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Recombinant human Growth Hormone (r-hGH) to treat HIV-associated Adipose Redistribution Syndrome (HARS): 12-week Induction and 24-Week Maintenance Therapy
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Reported by Jules Levin
XVI Intl AIDS Conference, Toronto, Aug 17, 200
authors: Melanie Thompson, Stephen Brown, Gary Richmond, Daniel Lee, Norma Muurahainem, Donald Kotler, and the Study 24380 Investigators Group.
Carl Grunfeld reported the results of this interesting study at the Late Breaker oral session on Thursday at the conference, among the 18 oral presentations, a long session. This study is a pivotal phase III trial as Serono has submitted an appication to the FDA for approval to use r-hGh to reduce fat accumulation associated with lipodystrophy.
Summary & Conclusions by Authors
Induction Therapy (r-hGH 4mg/day, wks 1-12)
--significant reduction in VAT on r-hGH 4mg/day vs placebo
--reduction in trunk fat
--improvement in cholesterol profile
Maintenance Therapy (r-hGH 2 mg alt days)
--fewer than 50% of patients on r-hGH regain >50% of VAT lost during induction therapy
--improvement in cholesterol profile
Safety Profile of r-hGH as anticipated
--AEs mostly mild to moderate
--Greater loss of VAT and trunk fat than of abdominal SAT and limb fat
--Transient increases in glucose, HbA1c, and insulin AUC
The study looked at the use of recombinant growth hormone to treat and reduce the accumulation of visceral fat, fat that can accumulate deep inside the belly (sometimes called lipohypertrophy). As you probably know lipodystrophy is the condition that includes what some HIV+ individuals have that can consist of the accumulation of belly fat or visceral fat. Some HIV+ individuals develop lipoatrophy, which is loss of fat in the face, limbs or trunk, and this condition appears to occur more often than fat accumulation and is usually more upsetting to individuals who have it. Some individuals develop both.
The study examined use of a daily dose of 4 mg of r-hGH for 12 weeks (induction) followed by 24 weeks (maintenance) of 2 mg on every other day. This study found that r-hGH reduced visceral fat at the end of 12 weeks using the higher dose, and improved dyslipidemia at the end of 12 weeks; however patients were permitted to use lipid-lowering drugs during the study. After 12 weeks on high dose visceral fat was reduced by a mean of -32.6 cm2. On average patients saw a 20% reduction in visceral fat. After the higher dose of 4 mg daily during weeks 1-12 some patients were randomized to receive a lower dose of r-hGH of 2 mg every other day for 24 weeks. After a total of 36 weeks of receiving r-hGH patients who had a reduction in VAT during the 12 week high dose period had a mean reduction of -26.6 cm2. So, they still had an improvement from the beginning of the study but they lost some of the improvement that had been achieved during the first 12 weeks. Since the study ended after 36 weeks, I think this study does not answer the question -- what happens to VAT using the same approach after 1 year or two years. Would there continue to be a loss in improvement in visceral fat.
There has been some concern that r-hGh can cause fat loss, which is particularly disconcerting for patients who have lipoatrophy. During the first 12 weeks, the higher dose induction phase of the study, trunk fat and limb fat decreased, but it was reported that by the end of the 24 week maintenance part of the study there were no changes in limb fat compared to baseline, when patients started the study. There have also been concerns that r-hGH can increase glucose. This can be of particular concern for patients with diabetes or insulin resistance. The prevalence of diabetes or insulin resistance is higher among HIV-infected individuals than the general population. Of note, insulin resistance or diabetes is often undetected among people with HIV so the true prevalence of insulin resistance and diabetes is probably underestimated. In this study, patients were not permitted to enter the study if they were diabetic or receiving medications for diabetes. As well patients with abnormal glucose at the time of screening for the study were excluded from the trial.
At this time r-hGH is sold by Serono (Serostim), but is approved by the FDA only for use for patients with HIV-associated wasting syndrome. It has been seen in a number of studies that it can reduce body fat and has been under study for this purpose for several years. Serono submiited to the FDA a supplemental application during the second quarter of 2006 for use of Serostim to treat accumulation of visceral fat, and this application is currently under review.
THE STUDY REPORT
Grunfeld provided this background.
Increased visceral adipose tissue (VAT) often is accompanied by subcutaneous lipoatrophy (fat loss) in the trunk, limbs and face.
Both have metabolic consequences (fat loss or gain can affect lipids and increase risk for heart disease; and glucose abnormalities are associated with body fat changes).
