Note: Descriptions are shown in the official language in which they were submitted.
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USE OF 3,7-DIAZABICYCLO'3,3,1!NONANE COMPOUNDS FOR THE TREATMENT AND/OR
PROPHYLAXIS OF ARRHYTHMIC EVENTS IN MALE HUMAN PATIENTS
Description
The present invention relates to a novel medicinal use of 3,7-diazabicyclo-
[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-
nonane
compounds, and most preferably to a novel riiedicinal use of tedisamil, and of
pharmaceutically acceptable acid addition salts and/or solvates of said
compounds.
9,9-Alkylene-3,7-diazabicyclononane compounds of formula I and their
pharmacological activities are known from published European Patent No. EP
103,833
and the corresponding U.S. Pat. No. 4,550,112, and Finnish Patent No. FI
76,338.
Compounds of formula I are a sub-group of the 9,9-N,N'-tetra-substituted 3,7-
diaza-
bicyclo[3.3.1]nonane compounds described in the aforementioned patent
specifications
and can be prepared by the methods described therein. The aforementioned
patent
specifications disclose that the compounds have useful cardio-active
properties,
particularly oxygen-saving effects and effects on the heart rate and heart
rhythm in
general, and are distinguished by a high physiological tolerance. Thus, the
compounds
show a satisfactory anti-arrhythmic action even at low doses. Moreover, the
undesired
negative effect on the contractile power of the heart is extremely low; i.e.
the compounds
have a particularly favourable ratio of anti-arrhythmic or the refractory
period of the heart
prolonging activities, to negative inotropic secondary activities.
Moreover, it is described in Burow et al., U.S. Pat. No. 5,164,401, the
compounds
also have a pronounced diuretic effect with a favourable ratio between sodium
and
potassium excretion.
Furthermore special salts and their manufacture of the 3,7-diazabicyclo[3,3,1]-
nonane compounds, in particular of 9,9-alkylene-3,7-diazabicyclo[3,3,1]nonane
compounds are described in US 5,324,732. Thus, US 5,324,732 describes fumaric
acid
salts of said compounds containing 1.5 moles of fumaric acid per mole of the
compound.
The document provides also a reference to some general pharmacological
activities of
the compounds of the formula I which are described in the published European
Patent
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2
No. EP 103,833 and in the corresponding US Patent No. 4,550,112. The US Patent
No.
4,912,113 also provides new 3,7-diazabicyclo[3,3,1]nonane compounds and their
pharmacological properties, and intermediates. However, none of the cited
patents
addresses any distinction of efFects when administering tedisamil to different
genders.
It is worthwhile to mention that the referenced prior art patent documents do
not
contain any clinical data related to human beings, however all the
pharmacological
evidence provided is limited to pre-clinical testing in animals like rats and
dogs. In
addition some of the pre-clinical results are also described in the scientific
literature. For
example Fischbach et al. describe "Tedisamil in a Chronic Canine Model of
Atrial Flutter"
(Journal of Cardiovascular Pharmacology, vol. 34, no. 2, August 1999, p. 212
to 218),
and also the "Conversion of Atrial Fibrillation by the Experimentasl
Antiarrhythmic Drug
Tedisamil in Two Canine Models" (Journal of Cardiovascular Electrophsiology,
vol. 12,
no. 10, October 2001, p. 1138 to 1144). However, Fischbach et al. do not
address any
distinction of effects when administering tedisamil to different genders. Opie
et al.
discuss on ~Tedisamil in Coronory Disease: Additional Benefits in Therapy of
Atrial
Fibrillation?" (Journal of Cardiovascular Pharmacology and Therapeutics, vol.
8, no.
supplement 1, 2003, p. S 33 to S 37). They give data and figures studies done
in the
isolated coronary-ligated rat heart, and on the efFects of tedisamil on
exercise-induced
ischemia on diastolic and systolic segment length, and on myocardial oxygen
consumption in exercising dogs. It is also stated that tedisamil has anti-
ischemic
properties, as studied in rat hearts, rabbits, running dogs, and humans;
however, Opie et
al. do not address any distinction of effects when administering tedisamil to
different
genders.
Furthermore, Julius Papp et al. have described the "Effects of Bertosamil on
Atrial
and Ventricular Treshold for Fibrillo-Flutter in Comparison with Quinidine in
Anaesthetized Cats" (Pharmaclogical Research, vol. 25, no. supplement 2, 1992,
p. 156
to 157), and the "EfFects of Bertosamil on Rabbit Atrial and Ventricular
Transmembrane
Potentials" (Pharmaclogical Research, vol. 25, no. supplement 2, 1992, p. 139
to 140).
