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,I
PPA Dose-Blood
Brief
1.
and Statement
in 3 phases:
will
be conducted
Phase I:
This
will
titration
with
in
20
(according
to
Screenin&
below)
normobaric
and upper
weight
lim its,
the
1983
subjects
25,
will
non-drug
will
Life
will
50,
day).
randomized
2 treatment
about
in
receive
the
first
10
alternate
regimen.
in
2,
5,
6, 7 and 8 hours
0,
1, 2,
drawn
of
at
blood
determinations).
PPA
The titration
c
by at
subjects
either
at
must
will
which
be
placebo
or
washout,
rate
0,
and blood
for
1
will
a l-day
post-dosing
endpoint
least
each of
positions
(venipuncture
20 and
Each titration
after
post-dosing
in
PPA doses
BP and.pulse
and standing
3 and 4 hours
levels
oral
hours,
day,
lower
Tables)
ages of
days,
to
BP *
defined
Company
(separated
manner
the
height
single
these
inpatient
be measured
3, 4,
for
between-the
of
Baseline
to +15$ of
using
second treatment
supine
-5
days
a double-blind
PPA, and on the
under
150 and 200 mg.
100,
On the
normotensive
Insurance
proceed
75,
involve
require
will
(within
(IO male and 10 female)
12.5,
step
described
oral
administered
clearly
respectively,
Metropolitan
rising
(PPA),
healthy,
criteria
The titration
45.
of
the
of Objectives:
be a placebo-controlled,
phenylpropanolmine
conducted
orally,
Response Study
of Study
The study
dose
w
Description
Pressure
will
l/2,
1,
will
be
estimation
follow
be.either
BP
that
--
PPA dose
baseline
The
which
studies
in
out-patient
Phase I,
response
Patients
weekly
at 0, 3, 4,
phase
visits
estimation
studies
in
repeated
II
maximal
will
consist
the
of
dose of
generate
to
a
the
are
and whether
In
will
undergo
dose
after
t.i.d.
PPA which,
during
rate
this
dose
the
phase
a single
post-dosing
and blood
4 hours
0,
will
l/2,
1,
of
drug
will
post-dosing
.
Again,
BP determinations.
2
will
be
points.
determine
whether
PPA changes
who have
dose
be drawn
and
with
accumulates
patients
3,*4,
2,
phase
,be monitored
at these
to
rechallenge
of PPA used in Phase I.
at
this
w
baseline
release
PPA dose and blood
designed
vasoactive
III:
a PPA
3 weeks of
during
BP and pulse
phase
be measured
follow
to
of PPA concentrations
this
dosing
Phase
3,
desigrred
be seen weekly
and 5 hours
BP response
2,
SDBP from
curve.
of
will
for
Phase
are
administration
these
The
in
or 200 mg.
phase
This
increase
caused a peak increase
in SDBP of 10% over
The drug will
be given as an immediate
(PPA+")*
capsule.
drawn
this
pressure
Phase II:
at
a peak
of 25% (PPA+25),
dose-blood
*
produces
In this
5,
for
6,
completed
with
the
phase BP will
7,
and 8 hours
PPA levels
blood-lettings
at 0,
1,
must
,The
study
chronic
this
treatment
development
drug
in
which
of
phase
with
tolerance
produced
is
designed
a vasoactive
to
the
significant
to
dose of
effects
BP elevations
3
determine
of
whether
PPA results
a dose
of
in Phase I.
in
the
2.
Selection
A.
of
Study
Inclusion
‘Population:
Criteria:
1.
Age 20-45.
2.
Weight
within
upper
limits,
-5%
and
+15$
of
respectively,
defined
in
Company
Tables.
Ability
to
for
1983 Metropolitan
the
the
Life
lower
and
height
as
Insurance
.
3.
sign
read,
the
informed
4.
Availability
for
5.
Ability
6.
to
comprehend
consent
the
understand
the
Willingness
to
abstain
or
other
the
tobacco,
from
Cola
and
supplements
to
the
protocol.
Coca
alcohol
to
study.
adhere
coffee,
methylxanthine-containing
food--e.g.,
vitamin
of
and
of
willingness
form.
duration
requirements
all
and
all
for
and
beverages
and
drugs
the
tea,
chocolate),
and
dietary
or
duration
of
the
study.
B.
Exclusion
1.
Fixed
2.
Current
Criteria:
need
for
any
drug
therapy.
cardiovascular,
gastrointestinal,
hematological,
endocrine
“.
pulmonary,
genito-urinary,
musculoskeletal,
disease.
4
neurological
or
3.
Prior
history
of
significant
cardiovascular,
gastrointestinal,
pulmonary,
hematological,
genito-urinary,
musculoskeletal
or
neurological
disease.
4.
Family
history
of
cardiovascular
significant
disease,
accident,
subarachnoid
aneurysm,
arterio-
hypertension,
cerebrovascular
hemorrhage,
venous
intracranial-
malformation
or brain
tumor.
