Vol. 81, No. 5
Printed
in U.S.A.
Journal
of Clinical
Endocrinology
and Metabolism
Copyright
0 1996 by The Endocrine
Society
Outcome
of a Four-Year
Randomized
Study of Daily
Versus Three Times Weekly Somatropin
Treatment
in
Prepubertal
Naive Growth
Hormone-Deficient
Children
MARGARET
H. MAcGILLIVRAY,
OF THE GENENTECH
JOYCE
BAPTISTA,
AND ANN
JOHANSON
State University of New York School of Medicine,
Children’s
Hospital of Buffalo (M.H.M.),
New York 14222; and Genentech, Inc. (J.B., A.J.), South San Francisco, California
94080
ABSTRACT
A comparison
was made of the growth
responses
of prepubertal
naive GH-deficient
children
who were randomly
assigned
to receive
0.3 mg/kgweek
recombinant
human
GH administered
either
daily
(QD) or three times weekly
(TIW) over 4 yr. The effects of the two
regimens
on annual growth
velocity,
change in height SD score, bone
maturation,
and age at onset of puberty
are presented
as the mean
2
BEHALF
During
each of the 4 yr, the annual
growth
velocity
was significantly greater
in the QD vs. TIW group. At 48 months,
the mean total
gain in height was 9.7 cm greater
in the QD group (38.4 ? 5.5) than
that in the TIW group (28.7 2 3.2; P = 0.0002).
The mean height SD
score at the end of each year was significantly
greater
in the QD group.
After 4 yr, the total gain in height SD score was 3.2 ? 1.2 in the QD
group compared
to 1.5 2 0.5 in the TIW group (P = 0.0003). The height
GH treatment regimen during the human pituitary GH era that ended in 1985 involved a
three times weekly (TIW) dosing schedule because it was
convenient, efficacious, and permitted rationing of scarce
supplies of hormone (1). Lower growth velocities were observed when the dosing schedule was less than TIW (l-5).
During the pituitary GH period, a limited number of short
term studies suggested that growth velocity could be further
increased if pituitary GH (pit GH) was administered six or
seven times each week compared to two or three injections
per week (6-9). Usually the growth improvement was seen
only in the first treatment year. Many of these initial studies
included prepubertal as well as pubertal previously treated
GH-deficient children, and the doses of pit GH were not
standardized for body weight or surface area. These variablesmay have contributed to the short lived benefits of daily
pit GH treatment.
After the introduction of recombinant human GH (rhGH)
in 1985, the TIW schedule continued to be used routinely
HE STANDARD
Received
July 24, 1995. Revision
received
November
14, 1995. Accepted December
6, 1995.
Address all correspondence
and rehuests for reprints
to: Dr. Margaret
H. MacGillivray,
State University
of New York School of Medicine,
Children’s
Hospital
of Buffalo,
Buffalo, New York 14222.
* The Genentech
Study Group
includes
the following
investigators:
Gilbert I’. August, Jennifer J. Bell, David R. Brown, Jose F. Cara, Thomas
I’. Foley, Jr., Mitchell
E. Geffner,
Joseph M. Gertner,
Ronald W. Gotlin,
Nancy J. Hopwood,
Barbara
M. Lippe, C. Patrick
Mahoney,
Thomas
Moshang,
Jr., Paul Saenger, Louis E. Underwood,
David T. Wyatt, and
Robert L. Rosenfield.
Buffalo,
SD score at 4 yr was 0.2 in the QD group
(pretreatment,
-2.9)
compared to -1.4 in the TIW group (pretreatment,
-2.9).
After
4 yr of rhGH
treatment,
the increment
in bone age was
similar
in the QD (4.9 i 1.0 yr) and TIW (4.8 t 1.1 yr) groups.
The
change in height age minus the change in bone age was more favorable
in the QD (1.2 ? 0.8 yr) than in the TIW (0.0 z 0.9 yr) group (P =
0.003).
The mean age at onset of puberty
in boys was the same in the QD
(13.2 yr) and TIW (13.0 yr) groups (P = 0.71), and the mean bone age
at the start of puberty
was also similar
(11.5 in QD and 11.3 in TIW
groups;
P = 0.66).
The advantages
of QD rhGH
treatment
in prepubertal
GH-delicient children
after 4 yr were additional
gains of 1.7 height SD score
and 9.7 cm in height over those treated
with the TIW regimen
(P =
0.0002). (J Clin Endocrinol Metab 81: 1806-1809,
1996)
SD.
