive effects on some typical
`deficit symptoms in dementia conditions. In recent stud(cid:173)
`ies [3, 4] evidence for neuromodulation in the glutama(cid:173)
`tergic system was found for memantine. In the state of a
`reduced glutamate release, after degeneration of neurons,
`memantine results in an improvement in signal trans(cid:173)
`mission and activation of neurons. In the state of a mas(cid:173)
`sive glutamate release, e.g. in ischaemia, memantine
`blocks the so-called NMDA (n-methyl-D-aspartate) re(cid:173)
`ceptors which mediate the excitotoxic action of gluta(cid:173)
`mate on neurons. These interesting preclinical findings,
`which seem to be inaccord with the glutamate hypothesis
`of dementia, in combination with clinical evidence of an
`influence of memantine on dementia, led us to perform
`the present study in double-blind and placebo-controlled
`design, in order to investigate the efficacy ofmemantine 1l
`in dementia.
`
`I) Akatinol Memantine®; manufacturer: Merz +Co., Frankfurt/
`Main (Fed. Rep. of Germany).
`
`774
`
`2. Patients and methods
`The study was performed unicentrically in ambulatory patients
`of both sexes with dementia syndrome, aged 65-80, living in old
`people's and nursing homes in a smaller town in southwest Ger(cid:173)
`many in the years 1988 through 1990.
`The study design was double-blind, randomized and placebo(cid:173)
`controlled. A duration of 6 weeks was considered sufficient, since
`previous studies had shown onset of action of the investigated
`medication after only 2 weeks.
`Finding patients with dementia syndrome willing to participate
`in a study and able to give consent who fulfill the requirements
`of a study protocol in dementia is a tedious and time consuming
`task. Patients with mild dementia, however, have still a better
`ability to understand the meaning of a double-blind, controlled
`study and are more easily enrolled than patients with more ad(cid:173)
`vanced diesease.
`The spontaneous readiness of patients to participate in a study
`is to all experience an essential prerequisite for cooperation and
`compliance and thus for the outcome of a study. This is partic(cid:173)
`ularly true for demented patients. Due to the long experience of
`the investigator in geronto-psychiatry getting consent by de(cid:173)
`mented patients not least depends on the relationship of personal
`confidence between patients and their doctor.
`
`2.1. Inclusion criteria
`The patients were informed about the nature, significance, and
`implications of the study and had to have given their consent to
`participation, which could be revoked at any time.
`Since memantine is registered for the indication of dement-ia syn(cid:173)
`drome and has been used clinically for years, an ethical com(cid:173)
`mittee's votum was not sought for the study.
`The diagnosis of a mild to moderate dementia syndrome was
`made on the basis of the Lausanne scheme [5], according to
`which a mild state is characterized by the absence of any detect(cid:173)
`able temporo-spatial orientation disturbances but the presence
`of isolated or multiple disturbances of the remaining basic in(cid:173)
`tellectual functions (memory, attention and concentration, com(cid:173)
`prehension, etc.) In the case of a moderate dementia syndrome,
`according to the Lausanne scheme, imcomplete temporo-spatial
`orientation disturbances are detectable (distinct deficits in cer(cid:173)
`tain aspects oftemporo-spatial orientation with maintenance of
`correct orientation in individual elements). At the same time,
`single or multiple disturbances of the remaining basic intellectual
`functions are present.
`A further inclusion criterion was a Sandoz Clinical Assessment
`Geriatric scale (SCAG) score of 50 or more.
`
`2.2. Exclusion criteria
`Patients with kidney function disturbances (creatinine 2 1.5
`mg/100 ml), cholestasis, uncompensated congestive heart fail(cid:173)
`ure, cerebral disturbances as a result of stroke or brain trauma
`(if the event was within 6 months prior to the study), with per(cid:173)
`sonality changes due to brain tumours, endogenous psychoses,
`abuse of drugs and/or alcohol, or Parkinson's disease, and pa(cid:173)
`tients with known intolerance to the test product were excluded.
`
`At'zneim.-Forsch./Drug Re~. 41 (II), Nr. 8 (1991)
`Ditzler- Me111antine
`
`IPR2015-00410
`Petitioners' Ex. 1010
`Page 5
`
`

