U.S. patent application number 17/145430 was filed with the patent office on 2021-05-06 for medical use of compound iii.
The applicant listed for this patent is Boehringer Ingelheim International GmbH. Invention is credited to Masashi ADACHI, Bodo BETZEMEIER, Tobias BRODMANN, Riccardo GIOVANNINI, Masanori ITO, Takayuki KAMATA, Yohei KAWABATA, Daniel MARCKART, Manabu NAKATANI, Holger ROSENBROCK, Michael Steven SAND, Ulrike WERTHMANN.
Application Number | 20210130362 17/145430 |
Document ID | / |
Family ID | 1000005329641 |
Filed Date | 2021-05-06 |
![](/patent/app/20210130362/US20210130362A1-20210506\US20210130362A1-2021050)
United States Patent
Application |
20210130362 |
Kind Code |
A1 |
SAND; Michael Steven ; et
al. |
May 6, 2021 |
MEDICAL USE OF COMPOUND III
Abstract
The present invention relates to compound III ##STR00001## and
its use for treatment and/or prevention of diseases of the
schizophrenia spectrum and other psychotic disorders, first
episodes of these diseases such as first episode of psychosis
(FEP), relapses of these diseases such as reduction of relapse in
patients with schizophrenia (REX). The invention also relates to
polymorphs of compound III, and pharmaceutical compositions
comprising compound III and/or its polymorphs.
Inventors: |
SAND; Michael Steven;
(Monroe, CT) ; ROSENBROCK; Holger;
(Mittelbiberach, DE) ; GIOVANNINI; Riccardo;
(Biberach an der Riss, DE) ; ADACHI; Masashi;
(Osaka, JP) ; BETZEMEIER; Bodo; (Biberach an der
Riss, DE) ; BRODMANN; Tobias; (Ingelheim am Rhein,
DE) ; KAMATA; Takayuki; (Hyogo, JP) ;
KAWABATA; Yohei; (Yamagata, JP) ; ITO; Masanori;
(Hyogo, JP) ; MARCKART; Daniel; (Budenheim,
DE) ; NAKATANI; Manabu; (Hyogo, JP) ;
WERTHMANN; Ulrike; (Biberach an der Riss, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boehringer Ingelheim International GmbH |
Ingelheim am Rhein |
|
DE |
|
|
Family ID: |
1000005329641 |
Appl. No.: |
17/145430 |
Filed: |
January 11, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15900823 |
Feb 21, 2018 |
10919898 |
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17145430 |
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62462621 |
Feb 23, 2017 |
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62526393 |
Jun 29, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/38 20130101;
C07D 487/04 20130101; C07B 2200/13 20130101; A61P 25/18 20180101;
A61K 31/519 20130101; A61K 45/06 20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; A61K 31/519 20060101 A61K031/519; A61K 47/38 20060101
A61K047/38; A61P 25/18 20060101 A61P025/18; A61K 45/06 20060101
A61K045/06 |
Claims
1. A method of using Compound III ##STR00009## for treating,
delaying or preventing a disorder selected from the group
consisting of: Schizophrenia spectrum and other psychotic
disorders, Schizophrenia, Psychosis, Schizotypal (personality)
disorder, Delusional disorder, Attenuated psychosis syndrome, Brief
psychotic disorder, Schizophreniform disorder, Schizoaffective
disorder, Substance/Medication-Induced Psychotic Disorder,
Psychotic Disorder, Psychotic Disorder Due to Another Medical
Condition, Other Specified Schizophrenia Spectrum and Other
Psychotic Disorders, Unspecified Schizophrenia Spectrum and Other
Psychotic Disorder, Catatonia Associated With Another Mental
Disorder, and Catatonic Disorder Due to Another Medical Condition,
the method comprising administering a pharmaceutically effective
amount of Compound III, or a pharmaceutically salt thereof, to a
patient in need thereof.
2. The method according to claim 1, where the method is for
treating, delaying, or preventing a first episode and/or relapse of
the disorder.
3. The method according to claim 1 for preventing the disorder.
4. The method according to claim 1 for treating attenuated
psychosis syndrome.
5. The method according to claim 2 for reducing relapse in
schizophrenia.
6. The method according to claim 1 for preventing first-episode of
psychosis.
7. The method according to claim 1, further comprising
administering Compound III, or a pharmaceutically acceptable salt
thereof, in combination with another antipsychotic drug.
8-9. (canceled)
10. The method of claim 1 for delaying the disorder.
11. The method of claim 2 for preventing the first episode and/or
relapse of the disorder.
12. The method of claim 2 for delaying the first episode and/or
relapse of the disorder.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compound III for the use in
the treatment of diseases of the schizophrenia spectrum and other
psychotic disorders, first episodes of these diseases like first
episode of psychosis (FEP), relapses of these diseases like
reduction of relapse in patients with schizophrenia (REX),
polymorphs of compound III, and pharmaceutical compositions
comprising compound III and/or its polymorphs.
BACKGROUND OF THE INVENTION
[0002] Schizophrenia spectrum and other psychotic disorders include
schizophrenia, psychosis, other psychotic disorders, and
schizotypal (personality) disorder. Furthermore they include
delusional disorder, attenuated psychosis syndrome, brief psychotic
disorder, schizophreniform disorder, schizoaffective disorder,
substance/medication-induced psychotic disorder, psychotic disorder
due to another medical condition, other specified schizophrenia
spectrum and other psychotic disorder, unspecified schizophrenia
spectrum and other psychotic disorder, catatonia associated with
another mental disorder (catatonia specifier), and catatonic
disorder due to another medical condition.
[0003] They are defined by clusters of symptoms including
delusions, hallucinations, disorganized thinking (speech), grossly
disorganized or abnormal motor behavior (including catatonia),
suicidal ideation, or negative symptoms (i.e. diminished emotional
expression or avolition) such as anhedonia and social withdrawal.
Suicidal behavior is sometimes in response to command
hallucinations to harm oneself or others.
[0004] A first episode of psychosis is the first time a person
experiences a psychotic episode.
[0005] Schizophrenia is a chronic, severe, and disabling brain
disorder affecting about one percent of the world's general
population. Schizophrenia affects men and women equally. It occurs
at similar rates in all ethnic groups around the world. Despite
advances in the treatment of schizophrenia over the past decades,
the illness continues to be associated with poor outcomes. These
poor outcomes are in part due to identification and intervention
late in the course of the illness, thus making it more challenging
to reverse.
[0006] In the Global Burden of Disease 2000 study, published in the
World Health Report 2001, schizophrenia is the 7th leading cause of
years lived with disability (YLDs) at global level, accounting for
2.8% of total global YLDs. Further the Disability Adjusted Life
Years (DALYs), reflecting the sum of years of potential life lost
due to premature mortality and the years of productive life lost
due to disability is estimated at 15.6 million. In the Global
Burden of Disease Study 2010", 1100 sequelae of over 220 diseases
were studied: the health state with the highest disability weight
was acute schizophrenia (Salomon J A, Vos T, Hogan D, Gagnon M,
Naghavi M, Mokdad A, et al. Lancet 2012; 380 (9859):2129-2143).
[0007] Due in part to the recognition of the terrible burden of
established disease, the emphasis in therapy is now shifting to
defining psychosis-risk syndromes and evaluating treatments that
can prevent transition to psychosis in these ultra-high risk groups
in addition to prompt intervention when psychosis occurs. Before
the occurrence of a first episode of psychosis, those at risk for
such an event also demonstrate similar symptoms at a reduced or
attenuated degree and are now categorized within DSM-V as
demonstrating "attenuated psychosis syndrome". A first episode is a
first manifestation of the disorder meeting the defining diagnostic
symptom criteria.
[0008] In subjects who progress from attenuated psychosis syndrome
to their first-episode of schizophrenia, relapse rates after
initial stabilization exceed 80% within five years, and the
occurrence of relapse itself represents an important predictor of
subsequent relapse, tripling healthcare costs in the year following
(Ascher-Svanum et al. BMC Psychiatry 2010, 10:2;
http://www.biomedcentral.com/1471-244X/10/2). Further, multiple
relapses have been associated with poorer long-term outcome
(Lieberman, J. A. (1993) Journal of Clinical Psychiatry, 54 (3
SUPPL.), pp. 13-17; Lieberman, J. A., Koreen, A. R., Chakos, M.,
Sheitman, B., Woerner, M., Alvir, J. Ma. J., Bilder, R. (1996)
Journal of Clinical Psychiatry, 57 (SUPPL. 9), pp. 5-9; Andreasen,
N.C., Liu, D., Ziebell, S., Vora, A., Ho, B.-C. (2013) American
Journal of Psychiatry, 170 (6), pp. 609-615).
[0009] Relapse in schizophrenia is defined as the reoccurrence of
previously treated psychotic symptoms and may include
hallucinations, delusions, strong and inappropriate emotions, and
disordered thought. It is also defined as any of the following:
re-hospitalization for psychiatric illness, or emergency room (ER)
visits for psychiatric illness, clinical worsening, or clinical
worsening as assessed by Positive and Negative Syndrome Scale
(PANSS), or worsening suicidal ideation and behavior as assessed by
the Columbia Suicide Severity Rating Scale (C-SSRS). In the course
of the illness most patients with schizophrenia experience multiple
relapses which are characterized by acute psychotic exacerbation
(DSM-V). Current antipsychotics do not eradicate schizophrenia
spectrum, other psychotic disorders or psychotic symptoms in the
majority of patients but only dampen them (Kapur S (2003) Am. J.
Psychiatry 160:13-23; Kapur S (2004) Trends Pharmacol. Sci.
25:402-406).
[0010] WO 2009/121919 discloses a number of pyrazolopyrimidinones
as potent PDE9 inhibitors. Among others, WO 2009/121919 discloses
compound III
##STR00002##
[0011] Further, WO 2009/121919 generically discloses that the
compounds exemplified therein may be used in the treatment of
cognitive impairment related to several diseases.