Body changes in fat is characterized by abdominal fat accumulation (truncal fat, but primarily VAT; and this may occur along with subcutaneous fat depletion (lipoatrophy).
Patients may exhibit:
--dyslipidemia, insulin resistance, glucose intolerance
--excess dorsocervical fat ("buffalo hump")
--poor quality of life, particularly psychological distress due to the fat loss in the trunk, face, and limbs and fat accumulation in the belly.
Phase III Trial Design
This is a double-blind, placebo-controlled trial of 326 individuals. The duration of the study is 36 weeks: 12 wks induction and 24 wks maintenance (arm A only). Study patients were randomized in a 3:1 ratio to GH 4 mg daily (Arm A, n=244) or to placebo given daily (Arm B, n=81) in the 12 week induction phase.
The Pre-Specified Efficacy Endpoint for the induction phase was the reduction of VAT at week 12 (GH 4 mg DD vs the placebo DD (daily dose).
Those who were on GH were then randomized in a maintenance phase over the next 24 weeks. Half of the patients received GH 2 mg AD (alternate day dosing) and half received placebo AD. The total study was 36 weeks. 92 patients were randomized to GH 2 mg AD and 93 patients were randomized to placebo. Those patients given placebo received GH 4 mg DD after the first 24 weeks of the study so they received GH 4 mg for 12 weeks until the end of the 36 week study.
Of note, the Pre-Specified Efficacy Endpoint for the Maintenance Phase was: during weeks 12 to 36, less than 50% of patients on GH 2 mg AD regain >50% of VAT that they lost during the induction phase (baseline to week 12).
ENDPOINTS & ELIGIBILITY
Induction and Maintenance Therapy Endpoints (EP):
Primary endpoint: VAT at week 12.
Key secondary EP:
--trunk fat on DEXA
--fasting lipid profile
--maintain reduced VAT
Eligibility Criteria:
Documented HIV infection
Receiving ART
Excess VAT by anthropometric criteria:
--men: WC >88.2 cm and WHR >/=0.95
--women: WC >75.3 and WHR >/= 0.90
Not diabetic or receiving medications for diabetes
Lipid-lowering agents permitted
Glucose tolerance criteria:
--fasting glucose <110 mg/dl; 2-hr glucose <140 mg/dl after 75 g oral glucose load
(VAT=Visceral Adipose Tissue on CT scan at L4-5)
WC=waist circumfrance
WHR=Waist:Hip ratio
BASELINE CHARACTERISTICS (mean)
Of note, 15% of study patients were women. Average CD4 count was 500 at baseline. CT scan VAT was 136 cm2 for the GH group and 135 for the placebo group (p=0.620). There were no differences in baseline characteristics between the patient groups receiving placebo or 4 mg DD GH except for patients receiving GH 93% used NRTIs compared to 100% receiving placebo.
Other baseline measures were:
DXA Trunk Fat: 12.3 kg for placebo group, 11.8 for GH group (p=0.346)
DXA Limb SAT: 6.1 kg for placebo, 5.6 kg for GH group (p=0.289)
Use of PI: 82% in both groups
Use of NNRTI: 46-47% for both groups
BMI: 27.8 kg/m3 for placebo, 27.2 kg/m3 for GH group ((p=0.629)
% Body Fat: 22% for both groups
PRIMARY & SECONDARY ENDPOINTS
Baseline to Week 12
The primary endpoint was a reduction in visceral adipose tissue (VAT). There was a 20% or slightly more decrease in VAT from baseline to week 12 by CT scan. This was significantly different compared to patients receiving placebo who tended to gain visceral fat (average increase of about 4%), p<0.001 for r-hGh vs placebo. There was also a statistically significant difference in SAT as SAT as measured by CT scan decreased on average about 6% for patients receiving GH compared to an increase in SAT by about 2% for patients receiving placebo.
This was paralleled by a statistically significant decrease in trunk fat (DXA scan) compared to placebo. Patients on GH had on average a decrease of about 20% of trunk fat compared to about 1% for patients on placebo. As well, there was a statistically significant decrease in limb SAT (DXA scan) for patients receiving GH compared to patients receiving placebo, although much less than the decrease in trunk fat. Patients receiving GH had a statistically significant decrease in limb SAT of on average about 5% compared to patients receiving placebo who had about 3% increase in limb SAT.
