Glucose Tolerance in Acromegaly: The Influence of GH-excess on Glucose Metabolism and Insulin Resistance

This study has been completed.

Sponsor:

Collaborators:

Pfizer

Ludwig-Maximilians - University of Munich

Information provided by (Responsible Party):

Baptist Gallwitz, University Hospital Tuebingen

ClinicalTrials.gov Identifier:

NCT00663000

First received: April 17, 2008

Last updated: September 13, 2014

Last verified: September 2014

History of Changes

Purpose

Observational, Cross-sectional, longitudinal, multi-center, diagnostic study

Cross-sectional part of the study: To evaluate the influence of acromegaly on glucose tolerance

Longitudinal part of the study: To evaluate the changes of impaired glucose tolerance during standard treatment of acromegaly. Adult patients with established acromegaly

Cross-sectional part of the study: 150 patients

Longitudinal part of the study: 58 patients

Condition
Acromegaly Diabetes Insulin Resistance Impaired Glucose Tolerance


Study Type:	Observational
Study Design:	Observational Model: Case-Only Time Perspective: Cross-Sectional
Official Title:	Observational, Cross-sectional, Longitudinal, Multi-center, Diagnostic Study to Evaluate the Influence of Acromegaly on Glucose Tolerance and to Evaluate the Changes of Impaired Glucose Tolerance During Standard Treatment of Acromegaly.

Resource links provided by NLM:

Genetic and Rare Diseases Information Center resources: Acromegaly

U.S. FDA Resources

Further study details as provided by Baptist Gallwitz, University Hospital Tuebingen:

Primary Outcome Measures:

To evaluate a correlation between IGF-I and glucose tolerance in patients with acromegaly.To evaluate changes of impaired glucose tolerance by different treatment options for acromegaly. [ Time Frame: cross-sectional; 1 year longitudinal ]

Secondary Outcome Measures:

Evaluate a correlation between body weight/BMI, age, family history of diabetes,duration of acromegaly and current medical treatment for acromegaly and glucose tolerance / insulin resistance [ Time Frame: cross-sectional, 1 year longitudinal ]

Biospecimen Retention: Samples Without DNA

serum


Enrollment:	138
Study Start Date:	April 2008
Study Completion Date:	December 2012
Primary Completion Date:	April 2011 (Final data collection date for primary outcome measure)

Groups/Cohorts
acromegalics Acromegaly in adult subjects either controlled or uncontrolled (Diagnosis should be based on OGTT where Acromegaly is defined as a lack of suppression of GH nadir to < 0.5 ng/dL, after oral administration of 75 g of glucose, OGTT and IGF-I levels at least 10 % above the normal value ± 2 SD). Written informed consent

Detailed Description:

TRIAL DESIGN Observational, cross-sectional (patients with normal glucose tolerance). longitudinal (patients with impaired glucose tolerance), multi-center, diagnostic study.

After checking the inclusion and exclusion criteria for the cross-sectional part of the study patients will be included for anamnesis according to Flow Chart Visit -1 (Screening Visit). After checking the glucose tolerance and the insulin resistance by HOMA-IR, the patients will be classified to the group with normal glucose tolerance defined as:

fasting plasma glucose < 110 mg/dl and/or 2-hour plasma glucose after an OGTT < 140 mg/dl or to the group with impaired glucose tolerance defined as:
- fasting plasma glucose ≥ 110 mg/dl (IFG) and/or 2-hour plasma glucose after an OGTT ≥ 140 mg/dl (IGT). For the HOMA-IR the cut off is 1.5.

For patients with normal glucose tolerance the study will end after Screening Visit (V -1).

After patient recruitment of the cross-sectional part is completed an interim analysis is planned to verify that all criteria for the longitudinal study part are achieved. The longitudinal part should start not later than one year after the last patient was examined in the cross-sectional part. For patients with impaired glucose tolerance the inclusion and exclusion criteria for the longitudinal part of the study will be checked (Baseline, Visit 0). If a patient might be included into the longitudinal part of the study a 12 months observation with 4 further visits will follow.

Primary Objective and Endpoint

Cross-sectional part of the study:

To evaluate a correlation between IGF-I and glucose tolerance in acromegalic patients. The inclusion should be performed in 2 stratification groups.

Following two groups are defined:

1/3 of patients with a controlled IGF-I (controlled means IGF-I in age and sex-related normal reference range.
2/3 of patients with an uncontrolled IGF-I (uncontrolled means IGF-I not in age and sex related normal reference range.

Longitudinal part of the study:

To evaluate changes of impaired glucose tolerance by different standard treatment options in acromegaly.