SUMMARY OF THE INVENTION
[0012] The objective technical problem underlying the present
invention is thus to provide a drug substance [0013] which may be
used in the treatment of: [0014] Schizophrenia spectrum and other
psychotic disorders, [0015] Schizophrenia, [0016] Psychosis, [0017]
Schizotypal (personality) disorder, [0018] Delusional disorder,
[0019] Attenuated psychosis syndrome, [0020] Brief psychotic
disorder, [0021] Schizophreniform disorder, [0022] Schizoaffective
disorder, [0023] Substance/Medication-Induced Psychotic Disorder,
[0024] Psychotic Disorder, [0025] Psychotic Disorder Due to Another
Medical Condition, [0026] Other Specified Schizophrenia Spectrum
and Other Psychotic Disorders, [0027] Unspecified Schizophrenia
Spectrum and Other Psychotic Disorder, [0028] Catatonia Associated
With Another Mental Disorder, or [0029] Catatonic Disorder Due to
Another Medical Condition.
[0030] In a clinical study designed to investigate compound III for
the treatment of cognitive impairment associated with schizophrenia
it was surprisingly found, that all serious adverse events (SAEs,
8/8) defined as psychiatric worsening occurred in the placebo arm
(100% of SAEs) versus none in any active arm (see Table 9 In FIG.
7). Compared to placebo, treatment of patients with schizophrenia
who are receiving antipsychotic therapy with compound III resulted
in statistically significant, clinically meaningful decrease in
psychiatric serious adverse events (hospitalization for serious
worsening of schizophrenia symptoms) and decrease in the intensity
and occurrence of suicidal ideation.
[0031] According to the present invention, compound III has
surprisingly been found to fulfil the above mentioned criteria
required for use in the treatment of: [0032] Schizophrenia spectrum
and other psychotic disorders, [0033] Schizophrenia, [0034]
Psychosis, [0035] Schizotypal (personality) disorder, [0036]
Delusional disorder, [0037] Attenuated psychosis syndrome, [0038]
Brief psychotic disorder, [0039] Schizophreniform disorder, [0040]
Schizoaffective disorder, [0041] Substance/Medication-Induced
Psychotic Disorder, [0042] Psychotic Disorder, [0043] Psychotic
Disorder Due to Another Medical Condition, [0044] Other Specified
Schizophrenia Spectrum and Other Psychotic Disorders, [0045]
Unspecified Schizophrenia Spectrum and Other Psychotic Disorder,
[0046] Catatonia Associated With Another Mental Disorder, or [0047]
Catatonic Disorder Due to Another Medical Condition.
[0048] Furthermore compound III can be used in the treatment of
first episodes of: [0049] Schizophrenia spectrum and other
psychotic disorders, [0050] Schizophrenia, [0051] Psychosis, [0052]
Schizotypal (personality) disorder, [0053] Delusional disorder,
[0054] Attenuated psychosis syndrome, [0055] Brief psychotic
disorder, [0056] Schizophreniform disorder, [0057] Schizoaffective
disorder, [0058] Substance/Medication-Induced Psychotic Disorder,
[0059] Psychotic Disorder Due to Another Medical Condition, [0060]
Other Specified Schizophrenia Spectrum and Other Psychotic
Disorders, [0061] Unspecified Schizophrenia Spectrum and Other
Psychotic Disorder, [0062] Catatonia Associated With Another Mental
Disorder, or [0063] Catatonic Disorder Due to Another Medical
Condition.
[0064] Furthermore compound III can be used in the treatment of
relapses of: [0065] Schizophrenia spectrum and other psychotic
disorders, [0066] Schizophrenia, [0067] Psychosis, [0068]
Schizotypal (personality) disorder, [0069] Delusional disorder,
[0070] Attenuated psychosis syndrome, [0071] Brief psychotic
disorder, [0072] Schizophreniform disorder, [0073] Schizoaffective
disorder, [0074] Substance/Medication-Induced Psychotic Disorder,
[0075] Psychotic Disorder Due to Another Medical Condition, [0076]
Other Specified Schizophrenia Spectrum and Other Psychotic
Disorders, [0077] Unspecified Schizophrenia Spectrum and Other
Psychotic Disorder, [0078] Catatonia Associated With Another Mental
Disorder, or [0079] Catatonic Disorder Due to Another Medical
Condition.
[0080] Furthermore compound III can be used in the prevention/delay
of: [0081] Schizophrenia spectrum and other psychotic disorders,
[0082] Schizophrenia, [0083] Psychosis, [0084] Schizotypal
(personality) disorder, [0085] Delusional disorder, [0086]
Attenuated psychosis syndrome, [0087] Brief psychotic disorder,
[0088] Schizophreniform disorder, [0089] Schizoaffective disorder,
[0090] Substance/Medication-Induced Psychotic Disorder, [0091]
Psychotic Disorder Due to Another Medical Condition, [0092] Other
Specified Schizophrenia Spectrum and Other Psychotic Disorders,
[0093] Unspecified Schizophrenia Spectrum and Other Psychotic
Disorder, [0094] Catatonia Associated With Another Mental Disorder,
or [0095] Catatonic Disorder Due to Another Medical Condition.
[0096] Furthermore compound III can be used in the prevention/delay
of first episodes and/or relapses of above mentioned diseases,
conditions and symptoms.
[0097] Furthermore compound III can be used in the treatment of
schizophrenia by disease stabilization, schizophrenia by reducing
the severity of relapses, schizophrenia by prevention of relapses,
or schizophrenia by delaying relapses.
[0098] Furthermore compound III can be used in the treatment of
symptoms of above mentioned diseases, conditions and symptoms.
[0099] Accordingly compound III can be used in the treatment of:
[0100] delusions, [0101] hallucinations, [0102] disorganized
thinking (speech), [0103] grossly disorganized or abnormal motor
behavior (including catatonia), [0104] suicidal ideation, or [0105]
negative symptoms.
[0106] Furthermore compound III can be used in the prevention/delay
of first episodes and/or relapses of above mentioned symptoms.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING
[0107] FIG. 1 shows the X-ray powder diffraction pattern of
Compound IIIa.
[0108] FIG. 2 shows the X-ray powder diffraction pattern of
Compound IIIb.
[0109] FIG. 3 shows the Raman spectrum of Compound IIIa.
[0110] FIG. 4 shows the Raman spectrum of Compound IIIb.
[0111] FIG. 5 shows the dissolution profiles of core tablets and
film-coated tablets containing 50 mg of Formulation 2 (Table 5 and
Table 6) produced from milled drug substance.
[0112] FIGS. 6A-6C (Table 8) include data showing the results of a
study using antipsychotic drugs for concomitant antipsychotic
therapy.
[0113] FIG. 7 includes data showing the Frequency [N (%)] of
subjects with serious adverse events by treatment, primary system
organ class and preferred term--treated set (TS).
DETAILED DESCRIPTION OF THE INVENTION
[0114] According to a first aspect, the present invention provides
compound III:
##STR00003##
for use in the treatment of: [0115] Schizophrenia spectrum and
other psychotic disorders, [0116] Schizophrenia, [0117] Psychosis,
[0118] Schizotypal (personality) disorder, [0119] Delusional
disorder, [0120] Attenuated psychosis syndrome, [0121] Brief
psychotic disorder, [0122] Schizophreniform disorder, [0123]
Schizoaffective disorder, [0124] Substance/Medication-Induced
Psychotic Disorder, [0125] Psychotic Disorder, [0126] Psychotic
Disorder Due to Another Medical Condition, [0127] Other Specified
Schizophrenia Spectrum and Other Psychotic Disorders, [0128]
Unspecified Schizophrenia Spectrum and Other Psychotic Disorder,
[0129] Catatonia Associated With Another Mental Disorder, or [0130]
Catatonic Disorder Due to Another Medical Condition.
[0131] According to a second aspect, the present invention provides
compound III for use in the treatment of first episodes of: [0132]
Schizophrenia spectrum and other psychotic disorders, [0133]
Schizophrenia, [0134] Psychosis, [0135] Schizotypal (personality)
disorder, [0136] Delusional disorder, [0137] Attenuated psychosis
syndrome, [0138] Brief psychotic disorder, [0139] Schizophreniform
disorder, [0140] Schizoaffective disorder, [0141]
Substance/Medication-Induced Psychotic Disorder, [0142] Psychotic
Disorder Due to Another Medical Condition, [0143] Other Specified
Schizophrenia Spectrum and Other Psychotic Disorders, [0144]
Unspecified Schizophrenia Spectrum and Other Psychotic Disorder,
[0145] Catatonia Associated With Another Mental Disorder, or [0146]
Catatonic Disorder Due to Another Medical Condition.
[0147] According to another aspect, the present invention provides
compound III for use in the treatment of relapses of: [0148]
Schizophrenia spectrum and other psychotic disorders, [0149]
Schizophrenia, [0150] Psychosis, [0151] Schizotypal (personality)
disorder, [0152] Delusional disorder, [0153] Attenuated psychosis
syndrome, [0154] Brief psychotic disorder, [0155] Schizophreniform
disorder, [0156] Schizoaffective disorder, [0157]
Substance/Medication-Induced Psychotic Disorder, [0158] Psychotic
Disorder Due to Another Medical Condition, [0159] Other Specified
Schizophrenia Spectrum and Other Psychotic Disorders, [0160]
Unspecified Schizophrenia Spectrum and Other Psychotic Disorder,
[0161] Catatonia Associated With Another Mental Disorder, or [0162]
Catatonic Disorder Due to Another Medical Condition.
