Rare Diseases Symptoms Automatic Extraction
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Enhancing crossover trial design for rare diseases: limiting ineffective exposure and increasing study power by enabling patient choice to escape early.
[familial mediterranean fever]
Addressing
the
two
most
important
considerations
in
designing
clinical
trials
,
i
.
e
.
maximizing
study
power
and
minimizing
patient
exposure
to
ineffective
treatment
,
is
particularly
challenging
for
trials
of
rare
diseases
.
The
familial
Mediterranean
fever
(
FMF
)
rilonacept
trial
(
Hashkes
et
al
.
,
Ann
Intern
Med
2012
;
157
:
533
-
41
)
demonstrates
a
novel
crossover
design
by
enabling
patient
choice
to
early
escape
for
rare
disease
.
To
investigate
the
effect
on
study
power
,
exposure
to
the
ineffective
treatment
arm
and
dropout
rate
by
implementing
early
escape
to
crossover
design
,
and
to
propose
a
Bayesian
modeling
approach
.
Based
on
the
FMF
trial
data
,
simulation
studies
compared
study
power
and
dropout
rate
among
three
types
of
designs
for
crossover
trial
:
traditional
without
early
escape
,
early
escape
per
-patient-choice
,
and
early
escape
per
-protocol
.
The
early
escape
per
patient
choice
or
per
protocol
design
achieved
0
.
89
±
0
.
12
and
0
.
78
±
0
.
20
of
the
study
efficiency
when
compared
to
the
traditional
crossover
design
assuming
no
dropout
.
Early
escape
per
patient
choice
compared
to
early
escape
per
protocol
improved
power
by
1
.
29
±
0
.
26
,
and
reduced
the
dropout
rate
by
8
-
29
%
,
but
with
greater
patient
exposure
to
the
less
effective
treatment
arm
.
The
results
of
the
FMF
trial
and
simulation
studies
suggest
that
allowing
early
escape
in
crossover
trial
enhanced
the
design
by
minimizing
patient
's
exposure
to
the
ineffective
treatment
arm
while
maintaining
a
reasonable
study
power
,
which
is
particularly
important
for
rare
disease
trials
.
Choice
between
the
two
types
of
early
escape
presents
tradeoff
between
study
power
and
exposure
to
ineffective
treatment
.
Diseases
Validation
Diseases presenting
"fever"
symptom
22q11.2 deletion syndrome
acute rheumatic fever
alexander disease
allergic bronchopulmonary aspergillosis
canavan disease
carcinoma of the gallbladder
child syndrome
congenital toxoplasmosis
cushing syndrome
cystinuria
dracunculiasis
erdheim-chester disease
esophageal adenocarcinoma
esophageal carcinoma
familial mediterranean fever
focal myositis
hodgkin lymphoma, classical
lamellar ichthyosis
legionellosis
locked-in syndrome
malignant atrophic papulosis
neonatal adrenoleukodystrophy
neuralgic amyotrophy
oculocutaneous albinism
papillon-lefèvre syndrome
pyomyositis
pyruvate dehydrogenase deficiency
scrub typhus
severe combined immunodeficiency
sneddon syndrome
systemic capillary leak syndrome
triple a syndrome
typhoid
waldenström macroglobulinemia
wolf-hirschhorn syndrome
This symptom has already been validated