Dose Escalation of Octreotide-LAR as First-Line Therapy in Resistant Acromegaly
NCT ID: NCT00461149
Last Updated: 2007-04-17
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE4
Total Enrollment
50 participants
Study Classification
INTERVENTIONAL
Study Start Date
1995-01-31
Study Completion Date
2006-12-31
Brief Summary
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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 mU/liter (equal to \<2.5 μg/liter) 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 (13,14): 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 57.6% and IGF-I levels in 45.5% and a greater than 50% tumor shrinkage in 44.4% (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 (13,14): 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 57.6% and IGF-I levels in 45.5% and a greater than 50% tumor shrinkage in 44.4% (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
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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).
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).
Conditions
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Acromegaly
Study Design
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Allocation Method
NON_RANDOMIZED
Intervention Model
SINGLE_GROUP
Primary Study Purpose
TREATMENT
Blinding Strategy
NONE
Interventions
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Octreotide-LAR
Intervention Type
DRUG
Eligibility Criteria
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Inclusion Criteria
* patients with newly diagnosed acromegaly
* age above 18 years
* no previous treatments for acromegaly
* age above 18 years
* no previous treatments for acromegaly
Exclusion Criteria
* primary surgery
* concomitant hyperprolactinemia if requiring combined treatment with dopamine-agonist
* primary treatment with lanreotide
* treatment duration less than 24 months
* concomitant hyperprolactinemia if requiring combined treatment with dopamine-agonist
* primary treatment with lanreotide
* treatment duration less than 24 months
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Federico II University
OTHER
Sponsor Role
lead
Principal Investigators
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Annamaria AL Colao, Prof.
Role: PRINCIPAL_INVESTIGATOR
University Federico II
Locations
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Department of Molecular and Clinical Endocrinology and Oncology University Federico II of Naples
Naples, , Italy
Site Status
Countries
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Italy
References
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Wright AD, Hill DM, Lowy C, Fraser TR. Mortality in acromegaly. Q J Med. 1970 Jan;39(153):1-16. No abstract available.
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RESULT
Bates AS, Van't Hoff W, Jones JM, Clayton RN. An audit of outcome of treatment in acromegaly. Q J Med. 1993 May;86(5):293-9.
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Etxabe J, Gaztambide S, Latorre P, Vazquez JA. Acromegaly: an epidemiological study. J Endocrinol Invest. 1993 Mar;16(3):181-7. doi: 10.1007/BF03344942.
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Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ, Ibbertson HK. Determinants of clinical outcome and survival in acromegaly. Clin Endocrinol (Oxf). 1994 Jul;41(1):95-102. doi: 10.1111/j.1365-2265.1994.tb03789.x.
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Abosch A, Tyrrell JB, Lamborn KR, Hannegan LT, Applebury CB, Wilson CB. Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results. J Clin Endocrinol Metab. 1998 Oct;83(10):3411-8. doi: 10.1210/jcem.83.10.5111.
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Swearingen B, Barker FG 2nd, Katznelson L, Biller BM, Grinspoon S, Klibanski A, Moayeri N, Black PM, Zervas NT. Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab. 1998 Oct;83(10):3419-26. doi: 10.1210/jcem.83.10.5222.
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RESULT
Orme SM, McNally RJ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab. 1998 Aug;83(8):2730-4. doi: 10.1210/jcem.83.8.5007.
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Ayuk J, Clayton RN, Holder G, Sheppard MC, Stewart PM, Bates AS. Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly. J Clin Endocrinol Metab. 2004 Apr;89(4):1613-7. doi: 10.1210/jc.2003-031584.
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RESULT
Holdaway IM, Rajasoorya RC, Gamble GD. Factors influencing mortality in acromegaly. J Clin Endocrinol Metab. 2004 Feb;89(2):667-74. doi: 10.1210/jc.2003-031199.
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RESULT
Kauppinen-Makelin R, Sane T, Reunanen A, Valimaki MJ, Niskanen L, Markkanen H, Loyttyniemi E, Ebeling T, Jaatinen P, Laine H, Nuutila P, Salmela P, Salmi J, Stenman UH, Viikari J, Voutilainen E. A nationwide survey of mortality in acromegaly. J Clin Endocrinol Metab. 2005 Jul;90(7):4081-6. doi: 10.1210/jc.2004-1381. Epub 2005 May 10.
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RESULT
Freda PU, Katznelson L, van der Lely AJ, Reyes CM, Zhao S, Rabinowitz D. Long-acting somatostatin analog therapy of acromegaly: a meta-analysis. J Clin Endocrinol Metab. 2005 Aug;90(8):4465-73. doi: 10.1210/jc.2005-0260. Epub 2005 May 10.