Cholesterol Profiles
Baseline to week 12
Non-HDL (bad cholesterol), a key atherogenic lipoprotein in patients with HIV-infection, had a highly statistically significant decrease from baseline for patients receiving GH compared to patients receiving placebo. The p-vale for the comparison in change between the plcebo vs the GH group was p=0.018. LDL cholesterol decreased in both groups, placebo (about 3%) and GH (about 7%0, and there was no difference statistically between the difference). The p-value for the change in HDL-C for the GH group was <0.0001; as well, this was the same p-value for the change in LDL in the GH group from baseline, and for the increase in HDL-C for the GH group. The p-value for the decrease in LDL from baseline for the placebo group was <0.05.
HDL cholesterol (good cholesterol) went up slightly for patients receiving GH, about 2%, but it was statistically significant compared to patients on placebo (p=0.031).
Grunfeld said patients who were dyslipidemic had the greatest favorable changes, decrease in non-HDL and increase in HDL.
Although Grunfeld did not review this in his presentation (speakers were limited to 7 minutes), the abstract said that at 36 wks, non-HDL-C remained decreased on r-hGH Maintenance therapy.
MAINTENANCE THERAPY
VAT: weeks 12 to 36
By the end of the maintenance phase, patients who had decreases in visceral fat maintained the decrease the end of the 24 week maintenance phase of the study. Although Grunfeld did not mention this in his talk the abstract for the conference said that at the end of 12 weeks the change in VAT for patients on GH was -32.6 cm2 and +0.5 cm2 for patients on placebo. As I report below for patients who nhad a decrease in VAT during weeks 1-12 they had a decrease in VAT of -26.6 cm2 after 24 weeks on the maintenance dose and a total of 36 weeks in the study. So they appeared to maintain an improvement but lost some improvement during the maintenance phase. Again, since the study is only 36 weeks how do we evaluate VAT changes one to two years later using this induction-maintenance approach?
The major efficacy endpoint for maintenance was met. Endpoint for this for success in this study was:
Less than 50% on r-hGH maintenance regained more than 50% of VAT lost during induction. And Grunfeld reported that 40.3% of patients receiving GH regained more than 50% of visceral fat they had lost during the induction phase of the study.
Endpoint for failure in this study was: Failure Rate= % who re-gained >50% of VAT lost during induction. Among those patients on placebo during the induction phase 53.7% regained more than 50% of visceral fat lost.
Grunfeld said the pre-determined study criteria focused on patients who lost VAT during week 1-12, which represented 85% of patients receiving GH. For these patients, who received GH 4 mg DD during induction and GH 2 AD in the maintenance phase the mean change in visceral adipose tissue area was -26.6 cm2, and the change from baseline was statistically significant (p<0.001). Patients who received GH during the first 12 weeks but were switched to placebo for the next 24 weeks had a mean change in visceral fat of -10.0 cm2, and the change from baseline was statistically significant.
When looking at all patients (ITT) from baseline to week 36, patients who received GH in weeks 1-12 and then placebo had a mean decrease in VAT of -7.9 cm2 compared to a decrease of -15.7 cm2 for patients who received GH throughout the study, and these changes were not statistically different from each other.
SAFETY: CD4, Fasting Glucose, IGF-I, Insulin AUC in those receiving induction-maintenance r-hGH 9baselinr to week 36)
Mean insulin AUC (ulU/mL-minute) increased from baseline to week 12 for patients receiving GH during the entire study as well as for patients who received placebo throughout the study. The increase for patients who received GH was greater by week 12 but decreased back to baseline values by week 24 and remained at that level at week 36. There did not appear to be much difference in CD4 counts between patients receiving placebo throughout the study and patients on GH. Mean fasting glucose (mg/dl) increased from baseline to week 12 from about 95 to 110 for patients receiving placebo and GH but then decreased back towards baseline. At week 36 both placebo & GH groups were back to baseline. Through the 36 weeks patients receiving GH had a slightly higher level but the levels were normal after week 2 and for the remainder of the 36 weeks. Remember, patients with glucose abnormalities were screened out of the study. Mean IGF-I (ng/ml) increased for patients receiving GH by week 12 as well as for patients receiving placebo, but the increase on GH was higher. After week 12 IGF-I levels decreased to baseline levels by week 24 and remaining there. But IGF-I remained elevated above baseline at week 24 and at week 36. The difference between placebo and GH was statistically significant (p<0.001).
MOST COMMON ADVERSE EVENTS (>/=10%)*
Week 12
*overall 95% of events were only mild to moderate in severity, this was reported in the slides. All serious adverse events were unlikely related, except for 1 possibly related (migraine).
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