Serostim® [somatropin (rDNA origin) for injection] is an anabolic and anticatabolic agent which exerts its influence by interacting with specific receptors on a variety of cell types including myocytes, hepatocytes, adipocytes, lymphocytes, and hematopoietic cells. Some, but not all of its effects, are mediated by insulin-like growth factor-I (IGF-I).
Human immunodeficiency virus (HIV)-associated wasting or cachexia, which commonly involves involuntary loss of lean body mass or body weight, is a metabolic disorder characterized by abnormalities of intermediary metabolism resulting in weight loss, inappropriate depletion of lean body mass (LBM), and paradoxical preservation of body fat. LBM includes primarily skeletal muscle, organ tissue, blood and blood constituents, and both intracellular and extracellular water. Depletion of LBM results in muscle weakness, organ failure, and death. Unlike nutritional intervention for HIV-associated wasting, in which supplemental calories are converted predominantly to body fat, Serostim® treatment resulted in a significant increase in LBM and a decrease in fat mass with a significant increase in body weight due to the dominant effect of LBM gain.
HIV-associated adipose redistribution syndrome (HARS) is characterized by abnormal
accumulation of trunk fat, including visceral adipose tissue (VAT), in patients
infected with HIV/acquired immune deficiency disorder (AIDS), the vast majority
of whom have been treated with highly active antiretroviral therapy (HAART).
VAT is comprised of the deep fat in the abdomen in the omental-mesenteric and
retroperitoneal compartments. HARS, a subset of HIV lipodystrophy, is more specifically
defined as maldistribution of body fat characterized by central fat accumulation
(lipohypertrophy) with or without lipoatrophy (subcutaneous fat depletion primarily
in the face and limbs). In HARS patients, fat may additionally accumulate in
the upper body subcutaneous area such as the dorsocervical area (i.e., "buffalo
hump"). These changes may be accompanied by metabolic disturbances including
insulin resistance, glucose intolerance, and dyslipidemia, as well as belly
image distress. Initial 12-week treatment with Serostim® resulted in decreases
in VAT, trunk fat, and patient-reported belly appearance distress (see CLINICAL
STUDIES). The clinical significance of these changes with respect to improved
cardiovascular risk profile or compliance with HAART has not been studied.
Effects on Protein<, Lipid, and Carbohydrate Metabolism
A one-week study in 6 patients with HIV-associated wasting has shown that treatment with Serostim® 0.1 mg/kg/day improved nitrogen balance, increased protein-sparing lipid oxidation, and had little effect on overall carbohydrate metabolism.
Decreases in trunk fat and total body fat, and increases in lean body mass
were observed during two double-blind, placebo-controlled studies wherein Serostim®
vs. placebo were administered daily for 12 weeks to patients with HARS. (see
CLINICAL STUDIES).
Effects on Nitrogen and Mineral Retention
In the one-week study in 6 patients with HIV-associated wasting, treatment with Serostim® resulted in the retention of phosphorous, potassium, nitrogen, and sodium. The ratio of retained potassium and nitrogen during Serostim® therapy was consistent with retention of these elements in lean tissue.
Physical Performance
Cycle ergometry work output and treadmill performance were examined in separate
12-week, placebo-controlled trials (see CLINICAL STUDIES). In both studies,
work output improved significantly in the group receiving Serostim® 0.1
mg/kg/day subcutaneously vs placebo. Isometric muscle performance, as measured
by grip strength dynamometry, declined, probably as a result of a transient
increase in tissue turgor known to occur with Serostim® therapy.
Pharmacokinetics
Subcutaneous Absorption: The absolute bioavailability of Serostim®
[somatropin (rDNA origin) for injection] after subcutaneous administration of
a formulation not equivalent to the marketed formulation was determined to be
70-90%. The t½ (Mean ± SD) after subcutaneous administration is significantly
longer than that seen after intravenous administration in normal male volunteers
down-regulated with somatostatin (3.94 ± 3.44 hrs. vs. 0.58 ±
0.08 hrs.), indicating that the subcutaneous absorption of the clinically tested
formulation of the compound is slow and rate-limiting.
Distribution: The steady-state volume of distribution (Mean ±
SD) following IV administration of Serostim® in healthy volunteers is 12.0
± 1.08 L.