However, also Papp et al. do not address any distinction of effects when
administering
tedisamil to difFerent genders.
Although Nicholas A. Flores pertains to clinical phase studies in humans under
the title "Tedisamil Solvay" in Current Opinion in Investigational Drugs, vol.
2, no. 1,
2001, p. 97 to 103), no distinction of the efFects of tedisamil on different
genders is
reported.
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3
It is the object of the invention to provide a novel medical use or a new
method of
treating male human patients in need of treatment and/or prophylaxis of anti-
arrhythmic
events.
Another object of the invention is to provide new anti-arrhythmic
pharmaceutical
compositions having an improved activity profile for the use in male human
patients.
The objects of the invention are achieved by surprisingly discovering that 3,7-
diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-
diazabicyclo[3,3,1]-nonane compounds, and most preferably tedisamil, and of
pharmaceutically acceptable acid addition salts and/or solvates of said
compounds are
particularly suitable for the treatment and/or prophylaxis of anti-arrhythmic
events in male
human patients, preferably for conversion of recent onset of atrial
fibrillation (Afib) or
flutter to normal sinus rhythm (NSR) in male human patients. According to a
further
aspect of the invention, the objects are achieved by providing an anti-
arrhythmic
pharmaceutical composition comprising an anti-arrhythmic amount effective in
male
human patients of at least one anti-arrhythmic active 3,7-diaza-
bicyclo[3,3,1]nonane
compound as described in the present invention.
The subject of the invention is therefore the use of the use of 3,7-diaza-
bicyclo[3,3,1]nonane compounds, its physiologically acceptable acid addition
salts and/or
solvates thereof for the production of a pharmaceutical preparation for the
treatment
and/or prophylaxis of anti-arrhythmic events in male human patients,
preferably for
conversion of recent onset of atrial fibrillation (Afib) or flutter to normal
sinus rhythm
(NSR) in male human patients.
The compounds suitable for this novel medicinal use in male human patients are
3,7-diazabicyclo[3,3,1]nonane compounds corresponding to the Formula I:
R2 R3
I
R1 ~N N~R4
wherein
R1 represents an alkyl group containing from 1 to 6 carbon atoms, an alkylene
group
containing from 3 to 6 carbon atoms having a double bond which is not linked
directly
to the nitrogen atom, a cycloalkylalkyl group containing from 4 to 9 carbon
atoms, or
a benzyl group,
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R2 represents a lower alkyl group, and
R3 represents a lower alkyl group, or
R2 and R3 together form an alkylene chain containing from 3 to 6 carbon atoms,
and
R4 represents an alkyl group containing from 1 to 6 carbon atoms, an alkenyl
group
containing from 3 to 6 carbon atoms having a double bond which is not linked
directly
to the nitrogen atom, a cycloalkylalkyl group containing from 4 to 9 carbon
atoms,
a group corresponding to the Formula a:
R5
/ /~ a
z
wherein
R5 represents hydrogen, halogen, lower alkyl or lower alkoxy, and
Z represents an alkylene chain containing from 1 to 3 carbon atoms or a
propenylene chain having a double bond which is conjugated with the phenyl
group, or
a group corresponding to the Formula b:
\ R6
a
CH
a R7
wherein
R6 represents hydrogen, halogen, lower alkyl or lower alkoxy, and
R7 represents hydrogen, halogen, lower alkyl or lower alkoxy,
or a physiologically acceptable acid addition salt andlor solvate thereof.
Particularly suited compounds for the novel medicinal use in male human
patients
according to the invention are compounds of Formula I, wherein R1 represents
an alkyl
group containing from 1 to 6 carbon atoms or a cycloalkylalkyl group
containing from 4 to
7 carbon atoms. In further preferred compounds of Formula I the substituent R4
represents an alkyl group containing from 1 to 6 carbon atoms, a
cycloalkylalkyl group
containing from 4 to 7 carbon atoms, or a group corresponding to Formula b.
