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

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)

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).