Dose Escalation of Octreotide-LAR as First-Line Therapy in Resistant Acromegaly (HDacro)

This study has been completed.
Sponsor:
Information provided by:
Federico II University
ClinicalTrials.gov Identifier:
NCT00461149
First received: April 13, 2007
Last updated: NA
Last verified: April 2007
History: No changes posted
  Purpose

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.


Condition Intervention Phase
Acromegaly
Drug: Octreotide-LAR
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Beneficial Effect of Dose Escalation of Octreotide-LAR as First-Line Therapy in Patients With Resistant Acromegaly

Resource links provided by NLM:


Further study details as provided by Federico II University:

Primary Outcome Measures:
  • GH and IGF-I control
  • tumor shrinkage

Secondary Outcome Measures:
  • Glucose tolerance.

Estimated Enrollment: 50
Study Start Date: January 1995
Study Completion Date: December 2006
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 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).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • patients with newly diagnosed 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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00461149

Locations
Italy
Department of Molecular and Clinical Endocrinology and Oncology University Federico II of Naples
Naples, Italy, 80131
Sponsors and Collaborators
Federico II University
Investigators
Principal Investigator: Annamaria AL Colao, Prof. University Federico II
  More Information

Publications:
American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 29: S43-48, 2006

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
ClinicalTrials.gov Identifier: NCT00461149     History of Changes
Other Study ID Numbers: NeuroendoUnit-1
Study First Received: April 13, 2007
Last Updated: April 13, 2007
Health Authority: Italy: National Monitoring Centre for Clinical Trials - Ministry of Health
Italy: The Italian Medicines Agency

Keywords provided by Federico II University:
Acromegaly
GH
IGF-I
Pituitary tumors
Octreotide

Additional relevant MeSH terms:
Acromegaly
Bone Diseases
Bone Diseases, Endocrine
Brain Diseases
Central Nervous System Diseases
Endocrine System Diseases
Hyperpituitarism
Hypothalamic Diseases
Musculoskeletal Diseases
Nervous System Diseases
Pituitary Diseases
Octreotide
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Gastrointestinal Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014