Ignite Creation Date:
2024-05-05 @ 5:30 PM
Last Modification Date:
2024-10-26 @ 9:32 AM
Study NCT ID:
NCT00461149
Status:
COMPLETED
Last Update Posted:
2007-04-17
First Post:
2007-04-13
Brief Title:
Dose Escalation of Octreotide-LAR as First-Line Therapy in Resistant Acromegaly
Sponsor:
Federico II University
Organization:
Federico II University
Study Overview
Official Title:
Beneficial Effect of Dose Escalation of Octreotide-LAR as First-Line Therapy in Patients With Resistant Acromegaly
Status:
COMPLETED
Status Verified Date:
2007-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
HDacro
Brief Summary:
Epidemiological data indicate that patients with active acromegaly have reduced life expectancy because of cardiovascular 60 and respiratory diseases 25 mainly 1-10 A post-treatment GH value 5 mUliter equal to 25 μgliter and IGF-I in the normal range for age are recognized as the most predictive survival indices
Since their introduction into clinical use approximately two decades ago somatostatin analogs have been considered a cornerstone of medical therapy for acromegaly After 12 months of treatment with octreotide-LAR control of GH and IGF-I excess is achieved in 54 and 63 of unselected patients 11 The proportion of subjects achieving IGF-I normalization increases significantly with time 12 Significant tumor shrinkage has also been reported in a number of studies 1314 an average 50 tumor decrease is achieved when the drug is used exclusively or before surgery or radiotherapy 14 In 99 unselected newly diagnosed patients after 12 months of treatment with somatostatin analogues we reported control of GH levels in 576 and IGF-I levels in 455 and a greater than 50 tumor shrinkage in 444 15
The dose of LAR in different studies ranged from 10-40 mg every 28 days q28d high doses are generally administered in patients who do not control GH and IGF-I excess with lower doses As reported in the meta-analysis 11 the rate of IGF-I normalization tended to be lower as octreotide-LAR dose was raised 90 in patients treated with 10 mg 61 with 20 mg and 53 with 30 mg However some further benefit by increasing the dose of octreotide-LAR was reported in some studies 16-18
Data on dose escalation of octreotide-LAR given as first-line therapy in newly diagnosed patients with acromegaly are lacking
Since their introduction into clinical use approximately two decades ago somatostatin analogs have been considered a cornerstone of medical therapy for acromegaly After 12 months of treatment with octreotide-LAR control of GH and IGF-I excess is achieved in 54 and 63 of unselected patients 11 The proportion of subjects achieving IGF-I normalization increases significantly with time 12 Significant tumor shrinkage has also been reported in a number of studies 1314 an average 50 tumor decrease is achieved when the drug is used exclusively or before surgery or radiotherapy 14 In 99 unselected newly diagnosed patients after 12 months of treatment with somatostatin analogues we reported control of GH levels in 576 and IGF-I levels in 455 and a greater than 50 tumor shrinkage in 444 15
The dose of LAR in different studies ranged from 10-40 mg every 28 days q28d high doses are generally administered in patients who do not control GH and IGF-I excess with lower doses As reported in the meta-analysis 11 the rate of IGF-I normalization tended to be lower as octreotide-LAR dose was raised 90 in patients treated with 10 mg 61 with 20 mg and 53 with 30 mg However some further benefit by increasing the dose of octreotide-LAR was reported in some studies 16-18
Data on dose escalation of octreotide-LAR given as first-line therapy in newly diagnosed patients with acromegaly are lacking
Detailed Description:
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 15T scanners using T1 weighted gradient recalled-echo in the sagittal and coronal planes as already reported 152122 The acquisitions were repeated before and after the administration of 01 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 sagittalcoronalaxial diametersπ6 According with previous studies 1321 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 mmolL at two consecutive measurements 25 Diabetes mellitus was diagnosed in another eight patients when 2 hours after the oGTT glucose was 11 mmolL 25 Impaired glucose tolerance IGT when glucose level was between 78 mmolL and 11 mmolL 2 hours after the oGTT andor impaired fasting glucose IFG when glucose level was between 56 and 69 mmolL at fasting were diagnosed in 20 patients 25 Glucose tolerance was normal below 56 mmolL 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 mULfasting glucose mmolL 225 HOMA-β 20insulin mUL glucose mmolL-35
Treatment protocol Before starting therapy all patients received an acute test with sc octreotide at a dose of 01 mg in the morning after an overnight fast and at least 2 hrs of bedrest to investigate each patients tolerability to somatostatin analogues 25 Then all patients were treated with octreotide-LAR im 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 25 μgliter and IGF-I levels in the normal range Group A or increased up to 30 mg every 28 days in patients with GH levels 25 μgliter andor IGF-I levels above the normal range After another 9 months of treatment with 30 mgq28d the dose was maintained in 15 patients achieving GH levels 25 μgliter and IGF-I levels in the normal range Group B while it was further increased to 40 mgq28 days if fasting GH levels were still 25 μgliter andor IGF-I levels were above the normal range Group C
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 15T scanners using T1 weighted gradient recalled-echo in the sagittal and coronal planes as already reported 152122 The acquisitions were repeated before and after the administration of 01 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 sagittalcoronalaxial diametersπ6 According with previous studies 1321 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 mmolL at two consecutive measurements 25 Diabetes mellitus was diagnosed in another eight patients when 2 hours after the oGTT glucose was 11 mmolL 25 Impaired glucose tolerance IGT when glucose level was between 78 mmolL and 11 mmolL 2 hours after the oGTT andor impaired fasting glucose IFG when glucose level was between 56 and 69 mmolL at fasting were diagnosed in 20 patients 25 Glucose tolerance was normal below 56 mmolL 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 mULfasting glucose mmolL 225 HOMA-β 20insulin mUL glucose mmolL-35
Treatment protocol Before starting therapy all patients received an acute test with sc octreotide at a dose of 01 mg in the morning after an overnight fast and at least 2 hrs of bedrest to investigate each patients tolerability to somatostatin analogues 25 Then all patients were treated with octreotide-LAR im 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 25 μgliter and IGF-I levels in the normal range Group A or increased up to 30 mg every 28 days in patients with GH levels 25 μgliter andor IGF-I levels above the normal range After another 9 months of treatment with 30 mgq28d the dose was maintained in 15 patients achieving GH levels 25 μgliter and IGF-I levels in the normal range Group B while it was further increased to 40 mgq28 days if fasting GH levels were still 25 μgliter andor IGF-I levels were above the normal range Group C
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None