5.
Significant
abnormality
on
physical
examination.
6.
Significant
abnormality
(as described
7.
Known
similar
allergy
drug
in Appendix
or
(or
pill).
5
adverse
any
on
laboratory
A),
or chest
reaction
decongestant
screen
x-ray.
to
PPA or
or
diet
--
Baseline
3.
BP Screening:
The'screening
Subjects
basis
who qualify
of
will,
the
inclusion
IO
measurements
in
supine
Monday,
will
readings
the
min.
time
and
means of
the
3 measurements
In
order
to
qualify
of
the
times
must
for
the
each of
be between
for
the
entry
3 days
BP's
day
both
Timing
observations
diagrammatically
for
the
on
defined
above
pulse
rate
and
made 3 times
8 AM and
4 PM on,
Korotkoff
Phase
and pulse
are
into
the
(as
defined
on which
standing
1 week.
5
rates
at
as
the
defined
SBP and DBP.
95 and 12'7 mmHg for
DBP in
of
1 week.
each
for
at
over
study
positions
of DBP.
mean BP's
81 mmHg for
summarized
of
the
BP
by 5 min)
Friday
out
criteria
have
(8AM and 4PM) for
study,
into
and standing
be used as the measure
each
entry
rest,
separated
Wednesday
be carried
and exclusion
a
the
will
for
after
(with
*
procedure
dose-titration
in Fig.
above)
for
measurements
60 and
positions.
BP screening
1.
both
are made
SBP and between
and supine
the
phase
period
is
\
I
\
.
1 0
L
c
”
.’ .
.
4.
Phase
I:
Study
A.
Procedure:
Subjects
the
basis
above
of
will
results
a
each
“treatmentrf
day.
For
Step
5 = 100 mg PPA,
PPA)
subjects
After
will
regimen
in-hospital
treatment
3
blood
times
with
day.
to
7 and
8 hours
post-dosing.
will
be
rates
at
timepoint
dosing
at
each
7 = 200 mg
PPA, or
least
a
ml
samples
of
be measured
2,
of
defined
timepoint.
3,
5,
4,
venous
6,
blood
concentrations
post-dosing.
Blood
be
PPA
supine
between
1,
l/2,
the
second
days,
will
to
placebo.
24 hours
on
rate
at
mg PPA,
manner
treatment
pulse
and
Seven
will
at
2
mg PPA, W
4 = 75
intervening
measurements.
made
Step
either
of
periods
4 hours
BP
3 measurements
and
and
follow
of
of
1 = 12.5
a double-blind
On both
estimates
3,
described
intervening
administered
for
must
each
be
pressures
obtained
in
period
prior
one
(Step
mg PPA,
washout
measurements,
2,
steps
day
min.
1,
consists
treatment
5
baseline,
titration
least
on
outlined
6 = 150 mg PPA and Step
will
study
As
be randomized
an out-patient
the
examinations
at
the
into
procedure.
the
3 = 50
Step
in-hospital
standing
screening
by
of
Step
alternate
and
of
each
= 25 mg PPA,
entrance
titration
separated
Step
a first
the
step
days
llwashouttv
for
of
begin
previously,
-
qualifying
at
Blood-lettings
pressures
as
the
and
means
pulse
of
the
*e
Subjects
will
receiving
a higher
unless
through
proceed
dose
a 25% increase
encountered
at
10% increase
preceding
interval
PPA at
each
in
supine
DBP from
supine
or subsequent
separating
sequence
of
any post-dosing
in
the
point,
DBP from
hourly
steps
steps,
succeeding
in
step,
baseline
association
baseline
in
BP measurement
titration
of
must
be
is
with
a
either
the
(PPA+25).
The
at
least
24
hours.
After
for
the
the
B.
Adverse
subject’s
laboratory
last
screen
Withdrawal
Reactions
.
1.
during
iii.
and
any position
any position
rate
>130/min
Irregular
pulse.
iv.
Sustained
chest
V.
Headache
vi.
vii.
viii.
Visual
in Appendix
Procedures
will
be drawn
A.
for
Handling
Criteria
DBP at
Pulse
blood
Phase I:
SBP in
ii,
step,
detailed
Criteria
Withdrawal
1.
titration
110
mm Hg or
exceeding
higher
170 mm Hg.
or <50/min.
discomfort.
disturbance.
Seizure.
Paraesthesia
or
or weakness,
localized.
8
either
generalized
or
ix.
other
Any
neurological
considered
be
by the
of
Nausea
X.
xi.
2.