T
ON
STUDY GROUP*
becauseof historical precedence. Subsequently, the effects of
daily VS. TIW administration of rhGH were compared in
naive as well as previously treated GH-deficient children.
Depending on the study, the dose of rhGH was either not
standardized or it was based on body weight. Again, the
observed enhancement of growth velocity with daily rhGH
treatment was observed mainly in the first year of treatment
(9-12).
The purpose of this collaborative multicenter study was to
compare the growth responses of naive prepubertal GHdeficient children randomized to either QD or TIW somatropin injections. The same total weekly dose of GH standardized for body weight was administered to the two
groups of children. The effects of the two regimens on bone
maturation and the onset of pubertal maturation were also
compared.
Subjects
and
Methods
Initially,
65 prepubertal
GH-deficient
children,
naive to prior GH
treatment,
were randomly
assigned to QD (n = 33) or TIW (n = 32) SC
rhGH treatment.
At the end of the first treatment
year, 51 participants
were still prepubertal
(Table 1). The diagnosis
of GH deficiency
was
based on peak GH levels less than 10 ng/mL
after 2 pituitary
stimulation
tests. Girls were required
to have a bone age of 10 yr or less and boys
a bone age of 11 yr or less. Data from boys and girls were combined
because prepubertal
growth
is not sex dependent.
At baseline, the study was designed to balance the two groups for sex,
age, bone age, height SD score, weight SD score, and midparental
target
height SD score. Pretreatment
growth
velocity
(2s~)
was 4.7 2 3.3 cm/yr
in the QD group (n = 30) and 4.3 -+- 1.8 cm/yr
in the TIW group (n =
30). Pretreatment
growth
data were incomplete
in five children.
1806
SOMATROPIN
TABLE
deficient
1. Pretreatment
patients
after
characteristics
for prepubertal
at least 12 months
of GH therapy
QD
No. of patients
Sex
Male
Female
Etiology
Idiopathic
Organic
Mean 2 SD (range)
Chronological
age (yr)
Bone
age (yr)
Growth
rate
(cm/yr)
Ht (cm)
Ht SD score
Wt (kg)
wt
TREATMENT
SD score
Midparental
target
ht
SD score
Pretreatment
predicted
adult htb SD score
GH-
(n = 23)
TIW
(n = 28)
16
7
26
2
0.06
16
7
23
5
0.34
P
V&la”
OF GH-DEFICIENT
CHILDREN
1807
on-treatment
results,
and changes
from pretreatment
measurements
were made with the two-tailed
Fisher’s exact test, the t test, and analysis
of covariance
(ANCOVA).
The covariates
were baseline chronological
age and midparental
target height SD score. In the ANCOVA
for height
SD score, pretreatment
height
SD score was also used as a covariate.
However,
in the ANCOVA
for growth
rate, pretreatment
growth
rate
was not a significant
predictor
of growth
response
and, thus, was not
used as a covariate.
Results are summarized
as the mean 2 SD.
Results
8.4 2 3.1
(2.9-14.2)
5.9 2 2.5
(2.0-11.4)
[n = 211
4.2 2 1.7
(0.9-7.4)
[n = 211
113.3 * 17.0
(79.3-148.2)
-2.7 2 1.1
f-4.3-0.6)
21.3 2 9.1
(8.8-146.2)
-0.2 + 1.3
(-2.4-3.0)
[n = 221
0.0 5 0.6
(-1.0-1.1)
-1.7 t 1.2
(-3.7-0.5)
[n = 201
8.2 2 2.7
(2.9-12.2)
6.7 t 2.4
(2.2-10.5)
[n = 271
4.2 2 1.4
(1.0-6.3)
[n = 261
112.4 -c 15.5
(80.8-133.8)
-2.8 2 1.0
(-5.6--0.4)
22.1 ? 7.0
(10.6-35.0)
0.7 +- 1.6
(-1.4-4.9)
0.81
-0.1 ? 0.7
(- 1.9-1.2)
-2.2 ? 1.1
(-4/l--0.7)
[n = 261
0.48
0.30
0.87
0.84
0.76
0.47
0.047
0.12
a By two-tailed
Fisher’s
exact test for sex and etiology,
and t test
for other variables.
b Bayley-Pinneau
predicted
adult height
and revised
Bayley-Pinneau predicted
adult height
for the younger
children
(QD, n = 10;
TIW, n = 11).