For the analysis of the different treatment options patients will be stratified into 5 treatment groups. Decision will be made according to next planned therapeutic intervention at Screening Visit (V -1):

Surgery
Treatment with somatostatin analoga (with or without combination of dopamine agonists)
Treatment with growth hormone receptor antagonist
Treatment with somatostatin analoga in combination with growth hormone receptor antagonist
Others (e.g. radiation, dopamine agonist monotherapy, no intervention)

Eligibility


Ages Eligible for Study:	18 Years to 75 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

Acromegaly in adult subjects (≥ 18 years) either controlled or uncontrolled (Diagnosis should be based on OGTT where Acromegaly is defined as a lack of suppression of GH nadir to < 0.5 ng/dL, after oral administration of 75 g of glucose, OGTT and IGF-I levels at least 10 % above the normal value ± 2 SD).
Written informed consent

Criteria

Inclusion Criteria:

Acromegaly in adult subjects (≥ 18 years) either controlled or uncontrolled (Diagnosis should be based on OGTT where Acromegaly is defined as a lack of suppression of GH nadir to < 0.5 ng/dL, after oral administration of 75 g of glucose, OGTT and IGF-I levels at least 10 % above the normal value ± 2 SD).
Written informed consent

Exclusion Criteria:

Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis, or persistent ALT, AST, alkaline phosphatase 3 x > upper limit of normal, or total bilirubin 2 x > upper limit of normal.
Renal failure (GFR ≤ 30 ml/min)
Abnormal clinical laboratory values considered by the investigator to be clinically significant and which could affect the interpretation of the study results.
History of malignancy of any organ system, treated or untreated, within the past 3 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin.
Suspected or known drug or alcohol abuse.
Any condition which in the opinion of the investigator makes the patient unsuitable for inclusion.
Participation in any other clinical trial with an investigational new drug.
Patients on longterm, continuous (more than 2 weeks/year) systemic therapy with glucocorticosteroids with exception of a substitution of a pituitary lack of ACTH/cortisol (e.g. patients with panhypopituitarism).
Instable heart insufficiency for example cardiomyopathy, congestive heart failure (NYHA class III or IV), unstable angina, sustained ventricular tachycardia, ventricular fibrillation).
Type I diabetes according to the guidelines of the European Diabetes Society or obvious other manifestations of other forms of diabetes (e.g. steroid diabetes).

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00663000

Locations


Germany
Dept. Internal Medicine, Div. Endocrinology, Charité Campus Mitte, University of Berlin
Berlin, Germany, 10117
Endokrinologikum Dresden
Dresden, Germany, 01069
Dept. Internal Medicine, Div. Endocrinology, University of Magdeburg
Magdeburg, Germany, 39120
Dept. Internal Medicine, Endocrinology, Max Planck Institute for Neuroscience and Psychiatry
München, Germany, 80804
Internistische/Endokrinologische Praxis Dr. Droste
Oldenburg, Germany, 26122
Dept. Medicine IV
Tuebingen, Germany, 72076

Sponsors and Collaborators

University Hospital Tuebingen

Pfizer

Ludwig-Maximilians - University of Munich

Investigators


Principal Investigator:	Baptist Gallwitz, MD, Prof.	Dept. Medicine IV. Tuebingen University

More Information

Publications:

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Abs R, Verhelst J, Maiter D, Van Acker K, Nobels F, Coolens JL, Mahler C, Beckers A. Cabergoline in the treatment of acromegaly: a study in 64 patients. J Clin Endocrinol Metab. 1998 Feb;83(2):374-8.

Ahmed S, Elsheikh M, Stratton IM, Page RC, Adams CB, Wass JA. Outcome of transphenoidal surgery for acromegaly and its relationship to surgical experience. Clin Endocrinol (Oxf). 1999 May;50(5):561-7.

Barkan AL, Halasz I, Dornfeld KJ, Jaffe CA, Friberg RD, Chandler WF, Sandler HM. Pituitary irradiation is ineffective in normalizing plasma insulin-like growth factor I in patients with acromegaly. J Clin Endocrinol Metab. 1997 Oct;82(10):3187-91.

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.

Biermasz NR, van Dulken H, Roelfsema F. Long-term follow-up results of postoperative radiotherapy in 36 patients with acromegaly. J Clin Endocrinol Metab. 2000 Jul;85(7):2476-82.

Caron P, Tabarin A, Cogne M, Chanson P, Jaquet P. Variable growth hormone profiles following withdrawal of long-term 30mg slow-release lanreotide treatment in acromegalic patients: clinical implications. Eur J Endocrinol. 2000 Jun;142(6):565-71.

Clemmons DR. Roles of insulin-like growth factor-I and growth hormone in mediating insulin resistance in acromegaly. Pituitary. 2002;5(3):181-3. Review.

Colao A, Pivonello R, Auriemma RS, De Martino MC, Bidlingmaier M, Briganti F, Tortora F, Burman P, Kourides IA, Strasburger CJ, Lombardi G. Efficacy of 12-month treatment with the GH receptor antagonist pegvisomant in patients with acromegaly resistant to long-term, high-dose somatostatin analog treatment: effect on IGF-I levels, tumor mass, hypertension and glucose tolerance. Eur J Endocrinol. 2006 Mar;154(3):467-77.