[0163] According to another aspect, the present invention provides
compound III for use in the prevention/delay of: [0164]
Schizophrenia spectrum and other psychotic disorders, [0165]
Schizophrenia, [0166] Psychosis, [0167] Schizotypal (personality)
disorder, [0168] Delusional disorder, [0169] Attenuated psychosis
syndrome, [0170] Brief psychotic disorder, [0171] Schizophreniform
disorder, [0172] Schizoaffective disorder, [0173]
Substance/Medication-Induced Psychotic Disorder, [0174] Psychotic
Disorder Due to Another Medical Condition, [0175] Other Specified
Schizophrenia Spectrum and Other Psychotic Disorders, [0176]
Unspecified Schizophrenia Spectrum and Other Psychotic Disorder,
[0177] Catatonia Associated With Another Mental Disorder, or [0178]
Catatonic Disorder Due to Another Medical Condition.
[0179] According to another aspect, the present invention provides
compound III for use in the prevention/delay of first episodes
and/or relapses of above mentioned diseases, conditions and
symptoms.
[0180] According to another aspect, the present invention provides
compound III for use in the treatment of schizophrenia by disease
stabilization, schizophrenia by reducing the severity of relapses,
schizophrenia by prevention of relapses, or schizophrenia by
delaying relapses.
[0181] According to another aspect, the present invention provides
compound III for use in the treatment of reduction of relapse in
schizophrenia.
[0182] According to another aspect, the present invention provides
compound III for use in the treatment of reduction of relapse in
patients with schizophrenia receiving antipsychotic therapy.
[0183] According to another aspect, the present invention provides
compound III for use in the treatment of attenuated psychosis
syndrome.
[0184] According to another aspect, the present invention provides
compound III for use in the prevention of first episode
psychosis.
[0185] According to another aspect, the present invention provides
compound III for use in the prevention of first episode psychosis
in individuals with attenuated psychosis syndrome.
[0186] According to another aspect, the present invention provides
compound III for use in the treatment of symptoms of above
mentioned diseases, conditions and symptoms.
[0187] According to another aspect, the present invention provides
compound III for use in the treatment of: [0188] delusions, [0189]
hallucinations, [0190] disorganized thinking (speech), [0191]
grossly disorganized or abnormal motor behavior (including
catatonia), [0192] suicidal ideation, or [0193] negative
symptoms.
[0194] According to another aspect, the present invention provides
compound III for use in the treatment of first episodes and/or
relapses of above mentioned symptoms.
[0195] According to another aspect, the present invention provides
compound III for use in the prevention/delay of first episodes
and/or relapses of above mentioned symptoms.
[0196] According to another aspect, the present invention provides
compound III according to any one of the preceding aspects,
characterized in that compound III is administered in addition to
treatment with another antipsychotic drug.
[0197] According to another aspect, the present invention provides
compound III according to any one of the preceding aspects,
characterized in that the antipsychotic drug is selected from the
group consisting of Aripiprazole, Risperidone, Quetiapine fumarate,
Olanzapine, Paliperidone, Lurasidone hydrochloride, Haloperidol,
Paliperidone palmitate, Ziprasidone hydrochloride, Quetiapine,
Ziprasidone, Blonanserin, Chlorpromazine hydrochloride,
Amisulpride, Haloperidol decanoate, Lithium carbonate, Asenapine
maleate, Sulpiride, Chlorpromazine, Flupentixol, Fluphenazine
decanoate, Flupentixol decanoate, Fluphenazine, Fluphenazine
hydrochloride, Iloperidone, Levomepromazine, Levosulpiride,
Loxapine, Lurasidone, Periciazine, Perospirone hydrochloride,
Perphenazine, Clozapine, and Pipamperone hydrochloride.
[0198] According to another aspect, the present invention provides
compound III according to any one of the preceding aspects,
characterized in that 10, 25, 50 or 100 mg of compound III are
administered.
[0199] According to another aspect, the present invention provides
compound III according to any one of the preceding aspects,
characterized in that compound III is administered once or twice
daily.
[0200] According to another aspect, the present invention provides
compound III according to any one of the preceding aspects,
characterized in that compound III is administered orally.
[0201] WO 2009/121919 discloses the synthesis of compound IIIa.
Now, it has surprisingly been found that another polymorphic form,
compound IIIb, exists. Both compound IIIa and compound IIIb,
respectively, can be synthesized in pure form. Compound IIIa was
obtained in a purity >95% (ratio between compound IIIa and
compound IIIb >95:5 based on XRPD) as well as compound IIIb in a
purity >95% (ratio between compound IIIb and compound IIIa
>95:5 based on XRPD). Further, both compound IIIa and compound
IIIb are characterized by its corresponding XRPD and Raman
data.
[0202] As used herein, the term "compound IIIa" refers to
crystalline form a of Compound III.
[0203] As used herein, the term "compound IIIb" refers to
crystalline form b of Compound III.
[0204] The polymorphic form resulting from the synthesis according
to WO 2009/121919, namely compound IIIa, shows a X-ray powder
diffraction pattern comprising peaks at the following 2-theta
values measured using monochromatic CuK.alpha.1 radiation of
.lamda.=1.54056 .ANG., 40 kV, 40 mA: 7.7.degree..+-.0.2.degree. and
9.0.degree..+-.0.2.degree..
[0205] The polymorphic form resulting from the synthesis according
to WO 2009/121919, namely compound IIIa, shows a X-ray powder
diffraction pattern comprising peaks at any one or all of the
following 2-theta values measured using monochromatic CuK.alpha.1
radiation of .lamda.=1.54056 .ANG., 40 kV, 40 mA:
17.3.degree..+-.0.2.degree., 21.3.degree..+-.0.2.degree.,
20.9.degree..+-.0.2.degree., 23.3.degree..+-.0.2.degree.,
9.0.degree..+-.0.2.degree., 14.7.degree..+-.0.2.degree.,
7.7.degree..+-.0.2.degree..
[0206] The polymorphic form resulting from the synthesis according
to WO 2009/121919, namely compound IIIa, shows a X-ray powder
diffraction pattern comprising peaks at the following 2-theta
values measured using monochromatic CuK.alpha.1 radiation of
.lamda.=1.54056 .ANG., 40 kV, 40 mA: 7.7.degree..+-.0.2.degree. and
9.0.degree..+-.0.2.degree., and the Raman spectrum comprises peaks
at any one or all of the following Raman shifts expressed in
wavenumbers in cm.sup.-1: 1190.+-.2, 1401.+-.2, 1675.+-.2.
[0207] The polymorphic form resulting from the synthesis according
to WO 2009/121919, namely compound IIIa, has a purity >75%
(ratio between compound IIIa and compound IIIb >75:25 based on
XRPD).
[0208] The polymorphic form resulting from the synthesis according
to WO 2009/121919, namely compound IIIa, has a purity >90%
(ratio between compound IIIa and compound IIIb >90:10 based on
XRPD).
[0209] The polymorphic form resulting from the synthesis according
to WO 2009/121919, namely compound IIIa, has a purity >95%
(ratio between compound IIIa and compound IIIb >95:5 based on
XRPD).
[0210] According to another aspect, the present invention provides
compound IIIb showing a X-ray powder diffraction pattern comprising
a peak at the following 2-theta value measured using monochromatic
CuK.alpha.1 radiation of .lamda.=1.54056 .ANG., 40 kV, 40 mA:
6.4.degree..+-.0.2.degree..
[0211] According to another aspect, the present invention provides
compound IIIb showing a X-ray powder diffraction pattern comprising
peaks at any one or all of the following 2-theta values measured
using monochromatic CuK.alpha.1 radiation of .lamda.=1.54056 .ANG.,
40 kV, 40 mA: 20.8.degree..+-.0.2.degree.,
21.1.degree..+-.0.2.degree., 21.6.degree..+-.0.2.degree.,
6.4.degree..+-.0.2.degree., 23.0.degree..+-.0.2.degree.,
25.2.degree..+-.0.2.degree., 12.9.degree..+-.0.2.degree..
[0212] According to another aspect, the present invention provides
compound IIIb showing a X-ray powder diffraction pattern comprising
peaks at the following 2-theta values measured using monochromatic
CuK.alpha.1 radiation of .lamda.=1.54056 .ANG., 40 kV, 40 mA:
6.4.degree..+-.0.2.degree., and the Raman spectrum comprises peaks
at any one or all of the following Raman shifts expressed in
wavenumbers in cm.sup.-1: 1182.+-.2, 1394.+-.2, 1663.+-.2.
[0213] According to another aspect, the present invention provides
compound IIIb having a purity >10% (ratio between compound IIIb
and compound IIIa >10:90 based on XRPD).
[0214] According to another aspect, the present invention provides
compound IIIb having a purity >20% (ratio between compound IIIb
and compound IIIa >20:80 based on XRPD).
[0215] According to another aspect, the present invention provides
compound IIIb having a purity >30% (ratio between compound IIIb
and compound IIIa >30:70 based on XRPD).
[0216] According to another aspect, the present invention provides
compound IIIb having a purity >40% (ratio between compound IIIb
and compound IIIa >40:60 based on XRPD).
[0217] According to another aspect, the present invention provides
compound IIIb having a purity >50% (ratio between compound IIIb
and compound IIIa >50:50 based on XRPD).
[0218] According to another aspect, the present invention provides
compound IIIb having a purity >60% (ratio between compound IIIb
and compound IIIa >60:40 based on XRPD).
[0219] According to another aspect, the present invention provides
compound IIIb having a purity >70% (ratio between compound IIIb
and compound IIIa >70:30 based on XRPD).
[0220] According to another aspect, the present invention provides
compound IIIb having a purity >75% (ratio between compound IIIb
and compound IIIa >75:25 based on XRPD).
[0221] According to another aspect, the present invention provides
compound IIIb having a purity >80% (ratio between compound IIIb
and compound IIIa >80:20 based on XRPD).