Exclusion
criteria
included
chromosomal
anomalies,
underlying
medical conditions
associated
with poor growth,
and hypothalamic
or
pituitary
tumors
diagnosed
or treated within
12 months before treatment. Subjects were removed
from each year-end
analysis if they entered
puberty
during that year of GH treatment.
Pubertal
children
continued
to receive their original
rhGH treatment
schedule
and will be assessed
in a separate analysis that evaluates
the impact of QD US. TIW rhGH
treatment
on pubertal
growth.
Replacement
thyroid
treatment
in five
children and maintenance
glucocorticoid
therapy
in three subjects were
the only additional
hormone
therapies
permitted.
The weekly
dose of
somatropin
was 0.3 mg/kg
given QD or TIW, SC.
During
the study,
height
measurements
were obtained
every
3
months by averaging
three consecutive
stadiometer
readings
made by
a trained
nurse or pediatric
endocrinologist.
Assessments
of bone age
were obtained
before and every year after treatment
was begun using
roentgenography
of the left wrist and hand. Interpretations
of bone
maturation
were made at the Fels Institute
(Yellow Springs, OH) without
knowledge
of treatment
status (13). Predicted
heights were calculated
using the Bayley-Pinneau
method
(14). The original
Bayley-Pinneau
data do not provide
predicted
heights for children
with a bone age less
than 6 yr. However,
Khamis and Roche (personal
communication)
have
revised the calculation
to include children whose bone ages are as young
as 3 yr. Where needed, we have used the latter method.
Height SD score
were calculated
from age- and sex-specific
normative
data for American
children
derived
from the National
Center for Health Statistics (15).
Research protocols
received
approval
from the institutional
review
board at each medical
center. Enrollment
was voluntary,
and written
informed
consent was obtained
from all parents
and children
before
participation.
Comparison
between the two groups for pretreatment
characteristics,
The QD (n = 23) and TIW (n = 28) groups who remained
prepubertal during the first 12 months of rhGH treatment
were similar for the following pretreatment characteristics:
sex, etiology, age, bone age, height, height SD score, weight,
weight SD score, predicted adult height SD score, and midparental target height SD score (Table 1). As the study progressed,the number of children comprising the QD and TIW
groups changed each year depending on the individuals
excluded because of puberty. The mean pretreatment chronological age for the QD and TIW groups who remained
prepubertal for each of the 4 yr of rhGH treatment is shown
in Table 2. The children in the QD group who remained
prepubertal during all 4 yr of the study had a slightly
younger age at baseline compared to the TIW group, but the
difference was not statistically significant (Table 2). Bone age
at baseline in the QD group (3.7 t 1.0 yr; n = 10) was
significantly younger than that in the TIW group (5.3 ? 1.8
yr; n = 12) at baseline (P = 0.02). As chronological age and
bone age were highly correlated, only one (chronological
age) was used as a covariate. However, results were similar
if bone age was used instead of chronological age as a covariate.
The mean annual growth velocity (Table 3 and Fig. 1) and
the mean annual cumulative height gain (Table 4) of the QD
group were significantly greater (P < 0.03) than those of the
TIW group during each of the 4 yr of rhGH treatment. At 48
months, the mean total gain in height was 9.7 cm greater (P
= 0.0002)in the QD group (total height gain = 38.4 k 5.5 cm,
n = 10) than that in the TIW group (28.7 2 3.2 cm; n = 13;
95% confidence interval, 5.9-13.4 cm). The mean height SD
score at the end of each year was significantly greater (P <
0.003) in the QD group, and after 4 yr, the total gain in ht SD
score was 3.2 5 1.2 in the QD group compared to 1.5 + 0.5
in the TIW group (P = 0.0003;Fig. 2). After 4 yr of treatment,
the height SD score (mean) in the QD group was 0.2compared
to -2.9 at the onset of treatment, whereas the height SD score
in the TIW group was - 1.4 compared to -2.9 at baseline(Fig.
2). Thus, at the end of year 4, the QD group had achieved an
additional gain of 1.7 height SD score over that observed in
the TIW group. Similar results were found when the analyses
TABLE
deficient
2. Pretreatment
patients
after
Months of GH
therapy
n
12
24
36
48
23
18
12
10
a By t test.
b Mean ? SD.
chronological
age for prepubertal
GH12, 24, 36, and 48 months
of GH therapy
QD (yr1
8.4
7.8
6.4
5.5
k
2
5
?
3.1b
3.0
2.5
1.1
n
28
22
14
13
TIM’ (yd
8.2
7.9
6.7
6.5
i
t
?
