CLINICAL STUDIES
Growth Hormone Deficiency (GHD) in Pubertal Patients
One open‑label, multicenter, randomized
clinical trial of two dosages of Nutropin was performed
in pubertal patients with GHD.
Ninety‑seven patients (mean age
13.9 years, 83 male, 14 female)
currently being treated with approximately 0.3 mg/kg/wk
of GH were randomized to 0.3 mg/kg/wk or
0.7 mg/kg/wk Nutropin doses. All patients were already
in puberty (Tanner stage ≥2) and had bone ages
≤14 years in males or
≤12 years in females. Mean baseline height
standard deviation (SD) score was –1.3.
The mean last measured height in all 97 patients
after a mean duration of 2.7±1.2 years, by
analysis of covariance (ANCOVA) adjusting for baseline height,
is shown below.
Last Measured Height
by Sex and Nutropin Dose
|
|
Last Measured
Height (cm) |
Height Difference Between
Groups (cm) |
|
Age (yr) |
0.3 mg/kg/wk |
0.7 mg/kg/wk |
|
Mean±SD (range) |
Mean±SD |
Mean±SD |
Mean±SE |
Male
|
17.2±1.3 (13.6 to 19.4) |
170.9±7.9 (n=42) |
174.5±7.9 (n=41) |
3.6±1.7 |
Female
|
15.8±1.8 (11.9 to 19.3) |
154.7±6.3 (n=7) |
157.6±6.3 (n=7) |
2.9±3.4 |
The mean height SD score at last measured height (n=97)
was –0.7±1.0 in the 0.3 mg/kg/wk
group and –0.1± 1.2 in the
0.7 mg/kg/wk group. For patients completing 3.5 or more
years (mean 4.1 years) of Nutropin treatment
(15/49 patients in the 0.3 mg/kg/wk group and
16/48 patients in the 0.7 mg/kg/wk group), the
mean last measured height was 166.1±8.0 cm in
the 0.3 mg/kg/wk group and
171.8±7.1 cm in the 0.7 mg/kg/wk
group, adjusting for baseline height and sex.
The mean change in bone age was approximately
one year for each year in the study in both dose
groups. Patients with baseline height SD scores above
–1.0 were able to attain normal adult heights with the
0.3 mg/kg/wk dose of Nutropin (mean height SD score at
near‑adult height=–0.1, n=15).
Thirty‑one patients had bone mineral
density (BMD) determined by dual energy x‑ray
absorptiometry (DEXA) scans at study conclusion. The two dose
groups did not differ significantly in mean SD score for total
body BMD (–0.9±1.9 in the
0.3 mg/kg/wk group
vs. –0.8±1.2 in the
0.7 mg/kg/wk group, n=20) or lumbar spine BMD
(–1.0±1.0 in the 0.3 mg/kg/wk group
vs. –0.2±1.7 in the 0.7 mg/kg/wk
group, n=21).
Over a mean duration of 2.7 years, patients in
the 0.7 mg/kg/wk group were more likely to have
IGF‑I values above the normal range than patients in
the 0.3 mg/kg/wk group (27.7% vs. 9.0%
of IGF‑I measurements for individual patients). The
clinical significance of elevated IGF‑I values is
unknown.
Effects of Nutropin on Growth Failure Due to Chronic Renal Insufficiency (CRI)
Two multicenter, randomized, controlled clinical trials
were conducted to determine whether treatment with Nutropin
prior to renal transplantation in patients with chronic renal
insufficiency could improve their growth rates and height
deficits. One study was a double‑blind,
placebo‑controlled trial and the other was an
open‑label, randomized trial. The dose of Nutropin in
both controlled studies was 0.05 mg/kg/day
(0.35 mg/kg/week) administered daily by subcutaneous
injection. Combining the data from those patients completing
two years in the two controlled studies results in
62 patients treated with Nutropin and
28 patients in the control groups (either
placebo‑treated or untreated). The mean first year
growth rate was 10.8 cm/yr for
Nutropin‑treated patients, compared with a mean growth
rate of 6.5 cm/yr for placebo/untreated controls
(p<0.00005). The mean second year growth rate was
7.8 cm/yr for the Nutropin‑treated group,
compared with 5.5 cm/yr for controls
(p<0.00005). There was a significant increase in mean
height standard deviation (SD) score in the Nutropin group
(−2.9 at baseline to −1.5 at
Month 24, n=62) but no significant change in the
controls (−2.8 at baseline to −2.9 at
Month 24, n=28). The mean third year growth rate of
7.6 cm/yr in the Nutropin‑treated patients
(n=27) suggests that Nutropin stimulates growth beyond
two years. However, there are no control data for the
third year because control patients crossed over to Nutropin
treatment after two years of participation. The gains
in height were accompanied by appropriate advancement of
skeletal age. These data demonstrate that Nutropin therapy
improves growth rate and corrects the acquired height deficit
associated with chronic renal insufficiency.