[0222] According to another aspect, the present invention provides
compound IIIb having a purity >90% (ratio between compound IIIb
and compound IIIa >90:10 based on XRPD).
[0223] According to another aspect, the present invention provides
compound IIIb having a purity >95% (ratio between compound IIIb
and compound IIIa >95:5 based on XRPD).
[0224] In another aspect, the present invention relates to compound
III, compound IIIa, compound IIIb or mixtures thereof for use in
the treatment of above mentioned diseases, conditions and
symptoms.
[0225] Further, it has surprisingly been found that by combining
hydroxypropyl cellulose and/or croscarmellose sodium with compound
III, IIIa or IIIb or a mixture thereof in a pharmaceutic
composition the drug load can be adjusted to the same level for all
dose strengths and a fast dissolution of the tablet can be reached
irrespective of the low intrinsic dissolution rate of compound III
in the physiologically relevant pH range above pH 4 (formulation 1,
Table 3, and/or formulation 2, Table 5, FIG. 5).
[0226] Another aspect of the present invention relates to the
pharmaceutical composition comprising compound III, IIIa or IIIb or
a mixture thereof and hydroxypropyl cellulose and/or croscarmellose
sodium.
[0227] According to another aspect, the present invention relates
to the pharmaceutical composition comprising corn starch and
hydroxypropyl cellulose and/or croscarmellose sodium.
[0228] According to another aspect, the present invention relates
to the pharmaceutical composition comprising lactose monohydrate,
hydroxypropyl cellulose, croscarmellose sodium, magnesium stearate
and pregelatinized starch or corn starch.
[0229] According to another aspect, the present invention relates
to a pharmaceutical composition comprising a tablet core consisting
of compound III, lactose monohydrate, hydroxypropyl cellulose,
croscarmellose sodium, magnesium stearate and pregelatinized starch
or corn starch.
[0230] According to another aspect, the present invention relates
to a pharmaceutical composition comprising a tablet core consisting
of 1-30% (wt/wt) compound III, 63-83% (wt/wt) lactose monohydrate,
5-25% (wt/wt) pregelatinized starch, 1-3% (wt/wt) hydroxypropyl
cellulose, 1-5% (wt/wt) croscarmellose sodium, and 0.5-3.5% (wt/wt)
magnesium stearate.
[0231] According to another aspect, the present invention relates
to a pharmaceutical composition comprising a tablet core consisting
of 8-24% (wt/wt) compound III, 53-70% (wt/wt) lactose monohydrate,
10-20% (wt/wt) pregelatinized starch, 1-3% (wt/wt) hydroxypropyl
cellulose, 1-5% (wt/wt) croscarmellose sodium, and 0.5-3.5% (wt/wt)
magnesium stearate.
[0232] According to another aspect, the present invention relates
to a pharmaceutical composition comprising a tablet core consisting
of 1-30% (wt/wt) compound III, 50-80% (wt/wt) lactose monohydrate,
5-20% (wt/wt) corn starch, 1-3% (wt/wt) hydroxypropyl cellulose,
1-5% (wt/wt) croscarmellose sodium, and 0.5-3.5% (wt/wt) magnesium
stearate.
[0233] According to another aspect, the present invention relates
to a pharmaceutical composition comprising a tablet core consisting
of 8-24% (wt/wt) compound III, 65-75% (wt/wt) lactose monohydrate,
5-20% (wt/wt) corn starch, 1-3% (wt/wt) hydroxypropyl cellulose,
1-5% (wt/wt) croscarmellose sodium, and 0.5-3.5% (wt/wt) magnesium
stearate.
[0234] Another aspect of the present invention relates to a
pharmaceutical composition as defined above for use in the above
mentioned diseases, conditions and symptoms.
[0235] Another aspect of the present invention relates to a method
of treatment of above mentioned diseases, conditions and
symptoms.
General Definitions
[0236] Terms not specifically defined herein should be given the
meanings that would be given to them by one skilled in the art in
light of the disclosure and the context.
[0237] If not otherwise specified, the term compound III relates to
the compound of the following structure
##STR00004##
in any polymorphic form or mixtures or pharmaceutically acceptable
salts or hydrates thereof.
[0238] The term "Subject" means a human patient.
[0239] The term "adverse event (AE)" means any untoward medical
occurrence, including an exacerbation of a pre-existing condition,
in a patient in a clinical investigation who received a
pharmaceutical product. The event did not necessarily have to have
a causal relationship with this treatment.
[0240] The term "adverse event (SAE)" means any AE which resulted
in death, was immediately life-threatening, resulted in persistent
or significant disability/incapacity, required or prolonged patient
hospitalisation, was a congenital anomaly/birth defect, or was to
be deemed serious for any other reason if it was an important
medical event when based upon appropriate medical judgement which
might jeopardise the patient and might require medical or surgical
intervention to prevent one of the other outcomes listed in the
above definitions.
EXPERIMENTAL PART
List of Abbreviations
AE Adverse Event
[0241] BID bis in die (twice daily dosing) ER emergency room ESI
electrospray ionization
FAS Full Analysis Set
[0242] HCl hydrochloric acid HPMC
hypromellose=hydroxypropylmethylcellulose HR high-resolution IDR
intrinsic dissolution rate=intrinsic solubility i.v. intravenous M
mole, mol/L
MedDRA Medical Dictionary for Drug Regulatory Activities
[0243] ml milliliter MS mass spectrometry m/z mass-to-charge ratio
NMR nuclear magnetic resonance PDE phosphodiesterase qd quaque die
(once a day) rpm revolutions per minute RT room temperature
SAE Serious Adverse Event
TMS Tetramethylsilane
TS Treated set
[0244] wt weight XRPD X-ray powder diffraction
Preparation and Physicochemical Characterization of Compound
III
Description of Analytical Methods Used
ESI Mass Spectrometry (ESI+)
TABLE-US-00001 [0245] Instrument QTOF HDMS Synapt (Micromass,
Manchester, UK) Instrument control software Masslynx 4.1 Ion source
ESI+ (Lockspray source) Lockspray/DXC on/off Calibration sodium
formate, Leu-Enkephalin lockmass calibration Resolution MS1(LM/HM)
4.7/15 Resolving power (FWHM) 14935 at m/z 312 (W mode) MCP voltage
1700 V Capillary voltage +3.0 kV Cone voltage 8 V Collision energy
2 eV Collision gas Argon Source temperature 120.degree. C.
Desolvation temperature 200.degree. C. Cone gas nitrogen 48 L/h
Desolvation gas nitrogen 600 L/h Sample inlet Via UPLC (Waters
Acquity System) Spray solvent flow rate 300 .mu.l/min Sample
concentration 0.5 mg/ml in acetonitrile/water (1:1/v:v), 0.5 .mu.l
injected Reagents 0.1% formic acid in acetonitrile (ULC/MS,
Biosolve) 0.1% formic acid in water (ULC/MS, Biosolve) Scan range
50-1000 u Scan time 0.16 s No. of scans combined 15 Data threshold
2.0%
.sup.1H NMR Spectroscopy
TABLE-US-00002 [0246] Instrument Bruker Avance III 600 NMR
spectrometer Frequency 600.38 MHz Software Bruker TopSpin .RTM.
version 3.0 Pulse program zg30 Solvent DMSO-d6, Sigma Aldrich,
Batch MKBT4612V Concentration 15.3 mg/0.6 ml Temperature 27.degree.
C. Calibration Tetramethylsilane (.ident.TMS: .delta. = 0.00 ppm)
Sweep width 12315 Hz Size 64K data points Pulse width 30 degree
Relaxation delay 2 s Number of scans 64 Dummy scans 2 Apodization
zerofilling to 128K data points exponential multiplication (LB:
1.00 Hz)
.sup.13C NMR Spectroscopy
TABLE-US-00003 [0247] Instrument Bruker Avance III 600 NMR
spectrometer Frequency 150.98 MHz Software Bruker TopSpin .RTM.
version 3.0 Pulse program zgpg30 Solvent DMSO-d6, Sigma Aldrich,
Batch MKBT4612V Concentration 15.3 mg/0.6 ml Temperature 27.degree.
C. Calibration Unified scale (IUPAC Recommendations 2001) Sweep
width 37879 Hz Size 64K data points Pulse width 30 degree
Relaxation delay 10 s Number of scans 3072 Dummy scans 4
Apodization zerofilling to 128K data points Exponential
multiplication (LB: 1.00 Hz)
X-Ray Powder (XRPD) Diagram
[0248] X-ray powder diagrams were generated using a STOE--STADI
P-diffractometer in transmission mode fitted with a MYTHEN-detector
and a Cu-anode as X-ray source with monochromatic CuK.alpha.1
radiation (.lamda.=1.54056 .ANG., 40 kV, 40 mA). The standard error
range for the 2-theta values is .+-.0.2.degree..
RAMAN Spectroscopy
[0249] Kaiser Optics RXN2 dispersive Raman PhAT Probe with 6 mm
optics, laser power 400 mW, Exposure time 1 sec. The spectral
resolution is 4 cm.sup.-1.
Preparation of Compound III
a) Preparation of Compound IIIa (Crude, Form a):
##STR00005##
[0251] 5-Amino-1H-pyrazole-4-carboxylic acid amide I (64.0 kg,
304.4 mol) and 2-pyridineacetic acid methyl ester II (69.1 kg,
457.1 mol) are suspended in tert.-Amyl alcohol (84 kg) and heated
to 80-90.degree. C. A solution of potassium tert.-amylate (25% in
toluene, 230.6 kg, 457.1 mol) is added at 80-90.degree. C. The
dropping funnel is rinsed with toluene (84 kg). The reaction
mixture is heated to reflux. After complete conversion the mixture
is cooled down to 55-65.degree. C. and water (192 kg) is added to
the reaction mixture.