`

`2. 3. Concomitant medication
`The permitted drugs comprised antihypertensives, coronary
`therapeutics, antidiabetics, digitalis, diuretics, and antirheumat(cid:173)
`ics, as long as the patients had already been taking such drugs.
`The excluded drugs were nootropics, drugs for promoting cere(cid:173)
`bral blood flow, antidepressants, neuroleptics, sleeping agents
`(except chloral hydrate or in exceptional cases a short-acting ben(cid:173)
`zodiazepine), antiparkinsonians, myotonolytics, reserpine, and
`drugs containing ergot alkaloids or their derivatives.
`
`The 5 ADL-tests used had been selected in a preliminary study
`from a number of described test methods [ 1 0], which differen(cid:173)
`tiated between healthy and derhented old people and were not
`too difficult for a demented patient. The individual test tasks
`were fitted onto a board so as to be easy for the old people to
`handle.
`2. 5. 7. To assess fine motor activity the tests Tapping and Tracing
`[11] were performed. The Tapping test measures wrist-finger
`speed and the Tracing test measures eye-arm-hand coordination
`and precision of the positioning movement.
`
`2.4. Course of the study
`The clinical scales and psychometric tests were performed by a
`gerontopsychatrist and a psychologist who were both known to
`the patients. The extemal conditions were familiar to the pa(cid:173)
`tients as well and were not changed during the period of the
`study. The psychometric tests were always carried out at the
`same time of day in order to exclude circadian influences.
`Before the beginning and at the end of the study a physical ex(cid:173)
`amination was .performed on each patient, including a laboratory
`investigation with observation of the inclusion and exclusion cri(cid:173)
`teria.
`The study schedule is given in Table 1.
`
`Table 1: Overview of the course of the study.
`-
`
`-7
`
`0
`
`3
`
`Study day
`
`0
`X
`X
`
`X
`X
`
`Dose
`Hachinski
`MMSE
`Physician's global
`impression
`SCAG
`SKT
`Fine motor activity
`ADL
`DOTES
`TWIS
`
`10
`
`20
`
`X
`
`X
`
`X
`X
`X
`X
`X
`X
`
`X
`X
`X
`X
`X
`X
`X
`
`7
`
`30
`
`14
`
`30
`
`28
`
`30
`
`X
`
`42
`
`30
`
`X
`X
`X
`X
`X
`X
`X
`
`2. 5. Methods of investigation
`2. 5.1. Physician's global impression: With regard to the demen(cid:173)
`tia syndrome the doctor's assessment of outcome was made on
`a 5-point scale (very good - good - moderate - poor - very
`poor). With regard to the change in state from the preceding
`investigation the doctor's assessment was made on a 3-point
`scale (improved - unchanged - worsened).
`2.5.2. Mini Mental State Evalution (MMSE) [6]: The MMSE was
`used at the screening examination to determine the severity of
`the dementia.
`2. 5. 3. The Hachinski scale [7] was used at the beginning of the
`study for diagnostic differentiation of primary degenerative de(cid:173)
`mentias, mixed forms, and multi-infarct dementias.
`2.5.4. The total SCAG score [8] served as a quantitative inclusion
`and evaluation criterion to determine the degree of senile invo(cid:173)
`lution and efficacy of the treatment. The patients were included
`if they had a total SCAG score of at least 50 points. The upper
`limit was 90 points, corresponding to a mild to moderate de(cid:173)
`mentia syndrome.
`2.5.5, The Syndrom-Kurztest (SKT) [9] was used to determine
`the patients' attention and memory disturbances.
`2.5.6. Activities of daily living (ADL test): To evaluate the pa(cid:173)
`tients' ability to cope with simple practical activities of daily life,
`the patients were asked to perform 5 simple instrumented tasks
`under the guidance of an investigator (psychologist) after de(cid:173)
`tailed instructions: fastening and unfastening 3 buttons, opening
`and closing 3 safety pins, tying bows in a similar way to shoe(cid:173)
`laces, sticking adhesive plaster onto a marked area after remov(cid:173)
`ing the protective film, reading off a 6-digit telephone number,
`and dialling the number on the telephone.
`The tests were explained to the patient beforehand, and he or
`she had the chance to perform each test three times, the first time
`being disregarded as a dummy run. In the second and third runs