Davies PH, Stewart SE, Lancranjan L, Sheppard MC, Stewart PM. Long-term therapy with long-acting octreotide (Sandostatin-LAR) for the management of acromegaly. Clin Endocrinol (Oxf). 1998 Mar;48(3):311-6. Erratum in: Clin Endocrinol (Oxf) 1998 May;48(5):673.

Eastman RC, Gorden P, Glatstein E, Roth J. Radiation therapy of acromegaly. Endocrinol Metab Clin North Am. 1992 Sep;21(3):693-712. Review.

Elmlinger MW, Kühnel W, Weber MM, Ranke MB. Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3). Clin Chem Lab Med. 2004;42(6):654-64.

Ezzat S, Forster MJ, Berchtold P, Redelmeier DA, Boerlin V, Harris AG. Acromegaly. Clinical and biochemical features in 500 patients. Medicine (Baltimore). 1994 Sep;73(5):233-40.

Fahlbusch R, Honegger J, Buchfelder M. Evidence supporting surgery as treatment of choice for acromegaly. J Endocrinol. 1997 Oct;155 Suppl 1:S53-5.

Feenstra J, de Herder WW, ten Have SM, van den Beld AW, Feelders RA, Janssen JA, van der Lely AJ. Combined therapy with somatostatin analogues and weekly pegvisomant in active acromegaly. Lancet. 2005 May 7-13;365(9471):1644-6. Erratum in: Lancet. 2005 May;365(9471):1620.

Feenstra J, van Aken MO, de Herder WW, Feelders RA, van der Lely AJ. Drug-induced hepatitis in an acromegalic patient during combined treatment with pegvisomant and octreotide long-acting repeatable attributed to the use of pegvisomant. Eur J Endocrinol. 2006 Jun;154(6):805-6.

Fløgstad AK, Halse J, Bakke S, Lancranjan I, Marbach P, Bruns C, Jervell J. Sandostatin LAR in acromegalic patients: long-term treatment. J Clin Endocrinol Metab. 1997 Jan;82(1):23-8.

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. Review.

Hansen I, Tsalikian E, Beaufrere B, Gerich J, Haymond M, Rizza R. Insulin resistance in acromegaly: defects in both hepatic and extrahepatic insulin action. Am J Physiol. 1986 Mar;250(3 Pt 1):E269-73.

Hunter SJ, Shaw JA, Lee KO, Wood PJ, Atkinson AB, Bevan JS. Comparison of monthly intramuscular injections of Sandostatin LAR with multiple subcutaneous injections of octreotide in the treatment of acromegaly; effects on growth hormone and other markers of growth hormone secretion. Clin Endocrinol (Oxf). 1999 Feb;50(2):245-51.

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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.

Osman IA, James RA, Chatterjee S, Mathias D, Kendall-Taylor P. Factors determining the long-term outcome of surgery for acromegaly. QJM. 1994 Oct;87(10):617-23.

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.

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van der Lely AJ, de Herder WW, Lamberts SW. A risk-benefit assessment of octreotide in the treatment of acromegaly. Drug Saf. 1997 Nov;17(5):317-24. Review.

van der Lely AJ, Muller A, Janssen JA, Davis RJ, Zib KA, Scarlett JA, Lamberts SW. Control of tumor size and disease activity during cotreatment with octreotide and the growth hormone receptor antagonist pegvisomant in an acromegalic patient. J Clin Endocrinol Metab. 2001 Feb;86(2):478-81.

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Wasada T, Aoki K, Sato A, Katsumori K, Muto K, Tomonaga O, Yokoyama H, Iwasaki N, Babazono T, Takahashi C, Iwamoto Y, Omori Y, Hizuka N. Assessment of insulin resistance in acromegaly associated with diabetes mellitus before and after transsphenoidal adenomectomy. Endocr J. 1997 Aug;44(4):617-20.


Responsible Party:	Baptist Gallwitz, Prof. Dr. med., University Hospital Tuebingen
ClinicalTrials.gov Identifier:	NCT00663000 History of Changes
Other Study ID Numbers:	T-7538
Study First Received:	April 17, 2008
Last Updated:	September 13, 2014

Keywords provided by Baptist Gallwitz, University Hospital Tuebingen:


acromegaly diabetes insulin resistance impaired glucose tolerance

Additional relevant MeSH terms:


Acromegaly Insulin Resistance Glucose Intolerance Hyperinsulinism Glucose Metabolism Disorders Metabolic Diseases Bone Diseases, Endocrine Bone Diseases Musculoskeletal Diseases	Hyperpituitarism Pituitary Diseases Hypothalamic Diseases Brain Diseases Central Nervous System Diseases Nervous System Diseases Endocrine System Diseases Hyperglycemia

ClinicalTrials.gov processed this record on July 26, 2017

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