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Preferred compounds for the novel medicinal use in male human patients
according to the invention are compounds of Formula 1, wherein R1 represents
an alkyl
group containing from 3 to 6 carbon atoms or a cycloalkylalkyl group
containing from 4 to
7 carbon atoms, and R4 represents an alkyl group containing from 3 to fi
carbon atoms
or a cycloalkylalkyl group containing from 4 to 7 carbon atoms. Said 3,7-
diazabicyclo-
[3,3,1]nonane compound may be a 9,9-alkylene-3,7-diazabicyclo[3.3.1]nonane
compound of Formula I wherein R2 and R3 together form an alkylene chain
containing
from 4 to 5 carbon atoms, and R1 and R4 independently of one another each
denote a
straight-chain or branched alkyl group of 3-4 carbon atoms or the
cyclopropylmethyl
group, and physiologically acceptable acid addition salts andlor solvates
thereof.
Preferred salts for this group of compounds are fumaric acid salts of 9,9-
alkylene-3,7-
diazabicyclo[3.3.1]nonane compounds containing 1.5 moles of fumaric acid per
mole of
compound of formula I.
Further preferred compounds for the novel medicinal use in male human patients
according to the invention are compounds selected from the group consisting of
N,N'-
dicyclopropyl-methyl-9, 9-tetramethylen-3,7-diazabicyclo[3,3,1]nonane
{tedisamil), N-
isobutyl-N'-isopropyl-9,9-pentamethylen-3,7-diazabicyclo[3,3,1]nonane, and
physiologically acceptable acid addition salts and/or solvates thereof.
Preferred salts for
this group of compounds are fumaric acid salts of N,N'-dicyclopropylmethyl-9,
9-
tetramethylene-3,7-diazabicyclo[3,3,1]nonane (tedisamil) or of N-isobutyl-N'-
isopropyl-
9,9-pentamethylene-3,7-diazabicyclo[3,3,1]nonane containing 1.5 moles of
fumaric acid
per mole of said 9,9-alkylene-3,7-diazabicyclo[3.3.1]-nonane compound.
Alternatively, as acid addition salts of the 3,7-diazabicyclo[3,3,1]nonane
compounds the hydrochloride salts are also very suitable for the novel
medicinal use
according to the present invention in male human patients.
Particularly preferred 3,7-diazabicyclo[3,3,1]nonane compounds are the 9,9-
alkylene-3,7-diazabicyclo[3.3.1]nonane compound tedisamil and the
physiologically
compatible acid addition salts and/or solvates thereof, these are most
preferably used as
compounds for the production of pharmaceutical preparations for the treatment
and/or
prophylaxis of of antiarrhythmic male human patients, preferably in conversion
of recent
onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in
male human
patients. If a tedisamil acid addition salt is used, it may preferably be used
according to
the invention in the form of tedisamil hydrochloride or in the form of
tedisamil
sesquifumarate for the treatment of male human patients. Further pharmacologic-
ally
compatible acid addition salts of tedisamil are known from European Patent No.
EP
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103,833. Thus, salts with inorganic acids, e.g. sulfuric acid or hydrohalic
acids, especially
hydrochloric acid; or with organic acids, for instance lower aliphatic
monocarboxylic or
dicarboxylic acids such as acetic acid, fumaric acid, tartaric acid, lactic
acid, malefic acid,
citric acid or salicylic acid; or with sulfonic acids, for instance lower
alkyl sulfonic acids
such as methane sulfonic acid, or benzene sulfonic acids optionally
substituted in the
benzene ring by halogen or lower alkyl, such as p-toluene sulfonic acid, are
suitable as
physiologically acceptable acid addition salts of the compounds of Formula I.
Surprisingly, it has been found that the 3,7,9, 9-tetra-substituted 3,7-
diazabicyclo[3,3,1]nonane compounds corresponding to Formula I are
distinguished by
superior effects in anti-arrhythmic male human patients, in particular in the
conversion of
recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm
(NSR) in male
human patients, in addition to the aforementioned already known general heart-
affecting
properties. The superior anti-arrhythmic effect of the compounds of Formula I
in male
human patients, in particular in the conversion of recent onset of atrial
fibrillation (Afib) or
flutter to normal sinus rhythm (NSR) in male human patients, can be
demonstrated by
clinical test data with human patients which prove the surprising suitability
of 3,7-
diazabicyclo[3,3,1]nonane compounds, e.g. of tedisamil and its acid addition
salts, for
the treatment and/or prophylaxis of anti-arrhythmic effects in male human
patients,
preferably for conversion of recent onset of atrial fibrillation (Afib) or
flutter to normal
sinus rhythm (NSR) in male human patients.