Post-Transplant Growth
The North American Pediatric Renal Transplant Cooperative
Study (NAPRTCS) has reported data for growth
post‑transplant in children who did not receive GH
prior to transplantation as well as children who did receive
Nutropin during the clinical trials prior to transplantation.
The average change in height SD score during the initial two
years post transplant was 0.15 for the 2391 patients who did not
receive GH pre-transplant and 0.28 for the 57 patients who did
(J Pediatr. 2000;136:376-382). For patients who were followed
for 5 years post-transplant, the corresponding changes in height
SD score were also similar between groups.
Turner Syndrome
One long‑term, randomized,
open‑label, multicenter, concurrently controlled
study, two long‑term, open‑label,
multicenter, historically controlled studies, and one
long‑term, randomized, dose‑response study
were conducted to evaluate the efficacy of GH for the treatment
of girls with short stature due to Turner syndrome.
In the randomized study GDCT, comparing
GH‑treated patients to a concurrent control group who
received no GH, the GH‑treated patients who received a
dose of 0.3 mg/kg/week given 6 times per week
from a mean age of 11.7 years for a mean duration of
4.7 years attained a mean near final height of
146.0 cm (n=27) as compared to the control group who
attained a near final height of 142.1 cm (n=19). By
analysis of covariance, the effect of GH therapy was a mean
height increase of 5.4 cm (p=0.001).
In two of the studies (85‑023 and
85‑044), the effect of long‑term GH
treatment (0.375 mg/kg/week given either
3 times per week or daily) on adult height was
determined by comparing adult heights in the treated patients
with those of age‑matched historical controls with
Turner syndrome who never received any
growth‑promoting therapy. In
Study 85‑023, estrogen treatment was delayed
until patients were at least age 14. GH therapy resulted in a
mean adult height gain of 7.4 cm (mean duration of GH
therapy of 7.6 years) vs. matched historical controls
by analysis of covariance.
In Study 85‑044, patients treated with
early GH therapy were randomized to receive
estrogen‑replacement therapy (conjugated estrogens,
0.3 mg escalating to 0.625 mg daily) at either
age 12 or 15 years. Compared with matched historical
controls, early GH therapy (mean duration of GH therapy
5.6 years) combined with estrogen replacement at age
12 years resulted in an adult height gain of
5.9 cm (n=26), whereas girls who initiated estrogen at
age 15 years (mean duration of GH therapy
6.1 years) had a mean adult height gain of
8.3 cm (n=29). Patients who initiated GH therapy after
age 11 (mean age 12.7 years; mean duration of GH
therapy 3.8 years) had a mean adult height gain of
5.0 cm (n=51).
Thus, in both studies, 85‑023 and
85‑044, the greatest improvement in adult height was
observed in patients who received early GH treatment and
estrogen after age 14 years.
In a randomized, blinded, dose‑response study,
GDCI, patients were treated from a mean age of
11.1 years for a mean duration of 5.3 years
with a weekly dose of either 0.27 mg/kg or
0.36 mg/kg administered 3 or 6 times weekly.
The mean near final height of patients receiving growth hormone
was 148.7 cm (n=31). This represents a mean gain in
adult height of approximately 5 cm compared with
previous observations of untreated Turner syndrome girls.
In these studies, Turner syndrome patients (n=181)
treated to final adult height achieved statistically significant
average estimated adult height gains ranging from
5.0–8.3 cm.
