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

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Brief Title

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

Official Title

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

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 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.
    

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).
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

GH and IGF-I control

Secondary Outcome

 Glucose tolerance.

Condition

Acromegaly

Intervention

Octreotide-LAR


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

50

Start Date

January 1995

Completion Date

December 2006


Eligibility 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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Annamaria AL Colao, Prof., , 

Location Countries

Italy

Location Countries

Italy

Administrative Informations


NCT ID

NCT00461149

Organization ID

NeuroendoUnit-1



Study Sponsor

Federico II University


Study Sponsor

Annamaria AL Colao, Prof., Principal Investigator, University Federico II


Verification Date

April 2007