DESGRIPTION OF CLINICAL STUDY DESIGN AND RESULTS
A) Phase II Clinical Study in Humans
The analysis of a first study in humans showed surprisingly that there is a
gender
difference related to efficacy, e.g. that male human patients show a higher
conversion
rate compared to women when treated with tedisamil. Furthermore, the male
human
patients show less safety issues than female human patients. Hence, it was
surprisingly
found that tedisamil as compared to female human patients shows specificity
for male
human patients in anti-arrhythmic treatment, and in particular in conversion
of recent
onset of atrial fibrillation (Afib) to normal sinus rhythm (NSR).
This first clinical study in humans was a Multi-Center, Double-Blind,
Randomized,
Placebo-Controlled, Sequential Ascending Dose Groups Study to evaluate the
Efficacy
and Safety of Intravenous Tedisamil in the Rapid Conversion to Normal Sinus
Rhythm in
Patients with Atrial Fibrillation or Flutter. The active ingredient used was
tedisamil
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dihydrochloride. The study was designed as a phase II study and executed in 35
to 40
centers in 3 to 4 countries. Study duration: Screening: up to 48 hours;
treatment (in-
patient): single 30-minute infusion; safety follow up: 24 hours (in-patient)
with continuous
telemetry and 28 day safety follow up.
The primary efficacy objective of the study was to demonstrate the superiority
of
any dose of tedisamil to placebo in the termination of atrial
fibrillation/flutter as measured
by the percentage of human patients converted to normal sinus rhythm (NSR)
(for at
least 60 seconds) at any time within 2.5 hours after the start of infusion, in
humans.
Secondary efficacy objectives were to determine the percentage of human
patients
remaining in sinus rhythm at 2.5 hours after initiation of the intravenous
infusion of
tedisamil versus placebo; to determine the percentage of human patients
remaining in
sinus rhythm at 24 hours after initiation of the intravenous infusion of
tedisamil versus
placebo; to determine the time to conversion after the start of the infusion
of tedisamil
versus placebo; and to determine the dose- and plasma concentration-response
relationships of tedisamil versus placebo. Safety objective: determining the
safety and
tolerability of tedisamil versus placebo.
The following methodology for the study in humans was applied: A multi-center,
double-blind, randomized, placebo-controlled, sequential ascending dose groups
study
to evaluate the efficacy and safety of intravenous tedisamil versus placebo.
The study
drug was infused over 30 minutes, receiving half the dose within 10 minutes
and half the
dose within the remaining 20 minutes The first patient group received 0.4
mg/kg
bodyweight (bw), infused as 0.2 mg/kg bw within 10 minutes, continued with 0.2
mg/kg
bw infused within 20 minutes. The next higher dose 0.6 mg/kg bw (0.3 mg/kg bw
infused
within 10 min, continued with 0.3 mg/kg bw infused within 20 minutes) was only
administered after the initial dose has been assessed (blinded) and found to
be safe. A
third stage may be added with a higher dose. Tedisamil blood concentrations
were
assessed during the infusion (at 10 and 30 minutes), at conversion to normal
sinus
rhythm, at recurrence and 24 hours after start of infusion.
Planned number of human subjects: 330 randomized (110 patients per dose group)
Diagnosis and Main Criteria for Inclusion:
Atrial fibrillation or flutter with a duration of > 3 hours and < 48 hours,
occurring as a first
or recurrent episode.
Test Product, Dose and Mode of Administration:
~ Tedisamil (0.4 mg/kg body weight)
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8
~ Tedisamil (0.6 mg/kg body weight)
Both dosages were given as an intravenous regimen.
Reference Therapy, Dose and Mode of Administration:
Placebo (vehicle) administered as a 30-minute intravenous infusion.
Duration of Treatment:
The total infusion time is 30 minutes, with half the dose infused within 10
minutes, and
half the dose infused within the remaining 20 minutes.
Criteria for Evaluation:
1 ) Efficacy:
Primary efficacy: the percentage of human patients converted to normal sinus
rhythm
(for at least 60 seconds) at any time within 2.5 hours after the initiation of
the infusion of
study drug.
Secondary efficacy: percentage of human patients in NSR at 2.5 and 24 hours
after start
of infusion; time to conversion; dose- and concentration-response
relationships.
2 Safet
Physical examination, ECG, 24-hour Holter monitoring, vital signs, laboratory
evaluations
and adverse events.