[0252] After phase separation ethanol (38.0 kg) and acetic acid
(11.0 kg) is added to the aqueous phase at 55-65.degree. C. A
second portion of acetic acid (11.0 kg) is added at 55-65.degree.
C. The dropping funnel is rinsed with ethanol (25 kg) and the
reaction mixture is cooled to 15-25.degree. C. The suspension is
filtered and the filter cake washed with water (256 kg). The
isolated material is dried at max. 60.degree. C. to give Compound
IIIa (crude, form a) (75.8-85.3 kg, 80-90%).
[0253] Optionally, crystallization can be initiated by seeding with
compound IIIa prior to addition of the second portion acetic
acid.
[0254] NMR (.sup.1H, 600 MHz, DMSO-d.sub.6): 12.26 (1H, s), 8.48
(1H, br. d), 8.05 (1H, s), 7.77 (1H, tb), 7.41 (1H, d), 7.28 (1H,
dd), 4.75 (1H, m), 4.20 (2H, s), 3.94 (2H, m), 3.49 (2H, m), 2.09
(2H, m), 1.80 (2H, m).
[0255] NMR (.sup.13C, 150 MHz, DMSO-d.sub.6): 158.4, 158.3, 156.7,
152.0, 149.6, 137.4, 134.5, 124.0, 122.6, 104.7, 66.4, 53.3, 43.3,
32.4.
[0256] HRMS (ESI): m/z 312 ([M+H].sup.+; 312.1465).
[0257] See Table 1 and FIG. 1 for characterizing data.
b) Preparation of Compound IIIb (Crude, Form b):
##STR00006##
[0259] 5-Amino-1H-pyrazole-4-carboxylic acid amide I (50.0 kg,
237.8 mol) and 2-pyridineacetic acid methyl ester II (53.9 kg,
356.6 mol) are suspended in tert.-Amyl alcohol (65.6 kg) and heated
to 80-90.degree. C. A solution of potassium tert.-amylate (25% in
toluene, 180.2 kg, 356.6 mol) is added at 80-90.degree. C. The
dropping funnel is rinsed with toluene (43.5 kg). The reaction
mixture is heated to reflux. After complete conversion the mixture
is cooled down to 55-65.degree. C. and water (150 kg) is added to
the reaction mixture. The mixture is cooled down to 15-25.degree.
C. After phase separation ethanol (23.7 kg) and acetic acid (17.2
kg) is added to the aqueous phase at 15-30.degree. C. The
suspension is stirred for 60 min at 15-25.degree. C. The suspension
is filtered and the filter cake washed with water (200 kg). The
isolated material is dried at max. 60.degree. C. to give Compound
IIIb (crude, form b) (51.8-59.2 kg, 70-80%).
[0260] NMR (.sup.1H, 600 MHz, DMSO-d.sub.6): 12.26 (1H, s), 8.48
(1H, br. d), 8.05 (1H, s), 7.77 (1H, tb), 7.41 (1H, d), 7.28 (1H,
dd), 4.75 (1H, m), 4.20 (2H, s), 3.94 (2H, m), 3.49 (2H, m), 2.09
(2H, m), 1.80 (2H, m).
[0261] NMR (.sup.13C, 150 MHz, DMSO-d.sub.6): 158.4, 158.3, 156.7,
152.0, 149.6, 137.4, 134.5, 124.0, 122.6, 104.7, 66.4, 53.3, 43.3,
32.4.
[0262] HRMS (ESI): m/z 312 ([M+H].sup.+; 312.1465).
[0263] See Table 2 and FIG. 2 for characterizing data.
c) Preparation of Compound IIIa (Unmilled, Form a) Via
Recrystallization
##STR00007##
[0265] Compound IIIa or IIIb (crude, form a or form b) (44.5 kg,
142.9 mol) is suspended in ethanol (474 kg) and water (13.4 kg).
The mixture is heated to reflux and stirred for 45 min. The
solution is cooled to 72-78.degree. C. and polish filtered. The
filter is rinsed with ethanol (54 kg). The mixture is cooled to
58-65.degree. C. Optionally, crystallization can be initiated by
seeding with compound IIIa (form a) after cooling to 58-65.degree.
C. The mixture is cooled to 0-10.degree. C. The suspension is
filtered and the filter cake washed with ethanol (70 kg). The
isolated material is dried at max. 60.degree. C. to give Compound
IIIa (unmilled, form a) (37.8-42.3 kg, 85-95%).
[0266] NMR (.sup.1H, 600 MHz, DMSO-d.sub.6): 12.26 (1H, s), 8.48
(1H, br. d), 8.05 (1H, s), 7.77 (1H, tb), 7.41 (1H, d), 7.28 (1H,
dd), 4.75 (1H, m), 4.20 (2H, s), 3.94 (2H, m), 3.49 (2H, m), 2.09
(2H, m), 1.80 (2H, m).
[0267] NMR (.sup.13C, 150 MHz, DMSO-d.sub.6): 158.4, 158.3, 156.7,
152.0, 149.6, 137.4, 134.5, 124.0, 122.6, 104.7, 66.4, 53.3, 43.3,
32.4.
[0268] HRMS (ESI): m/z 312 ([M+H].sup.+; 312.1465).
[0269] See Table 1 and FIG. 1 for characterizing data.
d) Preparation of Compound IIIb (Unmilled Form b) Via
Recrystallization
##STR00008##
[0271] Compound IIIa or IIIb (crude, form a or form b) (2.2 kg, 7.1
mol) is suspended in ethanol (4.4 L) and water (7.7 L) at room
temperature. Aqueous sodium hydroxide (45%, 691 g, 7.7 mol) is
added via a pump keeping the internal temperature at 15-25.degree.
C. The pump is rinsed with water (1.1 L) and the reaction mixture
stirred at room temperature for 35 min. Acetic acid (515 g, 8.4
mol) is added via a pump keeping the internal temperature at
15-25.degree. C. The pump is rinsed with ethanol (1.1 L) and the
reaction mixture stirred at room temperature for 75 min. The
suspension is filtered and the filter cake washed with water (8.8
kg). The isolated material is dried at max. 60.degree. C. to give
Compound IIIb (unmilled, form b) (2.0 kg, 92%).
[0272] NMR (.sup.1H, 600 MHz, DMSO-d.sub.6): 12.26 (1H, s), 8.48
(1H, br. d), 8.05 (1H, s), 7.77 (1H, tb), 7.41 (1H, d), 7.28 (1H,
dd), 4.75 (1H, m), 4.20 (2H, s), 3.94 (2H, m), 3.49 (2H, m), 2.09
(2H, m), 1.80 (2H, m).
[0273] NMR (.sup.13C, 150 MHz, DMSO-d.sub.6): 158.4, 158.3, 156.7,
152.0, 149.6, 137.4, 134.5, 124.0, 122.6, 104.7, 66.4, 53.3, 43.3,
32.4.
[0274] HRMS (ESI): m/z 312 ([M+H].sup.+; 312.1465).
[0275] See Table 2 and FIG. 2 for characterizing data.
e) Micronization Process Compound IIIa
[0276] The micronization was performed using the pilot plant
opposed jet mill 140 AFG (Hosokawa-Alpine AG, Augsburg) applying
the following process parameters for Compound IIIa (unmilled, form
a):
TABLE-US-00004 Milling Classifier Dosage Injector Pressure [bar]
Speed [rpm] [kg/h] pressure [bar] 5.0 3500 15.0 1
[0277] A particle size distribution in terms of x90<28 .mu.m was
achieved. For analysis laser diffraction/dry dispersion Sympatec
was used.
[0278] Solid state properties of Compound III crude (form a or b)
and Compound III unmilled (form a or b), respectively
Appearance In the solid state, the Compounds IIIa and IIIb are
white microcrystalline materials.
Crystallinity and Polymorphism
[0279] Compound IIIa is highly crystalline as can be seen in the
X-ray powder diffraction diagram in FIG. 1 and RAMAN spectrum in
FIG. 3.
[0280] The X-ray powder reflection and intensities (standardised)
are shown in Table 1.
TABLE-US-00005 TABLE 1 intensity I/I.sub.0 2 .THETA. [.degree.]
d-value [.ANG.] [%] 7.66 11.54 28 8.96 9.86 52 10.39 8.50 34 13.06
6.78 13 14.27 6.20 6 14.70 6.02 38 15.22 5.82 12 15.35 5.77 6 16.40
5.40 6 17.33 5.11 100 17.89 4.95 43 18.89 4.70 17 19.14 4.63 28
19.50 4.54 6 20.26 4.38 6 20.89 4.25 63 21.25 4.18 76 22.33 3.98 7
22.85 3.89 53 23.31 3.81 62 23.75 3.74 37 24.05 3.70 14 24.97 3.56
45 25.97 3.43 10 26.30 3.39 8 26.44 3.37 8 26.95 3.31 23 27.09 3.29
25 27.35 3.26 10 28.04 3.18 6
[0281] In Table 1 above the value "2-theta [.sup.0]" denotes the
angle of diffraction in degrees and the d-value [.ANG.] denotes the
specified distances in A between the lattice planes.
[0282] The crystalline Compound IIIa is characterised in that in
the x-ray powder diagram has, inter alia, the characteristic values
2-theta=17.3.degree..+-.0.2.degree. (100% relative intensity),
21.3.degree..+-.0.2.degree. (76% relative intensity),
20.9.degree..+-.0.2.degree. (63% relative intensity),
23.3.degree..+-.0.2.degree. (62% relative intensity),
22.9.degree..+-.0.2.degree. (53% relative intensity),
9.0.degree..+-.0.2.degree. (52% relative intensity),
25.0.degree..+-.0.2.degree. (45% relative intensity),
17.9.degree..+-.0.2.degree. (43% relative intensity),
14.7.degree..+-.0.2.degree. (38% relative intensity),
23.8.degree..+-.0.2.degree. (37% relative intensity),
10.4.degree..+-.0.2.degree. (34% relative intensity),
7.7.degree..+-.0.2.degree. (28% relative intensity),
19.1.degree..+-.0.2.degree. (28% relative intensity),
27.1.degree..+-.0.2.degree. (25% relative intensity),
27.0.degree..+-.0.2.degree. (23% relative intensity) (most
prominent peaks in the diagram of FIG. 1, Table 1).