Study/Group |
Study DesignRCT:
randomized controlled trial; MHT: matched
historical controlled trial; RDT: randomized
dose‑response trial
|
N at Adult Height |
GH Age (yr) |
Estrogen Age (yr) |
GH Duration (yr) |
Adult Height Gain
(cm)Analysis of covariance vs.
controls
|
GDCT |
RCT |
27 |
11.7 |
13 |
4.7 |
5.4 |
85-023 |
MHT |
17 |
9.1 |
15.2 |
7.6 |
7.4 |
85-044: A
|
MHT |
29 |
9.4 |
15.0 |
6.1 |
8.3 |
B
|
| 26 |
9.6 |
12.3 |
5.6 |
5.9 |
C
|
| 51 |
12.7 |
13.7 |
3.8 |
5.0 |
GDCI |
RDT |
31 |
11.1 |
8–13.5 |
5.3 |
~5Compared with
historical data
|
Idiopathic Short Stature (ISS)
A long‑term, open‑label, multicenter
study (86‑053) was conducted to examine the safety and
efficacy of Nutropin in pediatric patients with idiopathic short
stature, also called non‑GH deficient short stature.
For the first year, 122 pre‑pubertal subjects
over the age of 5 years with stimulated serum
GH≥10 ng/mL were randomized into
two treatment groups of approximately equal size; one
group was treated with Nutropin 0.3 mg/kg weekly
divided into three doses per week (TIW) and the other
group served as untreated controls. For the second and
subsequent years of the study, all subjects were
re‑randomized to receive the same total weekly dose of
Nutropin (0.3 mg/kg weekly) administered either daily
or TIW. Treatment with Nutropin was continued until a subject’s
bone age was >15.0 years (boys) or
>14.0 years (girls) and the growth rate was
<2 cm/yr, after which subjects were followed
until adult height was achieved. The mean baseline values were:
height SD score –2.8, IGF‑I SD score
–0.9, age 9.4 years, bone age
7.8 years, growth rate 4.4 cm/yr,
mid‑parental target height SD score –0.7,
and Bayley‑Pinneau predicted adult height SD score
–2.3. Nearly all subjects had predicted adult height
that was less than mid‑parental target height.
During the one‑year controlled phase of the
study, the mean height velocity increased by
0.5±1.8 cm (mean±SD) in the
no‑treatment control group and by
3.1±1.7 cm in the Nutropin group
(p<0.0001). For the same period of treatment the mean
height SD score increased by 0.4±0.2 and remained
unchanged (0.0±0.2) in the control group
(p<0.001).
Of the 118 subjects who were treated with
Nutropin in Study 86‑053, 83 (70%) reached
near‑adult height (hereafter called adult height)
after 2–10 years of Nutropin therapy. Their
last measured height, including post‑treatment
follow‑up, was obtained at a mean age of
18.3 years in males and 17.3 years in females.
The mean duration of therapy was 6.2 and 5.5 years,
respectively. Adult height was greater than pretreatment
predicted adult height in 49 of 60 males (82%) and 19
of 23 females (83%). The mean difference between adult
height and pretreatment predicted adult height was
5.2 cm (2.0 inches) in males and
6.0 cm (2.4 inches) in females
(p<0.0001 for both). The table (below) summarizes the
efficacy data.
Long‑Term Efficacy in Study 86‑053
(Mean±SD)
Characteristic |
Males(n=60) |
Females(n=23) |
Adult height (cm) |
166.3±5.8 |
153.1±4.8 |
Pretreatment predicted adult
height (cm) |
161.1±5.5 |
147.1±5.1 |
Adult height minus pretreatment
predicted adult height (cm) |
+5.2±5.0
|
+6.0±5.0
|
Adult height SD score |
–1.5±0.8 |
–1.6±0.7 |
Pretreatment predicted adult
height SD score |
–2.2±0.8 |
–2.5±0.8 |
Adult height minus pretreatment
predicted adult height SD score |
+0.7±0.7
|
+0.9±0.8
|
Nutropin therapy resulted in an increase in mean
IGF‑I SD score from –0.9±1.0 to
–0.2±0.9 in Treatment Year 1. During
continued treatment, mean IGF‑I levels remained close
to the normal mean. IGF‑I SD scores above +2
occurred sporadically in 14 subjects.
