Trial Information

Use of Somatostatin Analogue Therapy as Primary Medical Treatment of Acromegaly

Acromegaly is a disorder caused by excessive secretion of growth hormone (GH) usually
associated with a GH-secreting pituitary adenoma composed of somatotrophs or
somatomammotrophs. Acromegaly can also rarely (less than 1% of cases) be caused by
somatotroph hyperplasia, caused by the overproduction of Growth Hormone Releasing Hormone
(GHRH). The condition is rare with an estimated incidence of 200 new cases per year in the
UK based on a population of 50 million.

At the current time, the primary treatment of patients presenting with acromegaly due to a
functional pituitary tumour is surgery (transsphenoidal adenectomy). The aim of surgery is
to cure the condition i.e. return GH levels to normal. The advantage of this treatment
modality for individuals with small tumours is the likelihood of cure with a low probability
of long term defects in other hormonal axes. With larger tumours, however, the chance of
cure is less good, as is the chance of preserving other hormonal axes post-operatively.

The clinical studies that have been performed to date leave one key question unanswered:
would treatment with somatostatin analogue therapy pre-operatively, reduce tumour size
enough to produce a clinically significant improvement in surgical results with the
particular emphasis on lateral extension of tumour. Specifically, would surgical
pre-treatment increase the surgical cure rate? Would surgical pre-treatment with a
somatostatin analogue reduce the need for radiotherapy or the subsequent incidence of other
hormonal axes defects? This study aims to answer these questions.

Patients will be treated for 12 months with Somatuline Autogel which is administered by deep
sub-cutaneous injection. Somatuline Autogel will be the somatostatin analogue used for this
study. It is already routinely used for the treatment of Acromegaly in this region. As the
primary aim of the study is tumour shrinkage and there is some evidence that greater tumour
shrinkage is achieved with higher doses then the maximum tolerated dose will be used.
Injections will be performed every 28 days. The first dose administered will be 60 mg, if
this is tolerated 90 mg will be used for the second injection and again, if the dose is
tolerated then 120 mg will be given for the third and all subsequent injections.

Primary Objective: To test the hypothesis that a twelve month period of primary medical
treatment of acromegaly with Somatuline Autogel will produce clinically significant
reductions in tumour size from Baseline to Month 12 as assessed using MRI.

Secondary Objectives: Within-patient Comparisons of the effect of Primary Treatment with
Somatuline Autogel.

- To assess the change in tumour size at Month 3 and Month 6 compared to baseline
assessed using MRI.

- To assess the change in the GH and IGF-1 levels at all assessment timepoints in
comparison to the baseline visit.

- To assess the change in visual fields at all assessment timepoints in comparison to
baseline, as assessed using a Goldman Visual Fields Analyser.

- To assess the change in patient symptom scores at all assessment timepoints in
comparison to the baseline visit as assessed using numerical rating scales.

- To assess the change in quality of life scores (as assessed using the SF-36
questionnaire) at all assessment timepoints in comparison to the baseline visit.

- To determine the incidence of occurrence of new hormonal axes defects arising
pre-operatively between baseline and Month 12.

- To determine the proportion of patients requiring surgery during the twelve month study
period (i.e. those with tumour progression or intolerable symptoms on medical therapy).

- To evaluation the safety and tolerability of each dose of Somatuline Autogel, as
assessed by:

- the maximum tolerated dose for each patient,

- the incidence of adverse events (including findings on liver and gallbladder
ultrasound),

- changes in concomitant medication,

- the incidence of clinically significant changes in vital signs or ECG,

- the incidence of clinically significant laboratory or physical examination
findings.