[0283] Compound IIIa is characterised in that in the x-ray powder
diagram has strong unique reflections at the values
2-theta=7.7.degree..+-.0.2.degree., 9.0.degree..+-.0.2.degree..
[0284] The ratio of a mixture containing compound IIIa (crude, form
a) and a certain amount of compound IIIb (crude, form b) did not
change after storage under ambient conditions for 28 months.
[0285] RAMAN spectrum (characteristic bands) [cm.sup.-1]:
1190.+-.2, 1401.+-.2 and 1675.+-.2.
[0286] Compound IIIb is highly crystalline as can be seen in the
X-ray powder diffraction diagram in FIG. 2 and RAMAN spectrum in
FIG. 4.
[0287] The X-ray powder reflection and intensities (standardised)
are shown in Table 2.
TABLE-US-00006 TABLE 2 intensity I/I.sub.0 2 .THETA. [.degree.]
d-value [.ANG.] [%] 6.38 13.84 60 10.36 8.53 41 11.45 7.72 6 12.85
6.88 41 14.71 6.02 5 15.40 5.75 11 15.66 5.66 21 17.65 5.02 61
18.35 4.83 52 19.22 4.61 11 20.81 4.26 100 21.08 4.21 99 21.64 4.10
76 22.46 3.96 29 22.54 3.94 24 23.03 3.86 57 24.05 3.70 14 25.21
3.53 45 25.73 3.46 9 25.87 3.44 7 26.67 3.34 25 27.20 3.28 27 27.83
3.20 4 29.38 3.04 14 29.53 3.02 20 30.24 2.95 9
[0288] In Table 2 above the value "2-theta [.sup.0]" denotes the
angle of diffraction in degrees and the d-value [.ANG.] denotes the
specified distances in A between the lattice planes.
[0289] Compound IIIb is characterised in that in the x-ray powder
diagram has, inter alia, the characteristic values
2-theta=20.8.degree..+-.0.2.degree. (100% relative intensity),
21.1.degree..+-.0.2.degree. (99% relative intensity),
21.6.degree..+-.0.2.degree. (76% relative intensity),
6.4.degree..+-.0.2.degree. (60% relative intensity),
23.0.degree..+-.0.2.degree. (57% relative intensity),
25.2.degree..+-.0.2.degree. (45% relative intensity),
10.4.degree..+-.0.2.degree. (41% relative intensity),
12.9.degree..+-.0.2.degree. (41% relative intensity),
22.5.degree..+-.0.2.degree. (29% relative intensity),
27.2.degree..+-.0.2.degree. (27% relative intensity),
26.7.degree..+-.0.2.degree. (25% relative intensity) (most
prominent peaks in the diagram of FIG. 2, Table 2).
[0290] Compound IIIb is characterised in that in the x-ray powder
diagram has a strong unique reflection at the value
2-theta=6.4.degree..+-.0.2.degree..
[0291] RAMAN spectrum (characteristic bands) [cm.sup.-1]:
1182.+-.2, 1394.+-.2 and 1663.+-.2.
Examples for Pharmaceutical Composition
[0292] The pharmaceutical composition according to the invention is
a tablet for oral administration comprising a core, containing
compound III, IIIa or IIIb or a mixture thereof and hydroxypropyl
cellulose and/or croscarmellose sodium, and further comprising a
film coating, enveloping said core.
Examples for Formulation 1
TABLE-US-00007 [0293] TABLE 3 Composition of tablet core
formulation 1 Dose strength 10 mg 25 mg 50 mg Drug load (%, wt/wt)
16 8 16 Ingredient [mg/tab] [mg/tab] [mg/tab] compound III (Jet
milled) 10.000 25.000 50.000 Lactose monohydrate 36.875 209.375
184.375 Pregelatinized starch 12.500 62.500 62.500 Hydroxypropyl
cellulose 1.250 6.250 6.250 Croscarmellose sodium 1.250 6.250 6.250
Magnesium stearate 0.625 3.125 3.125 Sub-total: Core tablet 62.500
312.500 312.500
TABLE-US-00008 TABLE 4 Composition of film coated tablets
formulation 1 Dose strength 10 mg 25 mg 50 mg [mg/tab] [mg/tab]
[mg/tab] Core tablet 62.500 312.500 312.500 Film-coat* 2.500 7.500
7.500 Total Film-coated tablet 65.000 320.000 320.000 *Based on the
intended color, the film coat consists of different, and commonly
used amounts of hypromellose, propylene glycol, talc, titanium
dioxide, and iron oxides.
Examples for Formulation 2 (Shown in Table 5 and Table 6)
TABLE-US-00009 [0294] TABLE 5 Composition of tablet core of
formulation 2 Dose strength 10 mg 25 mg 50 mg all Drug load (%,
wt/wt) 11.76 11.76 11.76 11.76 Ingredient [mg/tab] [mg/tab]
[mg/tab] [%, wt/wt] compound III (Jet milled) 10.000 25.000 50.000
11.76 Lactose monohydrate 62.250 155.625 311.250 73.24 Corn starch
8.500 21.250 42.500 10.00 Hydroxypropyl cellulose 1.700 4.250 8.500
2.00 Croscarmellose sodium 1.700 4.250 8.500 2.00 Magnesium
stearate 0.850 2.125 4.250 1.00 Sub-total Core 85.000 212.5 425.000
100.00
TABLE-US-00010 TABLE 6 Composition of film coated tablets
formulation 2 Dose strength 10 mg 25 mg 50 mg [mg/tab] [mg/tab]
[mg/tab] Core tablet 85.000 212.5 425.000 Film-coat* 3.000 5.500
9.000 Total Film coated tablet 88.000 218.000 434.000 *Based on the
intended color, the film coat consists of different, and commonly
used amounts of hypromellose, propylene glycol, talc, titanium
dioxide, and iron oxides.
[0295] As one example for the fast and complete dissolution
characteristics of the formulations described, the dissolution
profiles of core tablets and film-coated tablets 50 mg (compare
Table 5 and Table 6) are shown in FIG. 5.
[0296] A pharmaceutical composition comprising compound III, IIIa
or IIIb or a mixture thereof in combination with hydroxypropyl
cellulose and/or croscarmellose sodium leads to adjustment of the
drug load to the same level for all dose strengths, and a fast
dissolution of the tablet can be reached irrespective of the low
intrinsic dissolution rate of compound III in the physiologically
relevant pH range above pH 4.
[0297] This results in a more flexible usage of the granules, as
they can be compressed to all dose strengths at adequate tablet
size and tablet weight. A coloured film coat can be added that
allows differentiation of the different dosage strengths.
[0298] Formulation 1 and formulation 2 can be obtained by using
either compound IIIa or compound IIIb or mixtures thereof,
respectively.
Manufacturing of Film-Coated Tablets:
A) Material Used
TABLE-US-00011 [0299] TABLE 7 Description of needed excipient
grades Particular preferred grade/type (in addition to
pharmacopoeial Ingredient USP/NF, Ph. Eur., JP specification)
Lactose monohydrate crystalline, fine Corn starch no additional
specification Pregelatinized starch no additional specification
Hydroxypropyl cellulose no additional specification Croscarmellose
sodium no additional specification Magnesium stearate Specific
surface area about 2-10 m.sup.2/g
B) Equipment Used
[0300] The following equipment was used in the process of preparing
the pharmaceutical composition according to the invention.
[0301] The formulation 1 is preferably produced using the following
equipment: [0302] Mixing vessel with propeller mixer for
granulation liquid; [0303] High shear mixer/granulator (e.g.
different scales of Glatt VG or Diosna type)+Wet screen machine
(e.g. Alexanderwerk)+Fluid-bed dryer (e.g. different scales of
Glatt GPCG or Glatt WSG type); [0304] Dry screen machine (e.g.
Quadro Comil); [0305] Free fall blender (e.g. Servolift or
container mixer); single punch or Rotary tablet press (e.g. from
supplier Fette, or Korsch, or Kilian); [0306] Mixing vessel with
propeller mixer and/or homogenizer for film coating suspension;
[0307] Film coater (i.e. film coater with perforated coating
drum)
[0308] The formulation 2 is preferably produced using the following
equipment: [0309] Mixing vessel with propeller mixer for
granulation liquid; [0310] Fluidized-bed granulator/dryer (e.g.
different scales of Glatt GPCG or Glatt WSG type) [0311] Dry screen
machine (e.g. Quadro Comil); [0312] Free fall blender (e.g.
Servolift or container mixer); single punch or Rotary tablet press
(e.g. from supplier Fette, or Korsch, or Kilian); [0313] Mixing
vessel with propeller mixer and/or homogenizer for film coating
suspension; [0314] Film coater (i.e. film coater with perforated
coating drum)
C) Process Description:
Granulation Liquid
[0315] As a first step the granulation liquid for the wet
granulation process is prepared. Purified water of about
10-90.degree. C. is filled into a suitable mixing vessel. Then a
binding agent such as hydroxypropyl cellulose or hypromellose is
stirred in, and the dispersion is cooled down if necessary to room
temperature. If necessary, the liquid is allowed to stand overnight
(completeness of solution/degassing) and stirred up before use. If
necessary, any weight loss is compensated with purified water. The
dry matter (solid content) of this granulation liquid is
preferrably in the range of 4-7% (wt/wt, assuming feasibility for a
range of 2-10%, wt/wt).