Metabolism: Although the liver plays a role in the metabolism of GH,
GH is primarily cleaved in the kidney. GH undergoes glomerular filtration and,
after cleavage within the renal cells, the peptides and amino acids are returned
to the systemic circulation.
Elimination: The t½ (Mean ± SD) in nine patients with HIV-associated
wasting with an average weight of 56.7 ± 6.8 kg, given a fixed dose of
6.0 mg recombinant hGH (r-hGH) subcutaneously was 4.28 ± 2.15 hrs. The
renal clearance of r-hGH after subcutaneous administration in nine patients
with HIV-associated wasting was 0.0015 ± 0.0037 L/h. No significant accumulation
of r-hGH appears to occur after 6 weeks of dosing as indicated.
Special Populations
Pediatric: Available evidence suggests that r-hGH clearances are similar
in adults and children, but no pharmacokinetic studies have been conducted in
children with HIV.
Gender: Biomedical literature indicates that a gender-related difference
in the mean clearance of r-hGH could exist (clearance of r-hGH in males >
clearance of r-hGH in females). However, no gender-based analysis is available
in normal volunteers or patients infected with HIV.
Race: No data are available.
Renal Insufficiency: It has been reported that individuals with chronic
renal failure tend to have decreased r-hGH clearance compared to normals, but
there are no data on Serostim® use in the presence of renal insufficiency.
Hepatic Insufficiency: A reduction in r-hGH clearance has been noted
in patients with severe liver dysfunction. However, the clinical significance
of this in HIV+ patients is unknown.
CLINICAL STUDIES
HIV-Associated Wasting or Cachexia
The clinical efficacy of Serostim® [somatropin (rDNA origin) for injection] in HIV-associated wasting or cachexia was assessed in two placebo-controlled trials. All study subjects received concomitant antiretroviral therapy.
Clinical Trial 1: A 12-week, randomized, double-blind, placebo-controlled
study followed by an open-label extension phase enrolled 178 patients with severe
AIDS wasting taking nucleoside analogue therapy (pre-HAART era). The primary
endpoint was body weight. Body composition was assessed using dual energy X-ray
absorptiometry (DXA) and physical function was assessed by treadmill exercise
testing. Patients meeting the inclusion/exclusion criteria were treated with
either placebo or Serostim® 0.1 mg/kg daily. Ninety-six percent (96%) were
male. The average baseline CD4 count/µL was 85. The results from one hundred
forty (140) evaluable patients were analyzed (those completing the 12-week course
of treatment and who were at least 80% compliant with study drug). After 12
weeks of therapy, the mean difference in weight increase between the Serostim®-treated
group and the placebo-treated group was 1.6 kg (3.5 lb). Mean difference in
lean body mass (LBM) change between the Serostim®-treated group and the
placebo-treated group was 3.1 kg (6.8 lbs) as measured by DXA. Mean increase
in weight and LBM, and mean decrease in body fat, were significantly greater
in the Serostim®-treated group than in the placebo group (p=0.011, p < 0.001,
p < 0.001, respectively) after 12 weeks of treatment (Figure 1). There were
no significant changes with continued treatment beyond 12 weeks suggesting that
the original gains of weight and LBM were maintained (Figure 1).
Treatment with Serostim® resulted in a significant increase in physical function as assessed by treadmill exercise testing. The median treadmill work output increased by 13% (p=0.039) at 12 weeks in the group receiving Serostim® (Figure 2). There was no improvement in the placebo-treated group at 12 weeks. Changes in treadmill performance were significantly correlated with changes in LBM.
Figure 1: Mean Changes in Body Composition
Figure 2: Median Treadmill Work Output
*p = 0.039
Clinical Trial 2: A 12-week, randomized, double-blind, placebo-controlled
study enrolled 757 patients with HIV-associated wasting, or cachexia. The primary
efficacy endpoint was physical function as measured by cycle ergometry work
output. Body composition was assessed using bioelectrical impedance spectroscopy
(BIS) and also by dual energy X-ray absorptiometry (DXA) at a subset of centers.