Statistical Methods:
All efficacy variables were evaluated separately for human patients with
atria) fibrillation
and human patients with atria) flutter. Percentages of conversion were
compared among
treatment groups using a logistic regression model with factors for treatment
group and
center. Times to conversion were compared among treatment groups using a Cox
proportional hazards model with factors for treatment group and center. Dose-
response
and concentration-response relationships were examined using descriptive
statistics.
For the calculation of the number of human patients the following assumptions
were
made:
1. For atria) fibrillation patients, the percentage of conversion to normal
sinus rhythm (at
any time within 2.5 hours after the initiation of the infusion) in the placebo
group is
equal to 20% and the clinically relevant difference is 20%.
2. For atria) flutter patients, the percentage of conversion to normal sinus
rhythm in the
placebo group is equal to 10% and the clinically relevant difference is 40%.
Interim analyses for efficacy was performed halfway the first and second
stages
by an external statistician. The purpose is to terminate a stage when the
tedisamil dose
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9
used in that stage is inefficacious. Technically, each interim analysis was a
predictive
power calculation for the comparison of tedisamil and placebo with respect to
the primary
efficacy variable. Blinded safety reviews were performed at the same time as
the efficacy
analyses and, in addition, at the end of the each stage (if applicable).
B) Phase III Clinical Study in Humans
The analysis of a second study in humans confirmed the finding of the first
study,
e.g. that there is a gender difference related to efficacy, e.g. that male
human patients
show a higher conversion rate compared to women when treated with tedisamil.
This second clinical study in humans was a Multi-Center, Double-Blind,
Randomized, Placebo-Controlled, Parallel Design Study to evaluate the Efficacy
and
Safety of Intravenous Tedisamil Sesquifumarate in the Rapid Conversion to
Normal
Sinus Rhythm in Subjects with Recent Onset Atrial Fibrillation or Flutter.
The active ingredient used was tedisamil sesqifumarate. The study was designed
as a phase II study and executed in 30 to 40 centers in 5 countries. Study
duration:
Screening: up to 48 hours; treatment (in-patient): single 30-minute infusion;
safety follow
up: 24 hours (in-patient) with continuous telemetry and 28 day safety follow
up.
The primary efficacy objective of the study in humans was to demonstrate the
superiority of any dose oftedisamil sesquifumarate to placebo in the rapid
conversion to
normal sinus rhythm (for at least 60 seconds), as measured by the percentage
of
subjects converted at any time within 2.5 hours after the start of infusion.
Secondary
efficacy objectives were to determine the percentage of subjects converting to
normal
sinus rhythm at any time within 2.5 hours after start of the intravenous
infusion and in
normal sinus rhythm at 2.5 hours after initiation of the infusion of tedisamil
sesquifumarate versus placebo; to determine the percentage of subjects
converting to
normal sinus rhythm at any time within 2.5 hours after start of the
intravenous infusion
and in normal sinus rhythm at 24 hours after initiation of the infusion of
tedisamil
sesquifumarate versus placebo; to determine the percentage of human subjects
converting to normal sinus rhythm at any time within 2.5 hours after start of
the
intravenous infusion and in normal sinus rhythm at hospital discharge; to
determine the
time to conversion to normal sinus rhythm after the start of the infusion of
tedisamil
sesquifumarate versus placebo; to determine the dose- and concentration-
response
relationships of tedisamil sesquifumarate versus placebo; and to determine the
energy
required for DC cardioversion of tedisamil sesquifumarate versus placebo.
Safety
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objective: determining the safety and tolerability of tedisamil sesquifumarate
versus
placebo.
The following methodology was applied: A multi-center, double-blind,
randomized,
placebo-controlled study to evaluate the efficacy and safety of intravenous
tedisamil
sesquifumarate versus placebo. The study drug was infused over 30 minutes,
receiving
half the dose within 10 minutes and half the dose within the remaining 20
minutes.
Subjects were randomly assigned to receive either:
- 0.32 mg tedisamil free base per kg bodyweight (bw) (0.16 mg/kg bw within 10
minutes, followed by 0.16 mg/kg bw within 20 minutes); or
- 0.48 mg tedisamil free base per kg bw (0.24 mglkg bw within 10 min, followed
by
0.24 mg/kg bw within 20 minutes); or
- 0.64 mg tedisamil free base per kg bw (0.32 mg/kg bw within 10 min, followed
by
0.32 mg/kg bw within 20 minutes); or
- a 30 minute placebo infusion.