Reference Type
RESULT
Cozzi R, Montini M, Attanasio R, Albizzi M, Lasio G, Lodrini S, Doneda P, Cortesi L, Pagani G. Primary treatment of acromegaly with octreotide LAR: a long-term (up to nine years) prospective study of its efficacy in the control of disease activity and tumor shrinkage. J Clin Endocrinol Metab. 2006 Apr;91(4):1397-403. doi: 10.1210/jc.2005-2347. Epub 2006 Jan 31.
Reference Type
RESULT
Bevan JS. Clinical review: The antitumoral effects of somatostatin analog therapy in acromegaly. J Clin Endocrinol Metab. 2005 Mar;90(3):1856-63. doi: 10.1210/jc.2004-1093. Epub 2004 Dec 21.
Reference Type
RESULT
Melmed S, Sternberg R, Cook D, Klibanski A, Chanson P, Bonert V, Vance ML, Rhew D, Kleinberg D, Barkan A. A critical analysis of pituitary tumor shrinkage during primary medical therapy in acromegaly. J Clin Endocrinol Metab. 2005 Jul;90(7):4405-10. doi: 10.1210/jc.2004-2466. Epub 2005 Apr 12.
Reference Type
RESULT
Colao A, Pivonello R, Auriemma RS, Briganti F, Galdiero M, Tortora F, Caranci F, Cirillo S, Lombardi G. Predictors of tumor shrinkage after primary therapy with somatostatin analogs in acromegaly: a prospective study in 99 patients. J Clin Endocrinol Metab. 2006 Jun;91(6):2112-8. doi: 10.1210/jc.2005-2110. Epub 2006 Mar 14.
Reference Type
RESULT
Turner HE, Vadivale A, Keenan J, Wass JA. A comparison of lanreotide and octreotide LAR for treatment of acromegaly. Clin Endocrinol (Oxf). 1999 Sep;51(3):275-80. doi: 10.1046/j.1365-2265.1999.00853.x.
Reference Type
RESULT
Cozzi R, Attanasio R, Montini M, Pagani G, Lasio G, Lodrini S, Barausse M, Albizzi M, Dallabonzana D, Pedroncelli AM. Four-year treatment with octreotide-long-acting repeatable in 110 acromegalic patients: predictive value of short-term results? J Clin Endocrinol Metab. 2003 Jul;88(7):3090-8. doi: 10.1210/jc.2003-030110.
Reference Type
RESULT
Colao A, Ferone D, Marzullo P, Cappabianca P, Cirillo S, Boerlin V, Lancranjan I, Lombardi G. Long-term effects of depot long-acting somatostatin analog octreotide on hormone levels and tumor mass in acromegaly. J Clin Endocrinol Metab. 2001 Jun;86(6):2779-86. doi: 10.1210/jcem.86.6.7556.
Reference Type
RESULT
Colao A, Lombardi G. Growth-hormone and prolactin excess. Lancet. 1998 Oct 31;352(9138):1455-61. doi: 10.1016/S0140-6736(98)03356-X.
Reference Type
RESULT
Giustina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Ho K, Veldhuis J, Wass J, Von Werder K, Melmed S. Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab. 2000 Feb;85(2):526-9. doi: 10.1210/jcem.85.2.6363.
Reference Type
RESULT
Colao A, Marzullo P, Ferone D, Spinelli L, Cuocolo A, Bonaduce D, Salvatore M, Boerlin V, Lancranjan I, Lombardi G. Cardiovascular effects of depot long-acting somatostatin analog Sandostatin LAR in acromegaly. J Clin Endocrinol Metab. 2000 Sep;85(9):3132-40. doi: 10.1210/jcem.85.9.6782.
Reference Type
RESULT
Colao A, Pivonello R, Rosato F, Tita P, De Menis E, Barreca A, Ferrara R, Mainini F, Arosio M, Lombardi G. First-line octreotide-LAR therapy induces tumour shrinkage and controls hormone excess in patients with acromegaly: results from an open, prospective, multicentre trial. Clin Endocrinol (Oxf). 2006 Mar;64(3):342-51. doi: 10.1111/j.1365-2265.2006.02467.x.
Reference Type
RESULT
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2006 Jan;29 Suppl 1:S43-8. No abstract available.
Reference Type
RESULT
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985 Jul;28(7):412-9. doi: 10.1007/BF00280883.
Reference Type
RESULT
Colao A, Pivonello R, Auriemma RS, Galdiero M, Savastano S, Lombardi G. Beneficial effect of dose escalation of octreotide-LAR as first-line therapy in patients with acromegaly. Eur J Endocrinol. 2007 Nov;157(5):579-87. doi: 10.1530/EJE-07-0383.
Reference Type
DERIVED
Other Identifiers
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NeuroendoUnit-1
Identifier Type: -
Identifier Source: org_study_id