*Managing pasireotide-associated hyperglycaemia in acromegaly with eucaloric very-low carbohydrate ketogenic diet versus diabetes medication: a multicentre, randomized, open-label proof-of-concept study*

Pasireotide is a second line medical treatment for acromegaly that can add
value for patients with insufficient control of disease on 1st generation SRL,
or 1st generation SRL + pegvisomant. A well-known advserse effect of
pasireotide is development of hyperglycemia in 50-70% of cases. Eucaloric
very-low carbohydrate ketogenic diet (VLCKD) improves hemoglobin a1c (HbA1c)
and fasting plasma glucose (FPG) levels and can show even a long-term effect on
glucose regulation in patients with acromegaly. Moreover, the eucaloric VLCKD
has improved disease control in patients with acromegaly.

The primary objective of this study is to evaluate the change in HbA1c from
start of intervention (baseline of the core study) to post-four months of
ketogenic diet compared to standard of care (core study) in patients developing
pasireotide-induced hyperglycemia.The secondary objectives are to evaluate:
* Differences between eucaloric very-low carbohydrate ketogenic diet and
standard of care (diabetes medication) regarding:
* Proportion of patients with target HbA1c (<48mmol/L / <6.5%) achieved without
glucose lowering drugs (beyond metformine monotherapy) in both arms
* Evaluation and sustainability of glycaemic control (HbA1c) and (dosage of)
anti-diabetic drugs need to reach control
* Biochemical control, and symptom score of acromegaly
* Quality of life
* Proportion of patients on 40 and 60 mg, , Proportion with normal IGF-1,
tolerability and safety of pasireotide
* Exploratory evaluation of all eligible subjects considered for and started
with pasireotide treatment to get a better insight into these complicated
acromegaly patients and their metabolic profile.
* Exploratory evaluation of other timepoints (start of pasireotide) to analyse
course of Hba1c development from start of pasireotide until the end of the core
study

Study type: multicenter combined observational and interventional randomized
controlled study. Allocation: randomized (1:1 ratio). Intervention model:
parallel assignment. Masking: non (open-label). Primary purpose: supportive
care.

We aim to include 30 acromegaly patients with pasireotide-induced
hyperglycaemia, to ensure that 20 patients complete the 4-month intervention.
Subjects will be randomized 1:1 to open-label eucaloric very-low carbohydrate
ketogenic diet (<40 g of carbohydrate) or standard of care (i.e. metformin,
followed by sitagliptin (DPP4-inhibitor), incretin-based therapy with
liraglutide (GLP-1 receptor agonist), and insulin) at the time hyperglycemia is
present. The randomized intervention period is 4 months (core phase of the
study). Randomized subjects who reach the end of the randomized phase can
continue with the open-label extension, and opt to continue their randomized
diet or DM drug treatment or freely choose the other alternative for another 4
months (extension study).

Study participants will have 8 visits to the outpatient clinic over a period of
16 months. This comes down to 480 minutes in total. During these visits,
physical exam/anthropometric measurements will be performed and 2 blood tubes
of 2,5 cc will be collected and 3 QoL questionnaires and one food diary will be
filled out (total visit: 60 minutes). The usual burden for a single patient is
3-outpatient visits over a period of 1 year, which takes about 60 minutes in
total and with the same volume of blood per visit.
Administering a eucaloric ketogenic diet did not produce any significant side
effects for a longer period of time. Therefore, we expect it is safe to use a
ketogenic diet for eight months in our subjects.
Pasireotide LAR (SOM230) has a similar safety profile as currently used
long-acting somatostatin analogs (Lanreotide autogel and Octreotide LAR), with
the exception for hyperglycemia-related events. This hyperglycemia is usually
manageable with proactive monitoring and prompt intervention.
The possible benefits entail treatment with Pasireotide LAR in combination with
a ketogenic diet that leads to an improvement in pasireotide-induced
hyperglycemia and/or better manageable hyperglycemia. We also hope that we are
able to reduce IGF-1 levels in a more sufficient way, improving
acromegaly-related QoL.