Planned number of human subj e~ cts:
212 randomized atrial fibrillation subjects (53 human subjects per treatment
group).
These subjects are the primary target population. In addition, 80 {20 per
treatment group)
subjects with atrial flutter considered to be enrolled within the scope of
this study.
However, the study could be terminated without all atrial flutter subjects
enrolled if the
planned number of atrial fibrillation subjects has been reached.
Diagnosis and Main Criteria for Inclusion:
Atrial fibrillation or flutter with a duration of > 3 hours and < 45 days,
occurring as a first
or recurrent episode.
Test Product, Dose and Mode of Administration:
Test Product, Dose and Mode of Administration:
- Tedisamil free base 0.32 mg/kg body weight (equivalent to 0.51 mg/kg
tedisamil
sesquifumarate and to 0.4 mg/kg tedisamil dihydrochloride
- Tedisamil free base 0.48 mg/kg body weight (equivalent to 0.77 mg/kg
tedisamil
sesquifumarate and to 0.6 mglkg tedisamil dihydrochloride
- Tedisamil free base 0.64 mg/kg body weight (equivalent to 1.02 mg/kg
tedisamil
sesquifumarate and to 0.8 mg/kg tedisamil dihydrochloride
The dosages will be given as an intravenous regimen.
Tedisamil doses in the protocol refer to tedisamil free base.
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Z1
Reference Therapy, Dose and Mode of Administration:
Placebo (vehicle) administered as a 30-minute intravenous infusion similar to
tedisamil
infusion.
Duration of Treatment:
The total infusion time is 30 minutes, with half the dose infused within 10
minutes, and
half the dose infused within the remaining 20 minutes.
Criteria for Evaluation:
1 Efficac
Primary efficacy: the percentage of human subjects converted to normal sinus
rhythm
(for at least 60 seconds) at any time within 2.5 hours after the initiation of
the infusion of
study drug.
Secondary efficacy: percentage of human subjects in normal sinus rhythm at any
time
within 2.5 hours and at 24 hours after start of infusion, as well as at
hospital discharge,
time to conversion, dose- and concentration-response relationships and DC
cardioversion energy.
2 Safet
Physical examination, ECG, 24-hour Hotter monitoring, vital signs, laboratory
evaluations
and adverse events.
Statistical Methods:
Percentages of conversion will be compared among treatment groups using the
(Pearson) chi-square statistics. Times to conversion will be compared among
treatment
groups using the log-rank test. Dose-response and concentration-response
relationships
and the energy required for DC conversion will be examined using descriptive
statistics.
Subjects with atrial fibrillation and atrial flutter will be separately
analyzed. In addition,
both populations will be pooled for analysis. All analyses involving the
atrial flutter subject
population will be considered as exploratory.
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Table I: Conversion of recent onset of atrial fibrillation (Afib) to NSR
Conversion to NSR at any time within 2.5 hrs after start of infusion.
ITT human patient sample; human patients with DC cardioversion are excluded.
Ant~arrhythrnic
Tre~tnient
inritt
Gender: TecC~sa~milv plabebo
Q4mgk ~ ,
( iaman f. 9 6 m~lk~
. . ~...) .. ........ ... . ... . .. ..
. . . ~.... .. . .
.
Atrial FibrillationMale 18135 (51.4 18 / 26 (69.2 2 / 24 (8.3
%) %) %)
Female 6 / 17 35.3 6 / 16 37.5 2 / 22 9.1
% %
Atrial FlutterMale 1 / 7 (14.3 1 / 5 (20.0 O / 10
%) %)
Female 0 / 2 2 I 6 33.3 0 / 3
%
Overall Male 19 / 42 (45.219 / 31 (61.3 2 / 34 (5.9
%) %) %)
-
Female 6 /19 (31.6 8 / 22 (36.4 2 / 25 (8.0
~ %) % ) %)
Table II: Conversion of recent onset of atrial fibrillation (Afib) to NSR
Conversion to NSR at any time within 2.5 hrs after start of infusion.
Human patients with atrial fibrillation
ITT human patient sample; human patients with DC cardioversion are excluded.