Patients meeting the inclusion/exclusion criteria were treated with either placebo,
approximately 0.1 mg/kg every other day (qod) of Serostim®, or approximately
0.1 mg/kg daily (qhs) of Serostim®. All results were analyzed in intent-to-treat
populations (for cycle ergometry work output, n=670). Ninety-one percent (91%)
were male and 88% were on HAART anti-retroviral therapy. The average baseline
CD4 count/µL was 446. Six hundred forty-six patients (646) completed the 12-week
study and continued in the Serostim® treatment extension phase of the trial.
Clinical Trial 2 results are summarized in Tables 1 and 2:
Table 1: Mean (Median) of Cycle Work Output (kJ) Response
after 12 weeks of Treatment ITT Population
| |
Placebo |
Half-Dose Serostimb |
Full-Dose Serostima |
| Cycle work output (kJ) |
n=222 |
n=230 |
n=218 |
| Baseline |
25.92 (25.05) |
27.79 (26.65) |
27.57 (26.30) |
| Change from baseline |
-0.05 (-0.25) |
2.48 (2.30) |
2.52 (2.40) |
| Percent change from baseline |
0.2% |
8.9% |
9.1% |
| Difference from Placebo |
|
|
|
| Mean (2-sided 95% C.I.) |
- |
2.53c (0.81, 4.25) |
2.57c(0.83, 4.31) |
| Median |
|
2.55 |
2.65 |
a approximately 0.1 mg/kg daily
b approximately 0.1 mg/kg every other day
c p < 0.01 |
Table 2: Mean (Median) Change from Baseline for Lean Body
Mass, Fat Mass and Body Weight
| |
Placebo |
Half-Dose Serostimb |
Full-Dose Serostima |
| |
n |
Mean
(Median) |
n |
Mean
(Median) |
n |
Mean
(Median) |
| Lean body mass (kg) (by BIS) |
222 |
0.97 (0.67) |
223 |
3.89 (3.65) |
205 |
5.84 (5.47) |
| Fat mass (kg) (by DXA) |
94 |
0.03 (0.01) |
100 |
-1.25 (-1.23) |
85 |
-1.72 (-1.51) |
| Body weight (kg) |
247 |
0.69 (0.68) |
257 |
2.18 (2.15) |
253 |
2.79 (2.65) |
a approximately 0.1 mg/kg daily
b approximately 0.1 mg/kg every other day |
The mean maximum cycle work output until exhaustion increased after 12 weeks by 2.57 kilojoules (kJ) in the Serostim® 0.1 mg/kg daily group (p < 0.01) and by 2.53 kJ in the Serostim® 0.1 mg/kg every other day group (p < 0.01) compared with placebo (Table 1). Cycle work output improved approximately 9% in both active treatment arms and decreased < 1% in the placebo group. Lean body mass (LBM) and body weight (BW) increased, and fat mass decreased, in a dose-related fashion after treatment with Serostim® and placebo (Table 2). The LBM results obtained by BIS were confirmed with DXA.
Patients' perceptions of the impact of 12 weeks of treatment on their wasting symptoms as assessed by the Bristol-Meyers Anorexia/Cachexia Recovery Instrument improved with both doses of Serostim® in Clinical Trial 2.
Extension Phase: All patients (n=646) completing the 12-week placebo-controlled
phase of Clinical Trial 2 continued Serostim® treatment into an extension
phase. Five hundred and forty eight of these patients completed an additional
12 weeks of active treatment. In these patients, changes in cycle ergometry
work output, LBM, BW, and fat mass either improved further or were maintained
with continued Serostim® treatment.
HIV-Associated Adipose Redistribution Syndrome (HARS)
The clinical efficacy of Serostim® [somatropin (rDNA origin) for injection]
for the treatment of patients with HARS was assessed in two double-blind, placebo-controlled
trials. The inclusion and exclusion criteria were essentially identical in both
studies. Patients with a history of diabetes, impaired fasting glucose or impaired
glucose tolerance were excluded. Approximately 20% of the patients screened
were excluded from study enrollment as a result of a diagnosis of diabetes or
glucose intolerance. Study subjects received concomitant antiretroviral therapy
and met the generally accepted criteria for excess central adipose tissue deposition
assessed by anthropometric methodology (e.g., waist circumference, waist:hip
ratio).