[0316] Both formulations 1 and 2 may be produced by high shear or
fluid bed granulation. For each formulation the preferred
production process is described below, but the production of each
formulation using either equipment leads to reasonable drug
product. The selection of the granulation process depends on
available equipment and on economic decisions.
High Shear Granulation Process
(Preferably for Production of Formulation 1)
[0317] For high shear granulation the required quantity of compound
III active ingredient (depending on the dose strength), lactose
monohydrate, corn starch or pregelatinized starch, and mannitol
(optionally) are filled in the product bowl of a high-shear
mixer/granulator, then mixed homogeneously for about 3-4 min using
impeller and chopper blades. Next, the granulation liquid is added
either manually or by spray nozzles and the wet mass is granulated
for about 2-3 min, again using impeller and chopper blades. After
discharging of the high shear mixer/granulator the wet granules are
wet-screened through a 3.0 mm mesh size sieve to destroy large
agglomerates.
[0318] The wet-screened material is transferred to a conventional
fluid bed drier (or alternatively to a tray drier) and dried at an
inlet air temperature of approximately 60-90.degree. C. Granules
are dried when the water activity of the resulting dry granules is
below 0.6. The dried granules are then dry screened with the help
of a Comil screen machine, The screened granules are filled into a
suitable free-fall blender, e.g. a container mixer, croscarmellose
sodium (crosslinked carboxymethylcellulose sodium) and MgStearate
are added subsequently, and blended for in sum 10-20 min,
preferably 15 minutes at a mixing speed of 10 rpm until
homogeneous.
Fluid Bed Granulation Process
(Preferably for Production of Formulation 2)
[0319] For the fluidised bed wet granulation process the required
quantity of compound III active ingredient (depending on the dose
strength and formulation variant), lactose monohydrate, corn starch
or pregelatinized starch, and mannitol (optionally) are filled in
the product bowl of a fluid-bed granulator, then mixed
homogeneously in the chamber of the fluid-bed granulator. Next, the
granulation liquid is added by spraying for granulation in the
chamber of the fluid-bed granulator at an inlet air temperature of
approximately 60-90.degree. C., preferably 75-85.degree. C. until
the target amount of granulation liquid is sprayed. After finishing
the granulation step, the granules are dried in the same chamber at
an inlet air temperature of approximately 60-90.degree. C. Granules
are dried when the water activity of the resulting dry granules is
below 0.6, while the compression properties of these granules are
improved by lower moisture contents. The dried granules are then
dry-screened using a Comil screening machine. The screened granules
are filled into a suitable free-fall blender, e.g. a container
mixer. Croscarmellose sodium (crosslinked carboxymethylcellulose
sodium) and Magnesium stearate are added either together or
subsequently, and blended either together, or subsequently, for in
sum 10-60 min, preferably 15 minutes at a mixing speed of 10 rpm
until homogeneous.
Compression
[0320] The final tableting blend is compressed on a suitable tablet
press (e.g. rotary press) to the respective target weight of the
required dose strength of compound III tablets using the
appropriate tools (e.g. in case of 10 mg tablets: 6 mm round;
biconvex; with bevelled edges, or 5.5 mm round; biconvex; with
bevelled edges, in case of 25 mg tablets: 8 mm round; biconvex;
with bevelled edges or 12.times.5.9 mm oblong shaped, in case of 50
mg tablets: 14.times.6.8 mm oblong shaped or 12.times.5.9 mm oblong
shaped). Predetermined hardness specifications for the different
tool dimensions have to be followed in order to achieve the
intended drug dissolution profile and product characteristics.
Tablets of all dosages are compressed to result in a tensile
strength of approximately 1.5 MPa, this tensile strength is
translated into individual hardness specifications for all dosages
according to the equations given in the USP/NF.
Film Coating
[0321] A colored film coating has to be applied to the tablet cores
in order to achieve a stable and consumer friendly product,
especially for product differentiation to prevent from medication
errors. For this purpose a coating suspension is prepared by
filling purified water into a suitable mixing vessel, and
dissolving propyleneglycol and then hydroxypropylmethylcellulose
with the help of a propeller or high shear stirrer. In a next step
an aqueous slurry of titanium dioxide, talc, iron oxide yellow
and/or iron oxide red if needed (in case of coloured film tablets)
is poured and stirred into the film-forming polymer solution. The
dry matter of this coating suspension is in the range of 10-15%,
preferrably about 12-13%. The suspension may also be prepared from
a ready to use dry mixture that contains the same or chemically
comparable components.
[0322] The above prepared tablet cores are filled into a suitable
film coater (i.e. with perforated pan and top spray system,
alternatively Accela Cota with a 36'' pan with perforated pan and
top spray system is also applicable, less proffered is a pan
coater), and preheated up to a temperature of approximately
40-50.degree. C. or above at an inlet air temperature of
approximately 60-70.degree. C., preferably at 65.degree. C. After
this product temperature is reached the coating suspension is
sprayed onto the cores with the help of one or more spray nozzles
at a spray pressure of about 1-5 bar depending on nozzle design,
production scale and spray rate. A spray rate of about 20-600 g/min
(depending on the batch size as well as drum speed and other
operating conditions) at an inlet air temperature of about
40-80.degree. C., preferably 60.degree. C. It is important to
control and maintain the product temperature during spraying at a
level of between 40-50.degree. C. to achieve a high quality
film-coat. After the spraying is finished the film-coated tablets
may be dried if needed, then cooled down to 40.degree. C. or below,
preferably to approx. 30.degree. C. before the equipment is
discharged. The total process time for the film-coating is in the
range of 1-4 hours (depending on the spray rate as well as the
batch size), other process durations are also feasible.
[0323] The film-coated tablets of formulations 1 and 2,
respectively, release the compound III active ingredient rapidly
and in a largely pH-independent fashion, with complete release
occurring within less than 60 min and release of the major fraction
(more than 80%) occurring within less than 45 min. In accordance
with the present invention, an increased dissolution rate of the
active ingredient (FIG. 5) is achieved. At least or more than 80%
of the drug load is dissolved typically after 45 min, more
typically after 30 min, and most typically after 15 min using the
paddle method (according to USP/NF and Ph. Eur. apparatus 2)
dissolution test conditions at 50 rpm and at pH 6.8 (900 mL of 0.05
M Phosphate buffer (FIG. 5).
[0324] Based on the quality of the tablets produced by the
industrial process, the use of compound IIIa for the manufacture of
formulation 2 is preferred.
[0325] Formulation 1 and formulation 2 are both useful
pharmaceutical compositions.
Clinical Trials
Prevention of Disease Relapse: Study Design, Inclusion Criteria of
Patients, Statistical Method
[0326] Regarding reducing the exacerbations of symptoms
characterizing relapse, including suicidality, the clinical trial
disclosed below was designed to show the efficacy of compound III
in improvement of cognitive impairment in patients with
schizophrenia as compared to placebo. All patients were on stable
antipsychotic treatment (see Table 8 in FIGS. 6A-6C). The study was
a multinational, multicentre, randomised, double-blind,
placebo-controlled, parallel group trial.
Study Medicine
[0327] Compound III (10, 25 and 50 mg) and matching placebo were
supplied as film-coated tablets (formulation 1).
Study Population
[0328] In total, 516 patients with schizophrenia on stable
antipsychotic treatment (Table 8 in FIGS. 6A-6C) as described below
were randomized into this trial.
Inclusion Criteria
[0329] Patients with established diagnoses of schizophrenia (per
Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-V) with the following clinical features: [0330] 1)
Clinically stable and are in the residual (non-acute) phase of
their illness for at least 8 weeks [0331] 2) Current antipsychotic
and concomitant psychotropic medications must meet the criteria
below: [0332] a) Maintained on current atypical (second generation)
antipsychotic medications (in any approved dosage form) [0333] b)
and on current dose for at least 8 weeks prior to randomisation,
and/or [0334] c) Maintained on current typical (first generation)
antipsychotic medications and on current dose for at least 6
months, optionally combined with anticholinergics if treated with a
stable dose for at least 6 months prior to randomisation, and/or
[0335] d) Maintained on current concomitant psychotropic
medications other than anticholinergics, antiepileptics and
lithium, and on current dose for at least 8 weeks prior to
randomisation. Antiepileptics and lithium are allowed if initiated
at least 6 months prior to randomisation. [0336] 3) Have no more
than a "moderate" severity rating on hallucinations and delusions
(Positive and Negative Syndrome Scale (PANSS)--positive syndrome
Hallucinatory Behavior item score.ltoreq.4 and Delusions item score
.ltoreq.4) [0337] 4) Have no more than a "moderate" severity rating
on positive formal thought disorder (PANSS-positive syndrome
Conceptual Disorganization item score .ltoreq.4) [0338] 5) Have a
minimal level of extrapyramidal symptoms (Simpson-Angus Scale total
score <6) and depressive symptoms (PANSS--general
psychopathology syndrome Depression item score .ltoreq.4)
Exclusion Criteria
[0338] [0339] 1) Patient treated with more than two antipsychotic
medications (including more than two dosage forms) [0340] 2) Any
suicidal behavior in the past 2 years (i.e. actual attempt,
interrupted attempt, aborted attempt, or preparatory acts or
behavior) [0341] 3) Any suicidal ideation of type 4 or 5 in the
Columbia Suicidal Severity Rating Scale (C-SSRS) in the past 3
months (i.e. active suicidal thought with intent but without
specific plan, or active suicidal thought with plan and intent)
[0342] 4) History or diagnosis of symptomatic and
unstable/uncontrolled gastrointestinal, hepatic, renal,
respiratory, cardiovascular, metabolic, immunological,
haematological or hormonal disorders [0343] 5) Diseases of the
central nervous system (including but not limited to any kind of
seizures, stroke or any psychiatric disorders other than
schizophrenia)
Randomization
[0344] Patients eligible for the trial based on the aforementioned
criteria were assigned at random in a 2:1:1:1:1 ratio to one of 5
study arms (placebo qd, 10 mg qd, 25 mg qd, 50 mg qd, and 100 mg
qd) and followed for 12 weeks of treatment.