Antiarrhythmic
Gende r i. . Treatment
(Humans) Age , with
Male Tedisamil placebo
< 65 rs 0.4 mglkg 0,~
~glkg
10 ! 20 (50.0
%) 13 / 18
(72.2 %) 1
! 14 (7.1
%)
>=65yrs 8/15(51.4%) 518(62.5%) 1/10(10%)
Total 18 / 35 (51.4 18 l 26 (69.22 / 24 (8.3
%) %) %)
Female < 65 yrs 2 ! 5 (40.0 1 / 3 (33.3 1 / 5 (20.0
%) %) %)
> = 65 4 / 12 (33.3 5 / 13 (38.5 1 / 17 (5.9
yrs %) %) %)
Total 6 /17 (35.3 6 /16 (37.5 2122 (9.1 %)
%) %)
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Table III: Conversion of recent onset of atrial fibrillation (Afib) to NSR
Conversion to NSR at any time within 2.5 hrs after start of infusion.
ITT human patient sample; human patients with DC cardioversion are excluded.
Antiar~hythryicI'reatinentvuith
Ge~ider. ',1'ec t~~ai~it Placebo ..
(~uxnans)a 4 nig/kg _ .~ 6 rri , . , : .
, ! ~
g ~.
Atrial FibrillationMale 18/ 35 (51.418 I 26 (69.22 I24 (8.3
%) %) %)
p-value,
ChiSq < 0.001 < 0.001
(vs
lacebo
Female 6 / 17 (35.36 / 16 (37.5 2 / 22 (9.1
%) %) %)
p-value,
ChiSq < 0.045 < 0.034
(vs
lacebo
Atrial FlutterMale 1 17 (14.3 1 / 5 (20.0 0 / 10
%) %)
p-value,
ChiSq 0.218 0.143
(vs
lacebo
Female 0 / 2 2 / 6 (33.3 0 / 3
%)
p-value,
ChiSq -- 0.257
(vs
lacebo
Overall Male 19 / 42 (45.219 / 31 (61.32 / 34 (5.9
%) %} %)
p-value,
ChiSq < 0.001 < 0.001
(vs
lacebo
Female 6 /19 {31.6 8 l 22 (36.4 2 / 25 (8.0
%) %)
p-value,
ChiSq < 0.045 < 0.018
(vs
lacebo
It can be seen from these data that the anti-arrhythmic male human patients
respond to the treatment with tedisamil more specifically than female human
patients in
the anti-arrhythmic treatment, and in particular in the conversion of recent
onset of atrial
fibrillation (Afib)Iflutter to normal sinus rhythm (NSR).
What is particularly surprising is the effectiveness of 3,7-diazabicyclo-
[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-
nonane
compounds, and most preferably of tedisamil, and of pharmaceutically
acceptable acid
addition salts and/or solvates in male human patients, as proved by the above
results of
the studies in humans, in the treatment and/or prophylaxis of anti-an-hythmic
events in
male human patients, in particular in the conversion of recent onset of atrial
fibrillation
(Afib) to NSR in male human patients, since such human gender difference
related to
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14
efficacy has never been observed before in a vast variety of investigations
with tedisamil
in both human genders, and in particular this gender specificity has neither
been
observed in pre-clinical animal studies, as described in the state of the art.
From the results regarding efficacy of tedisamil found in the studies with
human patients
it may be summarized thattedisamil-like 3,7-diazabicyclo-[3,3,1]nonane
compounds,
preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most
preferably tedisamil itself, as well as the acid addition salts, show higher
conversion rates
in male human patients as compared to female human patients. Extension of
infusion
beyond the times indicated above did not produce higher conversion rates. From
the
results it may be summarized regarding safety: Almost all observed TdP
(Torsade de
Point) in 30 min regimen were in female human patients. Only one male human
patient
showed TdP with high dosage on 0.72 in 3114 study.
As a therapeutic agent, 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably
of
9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably of
tedisamil, and of pharmaceutically acceptable acid addition salts and/or
solvates, may be
contained according to the invention, together with conventional
pharmaceutical
auxiliaries andlor carriers, in solid or liquid pharmaceutical preparations
dedicated to the
administration in humans. Examples of solid preparations are preparations
which can be
administered orally, such as tablets, coated tablets, capsules, powders or
granules, or
alternatively suppositories. These preparations may contain conventional
pharmaceutical
inorganic and/or organic carriers, such as talcum, lactose or starch, in
addition to
conventional pharmaceutical auxiliaries, for example lubricants or tablet
disintegrating
agents. Liquid preparations such as suspensions or emulsions of 3,7-
diazabicyclo-
[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-
nonane
compounds, and most preferably of tedisamil, and of pharmaceutically
acceptable acid
addition salts and/or solvates thereof, may contain the usual diluents such as
water, oils
and/or suspension agents such as polyethylene glycols and the like. Other
auxiliaries
may additionally be added, such as preservatives, taste correctives and the
like.