HARS Study 1 (24 weeks)
Induction Phase (12 weeks): A double-blind, placebo-controlled, parallel
group study randomized 245 patients with HARS. The co-primary efficacy endpoints
were change in visceral adipose tissue (VAT) and trunk:limb fat ratio after
12 weeks of treatment. Secondary efficacy endpoints included changes from baseline
to Week 12 in trunk fat, abdominal subcutaneous adipose tissue (SAT), total
body fat, lean body mass, various lipid parameters and patient reported outcome
(PRO) scores. Patients meeting the inclusion/exclusion criteria were treated
with either placebo, Serostim® 4 mg every other day (qod) or Serostim®
4 mg daily qhs. Eighty seven percent (87%) of patients were male, 80% were Caucasian,
97% were receiving treatment with nucleoside reverse transcriptase inhibitors
(NRTIs), and 30% were receiving treatment for dyslipidemia.
Maintenance Phase (12 Weeks): Patients completing the 12-week induction
phase who were treated with Serostim® 4 mg daily were rerandomized to therapy
with either Serostim® 4 mg qod or placebo for an additional 12 weeks. Patients
completing the 12 week induction phase who were treated with Serostim® 4
mg qod received Serostim® 4 mg qod for an additional 12 weeks, while patients
who were treated with placebo received Serostim® 4 mg daily for an additional
12 weeks. Two hundred and eight patients received study drug and had a maintenance
phase visit. The primary and secondary efficacy endpoints were the same as described
above.
HARS Study 2 (36 weeks)
Induction Phase (12 Weeks): A double-blind, placebo-controlled, parallel
group study randomized 326 patients with HARS. The primary efficacy endpoint
was change in VAT after 12 weeks of treatment. The secondary endpoints were
similar to those in HARS Study 1. Patients meeting the inclusion/exclusion criteria
were treated with either placebo or Serostim® 4 mg daily qhs. Baseline demographic
characteristics were very similar to Study 1.
Maintenance Phase (24 Weeks): Patients completing the 12-week induction
phase were rerandomized to treatment with either Serostim® 2 mg qod or placebo
for an additional 24 weeks. Two hundred fifty six patients received study drug
and had a maintenance phase visit. The primary and secondary efficacy endpoints
were the same as described above.
Induction Phase (Weeks 0-12) Results For Both Studies
The difference in the change from baseline to Week 12 in VAT (approximately
-20 cm2) was statistically significant after treatment with Serostim®
4 mg qod vs. placebo in Study 1 (Table 3). As seen in Tables 3 and 4, the differences
in the change from baseline to Week 12 in VAT (approximately -17-18 cm2)
were also statistically significant after treatment with Serostim® 4 mg
daily vs. placebo in both studies. The VAT response to treatment with Serostim®
4 mg qod vs. placebo in Study 1 was very similar to the response observed after
treatment with Serostim® 4 mg daily (Table 3). Patients with the largest
VAT levels at baseline manifested the largest reductions in VAT in response
to Serostim® treatment (data not shown).
Table 3: HARS Study 1 Induction Phase - Mean Change from
Baseline to Week 12 in Visceral Adipose Tissue (cm2)a
by Treatment Group (Modified ITT Population with LOCF)
| |
Placebo
n=57 |
Serostim® 4 mg
qod
n=58 |
Serostim® 4 mg
daily
n=61 |
| Baseline (SE)b |
133 (12) |
130 (14) |
138 (12) |
| Change from Baseline (SE)c |
-9 (6) |
-28 (7) |
-27 (6) |
| Difference from Placebo |
|
-20 (-38, -2) |
-18 (-35, -2) |
| for Change (95% CI)c |
|
p=0.034 |
p=0.031 |
| (a) Measured by computed tomography (CT) scan; (b) Analysis
of variance model with terms for treatment group, gender, and treatment-by-gender
interaction; (c) Analysis of covariance model with terms for treatment group,
gender, and treatment-by-gender interaction, and baseline VAT as covariate;
(d) CI = confidence interval and SE = standard error |
Table 4: HARS Study 2 Induction Phase - Mean Change from
Baseline to Week 12 in Visceral Adipose Tissue (cm2)a
by Treatment Group (Modified ITT Population with LOCF)
| |
Placebo
n=74 |
Serostim® 4 mg
daily
n=210 |
| Baseline (SE)b |
110 (11) |
116 (6) |
| Change from Baseline (SE)c |
-12 (5) |
-29 (3) |
| Difference from Placebo |
|
-17 (-29, -5) |
| for Change (95% CI) c |
|
p=0.005 |
| (a) through (d) Same as Table 3 |
Subgroup analysis by gender revealed that women did not have a significant reduction in VAT in response to Serostim® 4 mg daily as indicated by the descriptive statistics by gender in Table 5 (only results from Study 2 are shown, but the results from Study 1 were similar).