Phase
Any
e-
an
adverse
cardiac
physical
in
patient’s
and
the
has
subsided
for
an adverse
24
hours
be seen
At
the
and
adverse
a
medical
reaction
12-lead
out
React;ions
during
pressure
have
V
returned
Subjects
resolution
1 week
investigator,
staff
and
drug
9
the
screen
monitoring
and
until
the
to
the
normal
within
the
of
after
temporally
h.
continue
in-hospital
may be considered.
q.1/2
for
from
the
study
from
the
study
at
least
in-hospital
of
for
a complete
withdrawn
remain
monitored,
the
blood
withdrawal
the
study
immediately,
Cardiac
will
within
the
instituted,
and
prompting
will
from
ECG obtained,
A obtained.
re-examined
of
study.
hospitalized
carried
complete
of
withdrawn
pressure
reaction
dose
is
be
completely.
a carefully
the
the
Adverse
blood
signs
discretion
consent,
Handling
who
reaction
after
CIBA-GEIGY
with
blood
vital
range
from
prompt
depersonalization.
begun,
supine
of
to
vomiting.
will
Appendix
monitoring
of
subject
examination
detailed
sufficient
to
I:
monitoring
of
investigator
subject
and/or
for
reaction
monitoring
of
Feelings
Procedures
monitoring
severity
withdrawal
disturbance
for
reaction
hospital
with
and
discharge.
permission
obtaining
will
from
informed
PPA rechallenge
associated
with
the
--
_ .
Phase II:
5.
Phase II
dosing
in
with
invalve
the
dose
increase
in
supine
whichever
is
greater.
phase
must
by at least
During
pill
release
found
Phase
I
Commencement of
from
outpatient
formulation
baseline
be separated
t.i.d.
capsule
in
DBP over
open,
the
to
of
produce
PPA
a 10%
(PPA'I'
> or
50 mg,
dosing
with
PPA in
in
Phase I
last
step
2 days.
Phase II
counts
subjects
will
and
supine
3 weeks of
an immediate
either
this
k
will
will
be made,
standing
previously
described)
preceding
dose
withdrawn
at
of
new medication
BP's
and
0,
2,
PPA,
these
be seen weekly.
1,
pulse
3
and 7 ml
timepoints
concentrations.
and
bottles
rate
supplied,
measured
4 hours
samples
for
At each visit
of
after
the
venous
blood
estimations
Venipunctures
(as
must
of
follow
PPA
BP
determinations.
Data
from
than
1201,
subjects
of
found
prescribed
to
have used
PPA for
less
than
any weekly
80% or more
period
will
not
for
this
,.r
be included
phase,
in
but
Phase III
in
such
if
the
primary
subjects
compliance
effectiveness
will
analysis
be eligible
has been in
IO
for
the
participation
60-80% range.
Criteria
study,
will
for
and
withdrawal
procedures
be those
outlined
of
for
in
subjects
from
attention
to
Section
this
withdrawn
4 (Phase
I)
i’
.’/.li’Timing
titration
af
observations
step
are
and
summarized
-phase
interventions
diagrammatically
j
of
the
patients
above.
__
8, i
7
: .f,_^
for’. a typical
b
,Li
in -Fig.
2.
,’‘,
‘,_;
; I‘
‘<‘;
i,,
.,.I,,.,i,
:
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4x
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11
-
j
6.
This
phase
subjects
with
Because
that
Staridirig
phase
last
for
prior
for
of
the
assess
the
be carried
of
PPA+2S dose.
possibility
effects
to
2,
rate
and l/2,
administration
3
and
withdrawal
for
to
and pulse
must follow
procedures
described
must
BP's
oral
1,
a rechallenge
hypertensive
Seven ml samples
0,
of
of
out
on
PPA may
the
day
day of Phase II.
described
Venipunctures
Criteria
designed
the
and supine
after
consists
administration
rechallenge
the
solution.
the
study
is
to
the
previously
hours
the
a single
this
following
at
of
tolerance
develop,
8
.
Phase III:
attention
of
4
be measured
1, 2,
of
venous
hour
will
the
3,
4,
PPA"25
blood
will
post-dosing
5,
as
6 and
dose
in
be obtained
timepoints.
BP measurements.
of
the
to
Phase I in Section
12
subject
during
withdrawn
4B above.
this
subjects
phase and
are,
as
“4
7.
Follow-up
subjects
All
from
the
the
At
this
by
in
be
seen
regardless
adverse
visit
a
reaction
will
Appendix
be collected
1 week
whether
or
the
merely
of
carried
for
the
A.
13
will
In
laboratory
departure
departure
and
systems
out.
of
followed
interventions
review
examination
within
of
protocol-prescribed
physical
urine
must
study,
prompted
of
Visit:
be
was
completion
observations.
obtained
addition,
screen
blood
and
avjd
described
Appendix
Laboratory
A
Screen:
CBC, electrolytes,
CPK,
Ca++,
phosphatase,
BUN, creatinine,
AST,
ALT,
total
GGT, T3, TY, 12-lead
FBS, Alb,
Glob,
bilirubin,
PO4,
alkaline
ECG, urinalysis.
14
I.
/
.
-g
.*
.
1’
9
3
.*
.0
;“
.’
.’
/