+
2.7’
2.7
2.2
2.1
P value”
0.81
0.84
0.77
0.18
1808
MACGILLIVFWY,
BAPTISTA,
TABLE 3. Annual growth rate for prepubertal GH-deficient
patients after 12,24, 36, and 48 months of GH therapy
Months
n
Pretreatment
27
QD (c&-r)
4.1 r 1.6b
29
4.3 5 l.Bb
0.74
28
<0.0001
<0.0001
0.016
0.037
12-24
18
9.0 + 1.9
22
8.8 + 1.8
6.9 + 1.0
24-36
36-48
12
8.0 t 1.5
7.5 + 1.4
14
13
6.5 2 1.3
6.0 k 1.3
10
11.4 + 2.5
P value”
TIM’ bn&)
23
l
l
1996
No 5
TABLE
4. Total cumulative change in height for prepubertal
GHdeficient patients after 12,24,36, and 48 months of GH therapy
n
o-12
JCE & M
Vol81
AND JOHANSON
a By t test at pretreatment; during treatment analysis of covariante, where age was a significant covariate (P = 0.0005) for months
O-12, and midparental target height SD score was a significant covariate (P 5 0.02) for months O-12 and 12-24.
b Mean +- SD.
Months
n
QD (cd
n
TIW
O-12
O-24
23
18
11.5 + 2.5b
20.7 + 4.4
28
22
8.8
15.8
Ei
12
10
29.4
38.4 t2 5.3
5.5
13
14
(cm)
P value”
k 1.76
rt 2.2
<0.0001
<0.0001
2t 2.3
3.2
<0.0001
0.0002
a By analysis of covariance, where age was a significant covariate
(P < 0.02) for months O-12,0-24, and O-36, and midparental target
height SD score was a significant covariate (P < 0.007) for months
O-12 and O-24.
b Mean + SD.
28.7
22.4
. QD
0 nw
i
-
I
4
n=30
0 n=31
-I l
o
q
PretX
Year 1
Year 2
Year 3
Year 4
1. Annual growth rate (mean t SD) for prepubertal GH-deficient
patients at pretreatment and during years 1,2,3, and 4 of GH therapy. There was no between-treatment
group difference at pretreatment (P = 0.74, by t test). The mean annual growth rate in the QD
group was significantly greater than that in the TIW group (using
analysis of covariance, P < 0.0001 at years 1 and 2; P = 0.016 at year
3; P = 0.037 at year 4). Age was a significant covariate (P = 0.0005)
for months O-12; younger children had a faster growth rate. Midparental target height SD score (SDS) was a significant covariate (P 5
0.02) for months O-12 and 12-24; children oftaller parents grew more
rapidly.
FIG.
were restricted
to the subpopulation
of children
who remained prepubertal
all 4 yr. In general, the growth responses
correlated
negatively
with age during
the first year, positively with midparental
target height SD score in the first and
second years, and positively
with pretreatment
height SD
score in all 4 yr.
The increments
in bone age were similar in the two study
groups after 4 yr of rhGH therapy (4.9 ? 1.0 yr in the QD
group VS. 4.8 + 1.1 yr in the TIW group; P = 0.84). The
increase in height age was greater in the QD group (6.2 2 0.9
yr) than in the TIW group (4.8 + 0.9 yr; P = 0.002). The change
in height age minus the change in bone age was more fa-
I
pretx
23
28
I
Year 1
18
22
I
Year 2
12
14
I
Year 3
10
13
I
Year 4
FIG. 2. Height SD score (SDS; mean t SD) for prepubertal,
GH-deficient patients at pretreatment
and at years 1, 2, 3, and 4 of GH
therapy. There was no between-treatment
group difference at pretreatment (P = 0.90, by t test). The mean height SD score in the QD
group was significantly greater than that in the TIW group (using
analysis of covariance, P < 0.0001 at years 1 and 2; P = 0.0022at year
3; P = 0.0003 at year 4). Age was a significant covariate (P < 0.05)
at years 1,2, and 3; midparental target height SD score was significant
at years 1 and 2; and pretreatment height SD score was significant (P
< 0.002) at each year. There was a significant (P < 0.03) interaction
between age and treatment schedule at years 1, 2, and 3. Younger
patients had a greater increase in height SD score, and the effect of age
was more marked in the QD group than in the TIW group. Pretreatment height SD score correlated positively with height SD score at each
treatment year.
vorable in the QD group (1.2 & 0.8 yr) than in the TIW group
(0.0 rt 0.9 yr; P = 0.003; Table 5).