Table 5: HARS Study 2 Induction Phase - VAT (cm2)a
Descriptive Statistics by Gender
| Variable as Mean (SD)b |
Female |
Male |
| Placebo |
Serostim®
4 mg daily |
Placebo |
Serostim®
4 mg daily |
| |
n=9 |
n=31 |
n=65 |
n=179 |
| Baseline |
77 (50) |
87 (34) |
143 (54) |
144 (65) |
| Change from Baseline |
-7 (44) |
-7 (19) |
2 (33) |
-37 (39) |
| (a) Measured by computed tomography (CT) scan; (b) SD =
standard deviation |
Improvements in some secondary body composition endpoints (trunk fat, abdominal
SAT, total body fat, and lean body mass) were observed in both Serostim®
dose groups regardless of gender. Although a greater response was observed with
4 mg daily dosing, this dose was associated with a higher rate of adverse events,
dose reductions and study discontinuation (see PRECAUTIONS
and ADVERSE REACTIONS). Improvements
were not observed in other secondary endpoints including non-HDL cholesterol.
Maintenance Phase Results
In Study 2, VAT reaccumulated to the same extent in patients treated with Serostim® 2 mg qod and placebo.
The maintenance phase results from Study 1 are summarized in Table 6. In patients initially treated with Serostim® 4 mg daily during the induction phase, rerandomization to Serostim® 4 mg qod (vs. placebo) resulted in less reaccumulation of VAT, trunk fat and total body fat.
Table 6: HARS Study 1 Maintenance Phase: Descriptive Statistics
for Mean Changes from Week 12 to Week 24 in Various Body Composition Endpoints
in Patients Randomized to Placebo vs. Serostim® 4 mg qod After 12 Weeks
of Induction Therapy with Serostim® 4 mg Daily
| Variable as Mean (SD)C |
|
Placebo |
Serostim®
4 mg qod |
| Visceral Adipose Tissuea (cm2) |
Week 12 |
138.7 (46.2)
(n=25) |
114.1(75.0)
(n=27) |
| Change |
17.7 (32.3)
(n=25) |
5.7(41.4)
(n=27) |
| Trunk Fatb (kg) |
Week 12 |
8.3 (3.7)
(n=27) |
6.6(3.3)
(n=23) |
| Change |
1.2(1.5)
(n=27) |
0.3 (1.2)
(n=23) |
| Total Body Fatb (kg) |
Week 12 |
13.9(7.1)
(n=27) |
10.7 (5.5)
(n=23) |
| Change |
1.3 (2.2)
(n=27) |
0.2(1.9)
(n=23) |
| (a) Measured by computed tomography (CT) scan; (b) Assessed
by dual energy X-Ray absorptiometry (DEXA) scan; (c) SD = standard deviation |
Patient Reported Outcomes
Belly appearance distress, belly size estimation and belly profile assessment
(the essential PRO secondary efficacy endpoints) were measured using a validated
PRO instrument, the Body Image Impact Module (BUM) in both studies. Only results
for belly appearance distress and belly size estimation are discussed in that
the belly profile assessment was used to establish responder criteria for the
belly appearance distress and the belly size estimation. Both Serostim®
treatment groups manifested more improvement in belly appearance distress and
belly size estimation than placebo-treated patients. Although a greater response
was observed with 4 mg daily dosing during the induction phase, this dose was
associated with a higher rate of adverse events, dose reductions and study discontinuation
(see PRECAUTIONS and ADVERSE
REACTIONS). The improvements in belly appearance distress and belly
size estimation were sustained during the maintenance phase of Study 1.
The clinical significance of the changes described above in the HARS subsection
of the CLINICAL STUDIES section with respect to improved cardiovascular
risk profile or compliance with HAART has not been studied.
Last updated on RxList: 10/8/2007