`the time required to perform each test task was discreetly timed
`with a stopwatch and the quality of performance was evaluated
`on a 3-point scale (good - poor - not performed). The maxi(cid:173)
`mum time required for each individual test was limited to 2 min.
`Longer times were evaluated as not performed.
`
`Arzneim.-Forsch./Drug Res. 41 (II), Nr. 8 (1991)
`Ditzler- Memantlne
`
`2.6. Target parameters, secondary variables;
`and statistical methods
`The data obtained within the framework of the clinical study
`were documented in the form of raw value and distribution char(cid:173)
`acteristic tables. Data for patients who dropped out of the study
`were recorded in the form of casuistics. The response vai'iables
`for the statistical analysis were the baseline value difference of
`the total SCAG score, the total SKT score, and the total proc(cid:173)
`essing time for all subtests of the ADL test.
`The hypotheses (a) of a more distinct reduction in the total
`SCAG score (b) of a more pronounced increase in the total SKT
`score, and (c) of a more distinct decrease in the total processing
`time of the ADL tests under memantine than under a placebo
`were tested with the aid of the Mann-Whitney U-test at an actual
`conficence level of 5%. With appropriate Bonferroni-Holm a(cid:173)
`correction in individual statistical tests the nominal threshold of
`a* = 0.0167 must have been exceeded.
`All remaining variables were evaluated exploratively, inter alia
`with the aid of analyses of variance and non-parametric tests.
`The specified p-values should be understood as descriptive sig(cid:173)
`nificances.
`The size of the patient population for the present study was es(cid:173)
`timated with reference to an earlier pilot study, in which the
`change in the total SCAG score after treatment with Memantine
`yielded an estimated minimum random sample size of N ;::: 15
`patients per treatment group in order to demonstrate a dmg dif(cid:173)
`ference with 90 % confidence. Thus, it could be assumed that
`with N = 30 patients treated up to the end of the study a sufficient
`test reliability would be ensured. Accordingly, 60 patients were
`to be treated overall.
`The randomization was performed by the statistician. The code
`for each patient was contained in a sealed envelope which could
`be opened in the event of an adverse drug reaction leading to
`withdrawal from the study.
`
`2. 7. Medication and duration of treatment
`The patients were randomized to the memantine group or the
`placebo group, and from day 1 to day 3 they received 1 tablet
`containing 10 mg memantine (batch No. 80742) or the placebo.
`From day 4 to day 7 the dose was increased to 2 tablets, each
`containing 10 mg memantine or the placebo. After a week the
`dose was increased further to 3x 1 tablet in both groups, the last
`dose being administered not later than 5 p.m. The total duration
`of treatment was 42 days,
`The pharmaceutical formulations of placebo and active sub(cid:173)
`stance were externally identical and not distinguishable by either
`doctor or patient.
`Compliance was checked by the doctor on the basis of blister
`packs returned by the patients.
`
`2.8. Recording of adverse drug reactions (ADR)
`Specific questions were asked about ADR and recorded with the
`aid of standardized DOTES (Dosage Record and Treatment
`Emergence Symptom Scale) and TWIS (Tess write-in scale [7]).
`
`2.9. Dropouts
`Patients who refused to continue participation in the study or in
`whom the clinical picture had deteriorated so that remaining in
`the study would be ethically and medically unwarrantable, were
`to be excluded. Every decision about a dropout had to be docu(cid:173)
`mented and taken into account in the statistical evaluation. All
`dropouts in the first 2 weeks of the treatment were to be replaced,
`but ones who dropped out of the study later than 2 weeks were
`not to be replaced. Patients who dropped out because of events
`unrelated to the test product (e.g. because of a change of resi(cid:173)
`dence) could be replaced.
`
`775
`
`IPR2015-00410
`Petitioners' Ex. 1010
`Page 6
`
`