Variables Assessed
[0345] The results of the primary and key secondary efficacy
endpoints and the primary and secondary safety endpoints are
summarized below.
Efficacy Endpoints
[0346] The primary endpoint in this trial is the change from
baseline in cognitive function as measured by the Measurement and
Treatment research to Improve Cognition in Schizophrenia (MATRICS)
Consensus Cognitive Battery (MCCB) composite score after 12 weeks
of treatment. The key secondary efficacy endpoint is the change
from baseline in everyday functional capacity as measured by
Schizophrenia Cognition Rating Scale (SCoRS) global ratings after
12 weeks of treatment.
Safety Endpoints
[0347] The primary safety endpoints are as follows: [0348]
Occurrence of adverse events (AEs)/serious adverse events
(including the abnormalities of physical examination, vital signs,
electrocardiogram test and laboratory tests) [0349] Occurrence of
protocol-specified adverse events of special interest [0350]
Dramatic worsening of disease state as assessed by PANSS [0351]
Suicidality as assessed by Columbia Suicidal Severity Rating Scale
(C-SSRS)
[0352] The secondary safety endpoint is the change in
psychopathology symptoms as assessed by PANSS.
Statistical Methods
[0353] The statistical analysis was performed in a two-stage
fashion. Stage 1 analysis was performed after 70% of patients
complete the 12-week treatment period, and 30% of patients were
randomly selected from the 70% of patients for Stage 1 analysis.
Stage 1 analysis was considered as an internal-pilot study with the
objective to explore the Cambridge Neuropsychological Test
Automated Battery (CANTAB) endpoints, while Stage 2 was considered
as the confirmatory stage to formally test the primary endpoint
selected from Stage 1. No adaptation in trial conduct was made, and
only the statistical analysis plan was different for the two
stages. This report summarizes the results of the Stage 2
analysis.
[0354] Two analysis sets were used. The treated set (TS) consisted
of all patients who were randomised and treated with at least one
dose of study drug; this set was used for the analysis of safety
results. The full analysis set (FAS) consisted of all randomisation
patients who were treated with at least one dose of study drug and
had a baseline and at least one post-baseline on-treatment efficacy
measurement (MCCB or CANTAB) measurement. The FAS was used for the
primary analyses in both stages. For the Stage 1 analysis, only
patients who met the FAS definition were included and from those
patients, 120 were randomly selected based on the pre-defined
number of patients for each group.
[0355] In Stage 2, the primary efficacy endpoint was analysed using
the restricted maximum likelihood based mixed effects model with
repeated measurements (MMRM) for the change from baseline of the
selected CANTAB endpoints after 12 weeks of treatment. Descriptive
statistics were used for safety parameters and other efficacy
parameters.
Results
[0356] Surprisingly, a striking imbalance in both serious
psychiatric adverse events and suicidality were noted in that 8/8
(100%) of psychiatric SAEs for hospitalization for disease
worsening (i.e. schizophrenia, psychotic disorder), and suicidality
leading to hospitalization were noted in the placebo arm versus
none in any arm dosed with compound III (Table 9 in FIG. 7).
[0357] These SAEs occurred in subjects in the placebo arm across
geographic regions, in both males and females taking a number of
different antipsychotic medications.
[0358] These results show that by administration of compound III
suicidal ideations, schizophrenia, relapses of schizophrenia and
psychotic disorders can be successfully treated.
[0359] Further, the efficacy in the above mentioned indications may
be supported by clinical trials described below for
prevention/delay of first episode of psychosis and/or treatment of
attenuated psychosis syndrome:
Prevention of Symptoms Leading to a First-Episode of Psychosis:
Study Design, Inclusion Criteria of Patients, Statistical
Method
[0360] Regarding prevention of first episode of psychosis, the
clinical trial disclosed below is in planning conducted to evaluate
the efficacy, safety and tolerability of compound III given as an
oral tablet during 52 weeks of treatment of 50 mg, twice daily
(BID) compared to placebo in patients meeting diagnostic criteria
for attenuated psychosis syndrome as defined in DSM-V. The study is
designed to show superiority of compound III over placebo in
preventing first episode of psychosis, as well as improvement in
cognition and functional capacity.
[0361] The study is a multinational, multicentre, randomised,
double-blind, placebo-controlled, parallel group design.
Study Medicine
[0362] Compound III (50 mg) and matching placebo is supplied as
film-coated tablets (formulation 2).
Study Population
[0363] Patients who are 6 and 30 years old who meet diagnostic
criteria for Attenuated Psychosis Syndrome (APS) per DSM-V as
determined by the Structured Interview for Psychosis-Risk Syndromes
(SIPS) will be screened using an algorithm developed by the North
American Prodromal Longitudinal Study (NAPLS) consortia to select
individuals predicted to be at greater than 35% risk of conversion
to psychosis within the next 52 weeks.
Inclusion Criteria
[0364] 1) Meet diagnostic criteria for attenuated psychosis
syndrome as defined in DSM-V and determined by SIPS administered at
screening, and diagnosis confirmed by Central Rating Committee
after review of video-taped SIPS interview. [0365] 2) NAPLS risk
calculator score .gtoreq.0.20 at screening indicative of greater
than 35% risk of conversion to psychosis within the next 52 weeks.
[0366] 3) Patients who are antipsychotic medication-naive or who
are currently taking an antipsychotic medication. If taking an
antipsychotic medication, the dose can be decreased during the
trial (or discontinued entirely), but the dose cannot be increased
unless there is a significant worsening of psychosis symptoms.
[0367] 4) Age .gtoreq.16 and .ltoreq.30 years at the time of
consent/assent (if acceptable by local health authorities).
Exclusion Criteria
[0367] [0368] 1) Present or past diagnosis of schizophrenia,
schizophreniform, schizoaffective disorder, bipolar disorder I or
II, or major depressive disorder with psychotic symptoms according
to DSM-V. [0369] 2) Any suicidal behavior in the past 2 years (i.e.
actual attempt, interrupted attempt, aborted attempt, or
preparatory acts or behavior). [0370] 3) Any suicidal ideation of
type 4 or 5 in the Columbia Suicide Severity Rating Scale (C-SSRS)
in the past 3 months (i.e. active suicidal thought with intent but
without specific plan, or active suicidal thought with plan and
intent). [0371] 4) Known diseases of the central nervous system
(including but not limited to any kind of seizures or stroke).
[0372] 5) History of significant head injury (>5 minute without
consciousness). [0373] 6) Diagnosis of a serious developmental
disorder, mental retardation (documented IQ <70), cognitive
disorder, or acute attenuated symptoms exclusively related to
intoxication from a psychotropic substance.
Randomization
[0374] Patients eligible for the trial based on the aforementioned
criteria may be assigned at random in a 1:1 ratio to one of 2 study
arms (placebo bid, and 50 mg bid) and followed for 52 weeks of
treatment.
Variables Assessed
[0375] The results of the primary and key secondary efficacy
endpoints and the primary and secondary safety endpoints are
summarized below.
Efficacy Endpoints
Primary Endpoint:
[0376] The primary endpoint is time to first episode of psychosis
within a 52 week timeframe. First episode of psychosis defined
as:
[0377] One or more of the following Positive Symptoms (Scale of
Prodromal Symptoms (SOPS) criteria) in the psychotic range (rated
at level 6): [0378] Unusual Thought Content/Delusional Ideas [0379]
Suspiciousness/Persecutory Ideas [0380] Grandiosity [0381]
Perceptual Abnormalities/Hallucinations [0382] Disorganized
Communication AND either a symptom is seriously disorganizing or
dangerous OR one of the symptoms above occurred at least one hour
per day at an average frequency of four days/week over the past
month.
OR
[0383] A new prescription or increase in dose of an ongoing
antipsychotic medication for worsening of psychosis symptoms.
[0384] Time of onset of first episode psychosis is defined using
the rater's best estimate as recorded in the Scale of Prodromal
Symptoms (SOPS) interview or when the patient began taking a new
prescription or increased the dose of antipsychotic medication.
Secondary Endpoints:
[0385] Change from baseline in everyday functional capacity as
measured by Schizophrenia Cognition Rating Scale (SCoRS) total
score after 24 and 52 weeks of treatment [0386] Change from
baseline in the neurocognitive composite score of Measurement and
Treatment Research to Improve Cognition in Schizophrenia (MATRICS)
Consensus Cognitive Battery (MCCB) after 24 and 52 weeks of
treatment [0387] Change from baseline in Positive and Negative
Syndrome Scale (PANSS) positive items score, negative items score,
and total score after 52 weeks of treatment.
Safety Endpoints
[0388] The primary safety endpoints are as follows: [0389]
Occurrence of adverse events (AEs)/serious adverse events
(including the abnormalities of physical examination, vital signs,
electrocardiogram test and laboratory tests) [0390] Occurrence of
protocol-specified adverse events of special interest [0391]
Dramatic worsening of disease state as assessed by PANSS [0392]
Suicidality as assessed by Columbia Suicidal Severity Rating Scale
(C-SSRS)
[0393] The secondary safety endpoint is the change in
psychopathology symptoms as assessed by PANSS.
Statistical Methods
[0394] For the primary endpoint of time to first episode of
psychosis, the equality of the hazard rates will be tested by the
Wald test for the treatment effect in a stratified Cox proportional
hazards model at the two-sided 10% significance level. The model
includes the treatment effect as the only covariate and is
stratified by NAPLS risk calculator score and baseline use of
antipsychotics. Secondary change from baseline endpoints will be
analyzed using the restricted maximum likelihood (REML) based mixed
effects model with repeated measurements (MMRM).
* * * * *
References