The mean chronological
age at the onset of puberty for
boys was the same in the QD (13.2 yr) and TIW (13.0 yr)
groups. Similarly,
the mean bone ages at onset of puberty
were similar in the QD (11.5 yr) and TIW (11.3 yr) cohorts
(Table 6). The mean durations
of rhGH treatment before the
onset of puberty were similar in the two groups (QD, 2.6 yr;
TlW, 2.8 yr).
The predicted
mean adult height SD score at year 4 was
greater in the QD group (0.5 ? 1.2 yr; n = 9) than in the TIW
SOMATROPIN
TABLE
patients
TREATMENT
5. Bone age and height
age in prepubertal
after 48 months
of GH therapy
Month
0 to 48 Change
(vr: n = 10)
QD
Tlvl
(VI-: n = 11)
P value0
4.9 -c 1.0*
6.2 2 0.9
1.2 t 0.8
4.8 k l.lb
4.8 5 0.9
0.0 2 0.9
0.84
0.002
0.003
”
ABone age
AHt age
AHt age minus
Abone
GH-deficient
age
A, Maximum
change.
a By t test.
* Mean 5 SD.
TABLE
deficient
6. Age and bone
boys
age at the onset
(yr; if”=
Chronological
Bone age
Yr of GH
age
theranv
13.2
11.5
(n
2.6
2
?
=
2
15)
1.9’
1.2
13)
1.6
of puberty
TIW
(yr; n = 17)
13.0
11.3
(n
2.8
?
2
=
?
1.2*
0.7
15)
1.4
in GH-
P value”
0.71
0.66
OF GH-DEFICIENT
CHILDREN
Age at onset of puberty in boys during rhGH treatment
was not influenced by the different treatment regimens. Although bone maturation in the QD group might advance
more rapidly during puberty, thereby lessening the gains
made with this regimen, the more rapid catch-up growth that
had occurred before puberty without inappropriate bone age
advancement resulted in improved height at the start of
puberty and greater predicted height. Thus, taller adult
heights should be achieved in the QD group.
In summary, the advantages of QD rhGH treatment in prepubertal GH-deficient children after 4 yr were additional gains
of 1.7height SD scoreand 9.7 cm in height over thoseobserved
with the TIW regimen. Consequently, the mean height SD score
with QD treatment after 4 yr was 0.2VS.- 1.4in the TIW group.
Based on these observations, daily rhGH treatment is recommended to maximize the effectiveness of therapy.
0.63
a By t test.
* Mean + SD.
Acknowledgments
The authors
are indebted
Gesundheit
for their generous
group (-1.0 IT 1.5 yr; n = 10; P = 0.004). Before treatment,
the two groups had similar predicted adult height SD scores
(-2.0 t 1.3 and -2.2 ? 1.1, respectively; P = 0.78).
Discussion
GH secretionis pulsatile in normal children, with larger and
more frequent pulses occurring during sleep and several
smaller pulsestaking place during the remainder of the day.
Although the pharmacokinetic properties of GH were known
before the introduction of rhGH, the TIW dosing scheduleremained the conventional regimen for convenience. Becauseof
the relatively short half-life of GH, GH-deficient children
treated with the TlW schedules have very little GH in the
circulation during the “off” days. Also, insulin-like growth factor I UGF-I) levels are in the normal range on the day of GH
therapy, but fall to pretreatment low levels the following day
(16).The rationale that prompted comparisonof a daily US.TlW
rhGH treatment schedulewas basedon the assumption that a
more frequent dosing schedule would enhanceIGF-I generation and provide a pattern of circulating GH and IGF-I that
more closely resembled the physiological state.
In the present study of prepubertal GH-deficient children,
daily rhGH treatment resulted in sustained faster rates of
linear growth. In contrast to previous studies, an improved
height benefit from QD treatment was observed in each of the
4 yr. Although slightly younger baseline age and bone age in
the QD group who remained prepubertal for 4 yr may have
impacted favorably on growth, it is likely that the extra
height gains resulted mainly from daily rhGH treatment. In
fact, the age difference between the two groups has been
reported to account for only a 0.5 cm/yr difference in growth
rates (17). The mean total height gain in the QD group for the
4 yr was 9.7 cm more than that in the TIW group. The greater
height achieved in the group treated QD was not accompanied by undue advancement in bone age. As height age
advanced more than bone age in both groups, improved
adult height potential appears likely, with the gains being
greater in the QD group.
1809
to Joyce Kuntze,
contributions.
James
Frane,
and Neil
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