The 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-
diazabicyclo[3,3,1]-nonane compounds, and most preferably tedisamil, and
pharmaceutically acceptable acid addition salts and/or solvates thereof, can
be mixed
and formulated with the pharmaceutical auxiliaries and/or carriers in known
manner. For
the production of solid medicament forms dedicated to human beings, 3,7-
diazabicyclo-
[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-
nonane
compounds, and most preferably tedisamil, and pharmaceutically acceptable acid
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WO 2005/011690 PCT/EP2004/051532
addition salts and/or solvates thereof, can for example be mixed with the
auxiliaries
and/or carriers in conventional manner and can be wet or dry granulated. The
granules
or powder can be poured directly into capsules or be pressed into tablet cores
in
conventional manner. These can be coated in known manner if desired.
EXAMPLES
The following Examples 1 to 3 describe pharmaceutical preparations according
to
the invention which contain an active substance of Formula I, and also the
production of
such pharmaceutical preparations. The following examples explain the
production of
pharmaceutical preparations containing tedisamil dihydrochloride.
Pharmaceutical
preparations containing tedisamil sesquifumarate may be obtained in an
analogous
manner.
Example 1: Tablets Composition:
parts of N,N'-dicyclopropylmethyl-9,9-tetramethylen-3,7-
diazabicyclo[3,3,1]-nonane dihydrochloride
parts of corn starch
55 parts of lactose
5 parts of polyvinylpyrrolidone
2 parts of magnesium stearate
3 parts of talcum
Total 115 parts
PREPARATION METHOD
The active substance was mixed with corn starch and finely powdered lactose in
a mixer.
The resulting mixture was thoroughly moistened with a 20% solution of
polyvinylpyrrolidone ("Kollidon 25", from BASF) in deionized water. If
necessary,
additional deionized water was added. The moist granules were passed through a
2 mm
sieve, dried on trays at 40 DEG C. and then passed through a 1 mm sieve
(Frewitt
machine). After the granules had been mixed with magnesium stearate and
talcum,
tablets weighing 115 mg were pressed therefrom, so that each tablet contained
20 mg of
the active substance.
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16
Example 2: Capsules Composition
20 parts of N-isobutyl-N'-isopropyl-9,9-pentamethylen-3,7-
diazabicyclo[3,3,1]nonane dihydrogen fumarate
20 parts of corn starch
45 parts of lactose
3 parts of polyvinylpyrrolidone
1.5 partsof magnesium stearate
0.5 partsof highly dispersed
silicic acid
Total
90 parts
PREPARATION METHOD
The active substance was mixed with corn starch and finely powdered lactose in
a mixer.
The resulting mixture was thoroughly moistened with a 20% solution of
polyvinylpyrrolidone ("Kollidon 25", from BASF) in deionized water. If
necessary,
deionized water was added. The moist granules were passed through a 1.6 mm
sieve
(Frewitt machine), dried on trays at 40 DEG C., and then passed through a 1 mm
sieve
(Frewitt). After the granules had been mixed with magnesium stearate and
highly
dispersed silicic acid ("Aerosil 200", from Degussa), 90 mg thereof in each
case were
filled by means of an automatic encapsulating machine into size 4 hard gelatin
capsules,
so that each capsule contained 20 mg of active substance.
Example 3: Ampoules Composition (per ampoule)
mg N,N'-dicyclopropylmethyl-9,9-tetramethylen-3,7-diazabicyclo[3,3,1]nonane
dihydrochloride
16 mg Sodium chloride
Water for injection purposes to make up to 2.0 ml
PREPARATION METHOD
Sodium chloride was dissolved in water for injection purposes. The active
substance was
added and dissolved while stirring. Sufficient water for injection purposes
was added to
make up the final volume. The mixture was passed through a 0.25 µ membrane
filter.
2.15 ml aliquots were filled into brown glass ampoules, and the ampoules were
hermetically closed. The ampoules were sterilized with steam for 30 minutes at
121 DEG
C. 2 ml of the resulting injection solution contains 5 mg of the active
substance.
