Trial Information

Beneficial Effect of Dose Escalation of Octreotide-LAR as First-Line Therapy in Patients With Resistant Acromegaly

This is an analytical, interventional, 24-month, open, prospective study to investigate the
effect of progressive increase of octreotide-LAR doses in newly diagnosed patients with
acromegaly. Primary outcome measures were GH and IGF-I control and tumor shrinkage;
secondary outcome measure was glucose tolerance.

At diagnosis and every six months, 24-48 hours before changes in treatment doses was
applied, were measured:

1. Serum IGF-I levels twice in a single sample at the time 0 of the GH profile; GH levels
calculated as the mean value of 3-6 samples drawn every 30 min; the average value was
considered for the statistical analysis;

2. Tumor volume on MRI studies performed on clinical 1T and 1.5T scanners, using T1
weighted gradient recalled-echo in the sagittal and coronal planes, as already reported
(15,21,22). The acquisitions were repeated before and after the administration of 0.1
mmoles of gadolinium chelate (diethylene-triamine pentacetate). In all patients MRI was
performed at diagnosis and after 6, 12, and 24 months of treatment. The maximal
sagittal, axial and coronal diameters were measured, then tumor volume was calculated
by the De Chiro and Nelson formula [(volume= sagittal*coronal*axial diameters)*π/6].
According with previous studies (13,21) on post-treatment MRI, tumor shrinkage was
assessed as percent decrease of tumor volume compared with baseline.

3. Glucose tolerance by assaying glucose and insulin levels at fasting. Only at diagnosis
glucose and insulin were also measured every 30 minutes for 2 hours after the oral
administration of 75 g of glucose diluted in 250 ml of saline solution. In four
patients the glucose load was not performed because of overt diabetes (fasting glucose
was above 7 mmol/L at two consecutive measurements) (25). Diabetes mellitus was
diagnosed in another eight patients when 2 hours after the oGTT glucose was >11 mmol/L
(25). Impaired glucose tolerance (IGT) when glucose level was between >7.8 mmol/L and
<11 mmol/L 2 hours after the oGTT and/or impaired fasting glucose (IFG) when glucose
level was between 5.6 and 6.9 mmol/L at fasting were diagnosed in 20 patients (25).
Glucose tolerance was normal (below 5.6 mmol/L at fasting) in 24 patients. To predict
insulin resistance [HOMA-R (%)] and ß-cell function [HOMA-β (%)] was used the HOMA
(homeostatic model assessment) according with Matthews et al. (24). By assuming that
normal-weight healthy subjects aged <35 years have a HOMA-β of 100% and a HOMA-R of 1,
the values for individual patients can be assessed from the insulin and glucose
concentrations by the formulae: HOMA-R = [insulin (mU/L)*fasting glucose (mmol/L)] /
22.5; HOMA-β (%) = [20*insulin (mU/L)] / [glucose (mmol/L)-3.5].

Treatment protocol Before starting therapy, all patients received an acute test with s.c.
octreotide at a dose of 0.1 mg in the morning after an overnight fast and at least 2 hrs of
bedrest, to investigate each patient’s tolerability to somatostatin analogues (25). Then,
all patients were treated with octreotide-LAR i.m. at an initial dose of 20 mg every 28 days
for three months. Subsequently, LAR treatment was maintained at the same dose in patients
achieving GH levels ≤2.5 μg/liter and IGF-I levels in the normal range (Group A), or
increased up to 30 mg every 28 days in patients with GH levels >2.5 μg/liter and/or IGF-I
levels above the normal range. After another 9 months of treatment with 30 mg/q28d, the
dose was maintained in 15 patients achieving GH levels ≤2.5 μg/liter and IGF-I levels in the
normal range (Group B) while it was further increased to 40 mg/q28 days if fasting GH levels
were still >2.5 μg/liter and/or IGF-I levels were above the normal range (Group C).