Adult Growth Hormone Deficiency (GHD)
Two multicenter, double‑blind,
placebo‑controlled clinical trials were conducted
using Nutropin [somatropin (rDNA origin) for injection] in
GH‑deficient adults. One study was conducted in
subjects with adult‑onset GHD, mean age
48.3 years, n=166, at doses of 0.0125 or
0.00625 mg/kg/day; doses of 0.025 mg/kg/day
were not tolerated in these subjects. A second study was
conducted in previously treated subjects with
childhood‑onset GHD, mean age 23.8 years,
n=64, at randomly assigned doses of 0.025 or
0.0125 mg/kg/day. The studies were designed to assess
the effects of replacement therapy with GH on body composition.
Significant changes from baseline to Month 12 of
treatment in body composition (i.e., total body % fat
mass, trunk % fat mass, and total body % lean
mass by DEXA scan) were seen in all Nutropin groups in both
studies (p<0.0001 for change from baseline and vs.
placebo), whereas no statistically significant changes were seen
in either of the placebo groups. In the adult‑onset
study, the Nutropin group improved mean total body fat from
35.0% to 31.5%, mean trunk fat from
33.9% to 29.5%, and mean lean body mass from
62.2% to 65.7%, whereas the placebo group had
mean changes of 0.2% or less (p=not significant). Due to
the possible effect of GH‑induced fluid retention on
DEXA measurements of lean body mass, DEXA scans were repeated
approximately 3 weeks after completion of therapy; mean
% lean body mass in the Nutropin group was
65.0%, a change of 2.8% from baseline, compared
with a change of 0.4% in the placebo group
(p<0.0001 between groups).
In the childhood‑onset study, the
high‑dose Nutropin group improved mean total body fat
from 38.4% to 32.1%, mean trunk fat from
36.7% to 29.0%, and mean lean body mass from
59.1% to 65.5%; the low‑dose Nutropin
group improved mean total body fat from 37.1% to
31.3%, mean trunk fat from 37.9% to
30.6%, and mean lean body mass from 60.0% to
66.0%; the placebo group had mean changes of
0.6% or less (p=not significant).
Mean Changes from Baseline to Month 12 in
Proportion of Fat and Lean by DEXA for Studies M0431g and
M0381g (Adult‑onset and Childhood‑onset
GHD, respectively)
|
M0431g |
M0381g |
Proportion |
Placebo (n=62) |
Nutropin (n=63) |
Between-Groups t‑test
p‑value |
Placebo (n=13) |
Nutropin 0.0125
mg/kg/day (n=15) |
Nutropin 0.025
mg/kg/day (n=15) |
Placebo vs. Pooled
Nutropin t‑test
p‑value |
Total body percent
fat
|
|
|
|
|
|
|
|
Baseline |
36.8 |
35.0 |
0.38 |
35.0 |
37.1 |
38.4 |
0.45 |
Month 12 |
36.8 |
31.5 |
| 35.2 |
31.3 |
32.1 |
|
Baseline to Month 12
change |
−0.1
|
−3.6
|
<0.0001 |
+ 0.2
|
−5.8
|
−6.3
|
<0.0001 |
Post-washout |
36.4 |
32.2 |
| N/A |
N/A |
N/A |
|
Baseline to post-washout change |
−0.4
|
−2.8
|
<0.0001 |
N/A |
N/A |
N/A |
|
Trunk percent
fat
|
|
|
|
|
|
|
|
Baseline |
35.3 |
33.9 |
0.50 |
32.5 |
37.9 |
36.7 |
0.23 |
Month 12 |
35.4 |
29.5 |
| 33.1 |
30.6 |
29.0 |
|
Baseline to Month 12
change |
0.0
|
−4.3
|
<0.0001 |
+ 0.6
|
−7.3
|
−7.6
|
<0.0001 |
Post-washout |
34.9 |
30.5 |
| N/A |
N/A |
N/A |
|
Baseline to post-washout change |
−0.3
|
−3.4
|
| N/A |
N/A |
N/A |
|
Total body percent
lean
|
|
|
|
|
|
|
|
Baseline |
60.4 |
62.2 |
0.37 |
62.0 |
60.0 |
59.1 |
0.48 |
Month 12 |
60.5 |
65.7 |
| 61.8 |
66.0 |
65.5 |
|
Baseline to Month 12
change |
+ 0.2
|
+ 3.6
|
<0.0001 |
−0.2
|
+ 6.0
|
+ 6.4
|
<0.0001 |
Post-washout |
60.9 |
65.0 |
| N/A |
N/A |
N/A |
|
Baseline to post-washout change |
+ 0.4
|
+ 2.8
|
<0.0001 |
