PasiAcroKeto

Background

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 adverse 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.

Objectives

The primary objective: 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:

• Differences between eucaloric very-low carbohydrate ketogenic diet and standard of care (diabetes medication) regarding:
• Proportion of patients with target HbA1c <48 mmol/L(<6.5%) achieved without glucose lowering drugs (beyond metformin 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 design

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.

Study population

Adult patients with a confirmed diagnosis of acromegaly (for whom surgery is not an option, or for whom surgery has failed) and with inadequately GH and/or IGF-1 control (>0.8xULN) or active disease symptoms with first-generation SRL, or with inadequately GH and/or IGF-1 control (>0.8xULN) or active disease symptoms on second-line medical treatments for acromegaly (pegvisomant monotherapy or combination therapy with first generation SRL and pegvisomant or dopamine agonist, respectively) and with a baseline Hba1c <44 mmol/L(6.2%) – including those pre-treated with metformin in case of HbA1c ≥44 mmol/L(6.2%) and ≤ 64 mmol/L(8.0%) – in whom pasireotide is considered in the clinical setting.

Intervention (if applicable)

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).

Main study parameters/endpoints

Evaluation of effect of treatment with eucaloric very-low carbohydrate ketogenic diet or diabetes medication on glycaemic control of pasireotide:

• Change in HbA1c from start core study to the end of the intervention (ketogenic diet vs standard of care)

If you have suitable participants, please contact Eline te Nijenhuis or one of the principal investigators if you would like to discuss whether your patiënt is suitable for this study.

Documents
CCMO/onderzoeksportaal – NL-005540
Subject information letter and subject consent form

Participating hospitals
Leiden University Medical Center
Erasmus Medical Center

Contact information

Coördinating researcher

Mrs. Drs. L.C. (Eline) te Nijenhuis-Noort
LUMC, Department of endocrinology
P.O. Box 9600, internal address: C7-Q-057
2300 RC Leiden
Email: l.c.te_nijenhuis@lumc.nl

ErasmusMC, Department of internal Medicine/dietetics
P.O. Box 2040, internal address: Na-420
3000 CA Rotterdam
Email: l.tenijenhuis-noort@erasmusmc.nl

Principal Investigators

Prof. Dr. N.R. Biermasz, internist-endocrinologist LUMC

Dr. J. Refardt, internist-endocrinologist ErasmusMC

Dr. S.J.C.M.M. Neggers, internist-endocrinologist ErasmusMC

Dr. K.A.C. Berk, university lecturer and dietitian ErasmusMC