`

`

`

`

`

`

`

`Table 5: Physician-'s global impression of the dementia syndrome and patients' general health status. From the 14th day the assessment was significantly
`better for the memantine (Mem.) group as compared to placebo (Plac.).
`
`Day -7
`
`Day 0
`
`Day 3
`
`Time
`
`Day 7
`
`Day 14
`
`Day 28
`
`Day42
`
`Plac. Mem.
`
`Plac. Mem.
`
`Plac. Mem.
`
`Plac. Mem.
`
`Plac. Mem.
`
`Plac. Mem.
`
`Plac. Mem.
`
`Dropouts
`
`Physician's global impression
`Good
`Moderate
`Poor
`Very poor
`Total N =
`
`N
`
`N
`
`N
`
`N
`
`6
`16
`11
`1
`34
`
`3
`17
`12
`
`32
`
`3
`14
`16
`1
`34
`
`1
`19
`12
`
`32
`
`N
`
`5
`
`18
`11
`
`34
`
`N
`
`2
`
`18
`12
`
`32
`
`N
`
`5
`
`16
`13
`
`34
`
`N
`
`2
`
`20
`10
`
`32
`
`N
`
`5
`
`1
`15
`13
`
`34
`
`N
`
`2
`
`1
`24
`5
`
`32
`
`N
`
`5
`
`1
`7
`13
`
`4
`
`N
`
`2
`
`15 --
`20
`3
`
`32
`
`N
`
`5
`
`3
`16
`10
`
`34
`
`N
`
`2
`
`14
`13
`3
`
`32
`
`Table 6: Physician's global impression of the change in condition to the preceding examination. Under n1emantine (Mem.) there was a significant
`improvement in the patients' condition since the preceding assessment compared to the placebo (Plac.) group beginning with day 14.
`
`Day-7
`
`Day 0
`
`Day 3
`
`Time
`
`Day 7
`
`Day 14
`
`Day 28
`
`Day 42
`
`Plac. Mem.
`
`Plac, Mem.
`
`Plac.
`
`Plac. Mem.
`
`Dropouls -
`
`Change in condition
`Improved
`Unchanged
`Deteriorated
`TotalN=
`
`N
`
`N
`
`N
`
`N
`
`34
`
`34
`
`32
`
`32
`
`33
`1
`34
`
`30
`2
`32
`
`Mem.
`
`Plac. Mem.
`
`Plac. Mem.
`
`Plac. Mem.
`
`N
`
`5
`
`29
`
`32
`
`N
`
`2
`
`29
`1
`32
`
`N
`
`5
`
`28
`1
`34
`
`N
`
`2
`
`3
`27
`
`32
`
`N
`
`5
`
`2
`25
`2
`34
`
`N
`
`2
`
`10
`20
`
`32
`
`N
`
`5
`
`3
`20
`6
`34
`
`N
`
`2
`
`17
`13
`
`32
`
`N
`
`5
`
`8
`19
`2
`34
`
`N
`
`2
`
`20
`10
`
`32
`
`Table 7: Nnmbers of patients with reports in DOTES.
`
`Day 14
`
`Day 42
`
`Symptom
`
`Memantine Placebo Memantine Placebo
`
`Excitation/agitation
`Depressed mood
`Increased motor
`activity
`Reduced motor
`activity
`Insomnia
`Tremor
`Dystonic symptoms
`Restlessness
`Dry mouth
`Blurred vision
`Tachycardia
`Sweating
`Dizziness
`Constipation
`Headache
`
`5
`1
`6
`
`1
`
`6
`1
`1
`15
`2
`1
`
`1
`4
`
`2
`
`2
`2
`1
`
`1
`
`2
`-
`-
`2
`-
`1
`
`-
`1
`
`1
`
`1
`
`2
`
`1
`3
`
`1
`2
`
`-
`
`1
`
`2
`
`-
`1
`
`-
`
`1
`
`4. Discussion
`Treatment of the dementia syndrome remains an unre(cid:173)
`solved therapeutic problem. The patients suffer distur(cid:173)
`bances and deficits in important brain functions, which
`are progressive to varying degrees and which seriously
`impair the individual organization of their life and, in(cid:173)
`creasingly as the disease progresses, their management of
`simple everyday activities and their social relationships.
`The memory disturbances, the impairment of abstract
`thinking and judgement with increasing inability to over(cid:173)
`come everyday problems of a personal, familial, and
`work-related nature, the temporo-spatial orientation dis(cid:173)
`turbances, and the impairment of higher cortical func(cid:173)
`tions with progressive aphasia, apraxia, and agnosia
`eventually compel the dementia patient to depend on ex(cid:173)
`ternal care. The sad fate of dementia sufferers is shared
`
`A