N/A |
N/A |
N/A |
|
In the adult‑onset study, significant decreases
from baseline to Month 12 in LDL cholesterol and
LDL:HDL ratio were seen in the Nutropin group compared to the
placebo group, p<0.02; there were no statistically
significant between‑group differences in change from
baseline to Month 12 in total cholesterol, HDL
cholesterol, or triglycerides. In the childhood‑onset
study, significant decreases from baseline to Month 12
in total cholesterol, LDL cholesterol, and LDL:HDL ratio were
seen in the high‑dose Nutropin group only, compared to
the placebo group, p<0.05. There were no statistically
significant between‑group differences in HDL
cholesterol or triglycerides from baseline to Month 12.
In the childhood‑onset study, 55% of
the patients had decreased spine bone mineral density (BMD)
(z‑score <–1) at baseline. The
administration of Nutropin (n=16) (0.025 mg/kg/day) for
two years resulted in increased spine BMD from baseline
when compared to placebo (n=13) (4.6% vs. 1.0%,
respectively, p<0.03); a transient decrease in spine BMD
was seen at six months in the
Nutropin‑treated patients.
Thirty‑five percent of subjects treated with
this dose had supraphysiological levels of IGF‑I at
some point during the study, which may carry unknown risks. No
significant improvement in total body BMD was found when
compared to placebo. A lower GH dose (0.0125 mg/kg/day)
did not show significant increments in either of these bone
parameters when compared to placebo. No statistically
significant effects on BMD were seen in the
adult‑onset study where patients received GH
(0.0125 mg/kg/day) for one year.
Muscle strength, physical endurance, and quality of life
measurements were not markedly abnormal at baseline, and no
statistically significant effects of Nutropin therapy were
observed in the two studies.
A subsequent 32‑week, multicenter,
open‑label, controlled clinical trial (M2378g) was
conducted using Nutropin AQ, Nutropin Depot, or no treatment in
adults with both adult‑onset and
childhood‑onset GHD. Subjects were randomized into the
three groups to evaluate effects on body composition,
including change in visceral adipose tissue (VAT) as determined
by computed tomography (CT) scan.
For subjects evaluable for change in VAT in the Nutropin
AQ (n=44) and untreated (n=19) groups, the mean age was
46.2 years and 78% had adult‑onset
GHD. Subjects in the Nutropin AQ group were treated at doses up
to 0.012 mg/kg per day in women (all of whom received
estrogen replacement therapy) and men under age
35 years, and up to 0.006 mg/kg per day in men
over age 35 years.
The mean absolute change in VAT from baseline to
Week 32 was –10.7 cm2 in
the Nutropin AQ group and +8.4 cm2
in the untreated group (p=0.013 between groups). There was a
6.7% VAT loss in the Nutropin AQ group (mean percent
change from baseline to Week 32) compared with a
7.5% increase in the untreated group (p=0.012 between
groups). The effect of reducing VAT in adult GHD patients with
Nutropin AQ on long‑term cardiovascular morbidity and
mortality has not been determined.
Visceral Adipose Tissue by Computed Tomography Scan:
Percent Change and Absolute Change from Baseline to Week 32
in Study M2378g
|
Nutropin AQ (n = 44) |
Untreated (n = 19) |
Treatment Difference (adjusted mean) |
p-value |
Baseline VAT
(cm2)(mean) |
126.2 |
123.3 |
|
|
Change in VAT
(cm2)(adjusted mean) |
-10.7 |
+8.4 |
-19.1 |
0.013
|
Percent change in VAT
(adjusted mean) |
-6.7 |
+7.5 |
-14.2 |
0.012
|
|