Managing Pasireotide-associated Hyperglycaemia in Acromegaly With Ketogenic Diet

Condition(s) studied

Investigational drug(s) / intervention(s)

Ketogenic diet: Subjects randomized to the eucaloric very-low carbohydrate ketogenic diet start with an ad libitum ketogenic diet of which only the amount of carbohydrates is restricted (\<40 g of carbohydrate, approximately 155 g of fat, and approximately 115 g of protein per day). This amount of carbohydrates will lead to ketogenesis. Emphasis is placed on the use of products high in polyunsaturated and monounsaturated fatty acids (diet margarines, oils, fish, nuts), preferably with vegetable and marine sources of protein, in concordance with the national nutritional guidelines and the Mediterranean diet (11). We aim for a eucaloric diet, not restricting energy intake. For women we aim at 2000 kcal/day, for men 2500 kcal/day.

Diabetes Medication: Subjects randomized to the diabetes medication arm will be treated with diabetic drugs according to the current Dutch guidelines, and the recently published consensus stategement for the treatment of pasireotide-induced hyperglycemia (outlined in Fig 2.) (22). Dose escalation or medication switches are made every 2-4 weeks at the discretion of the treating physician aiming at a normal Hba1c of \<44 mmol/L (Hba1c\<6.2%).

Study summary

Rationale: 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.

Objective: 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 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) Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Study participants will have 8 visits to the outpatient clinic over a period of 12-15 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.

Eligibility

Primary outcome measure(s)

• Hemoglobin A1c (HbA1c) level — At baseline, and 3 months, 7 months, 9, 11 and 13 months after initiation of pasireotide treatment.
  Glycaemic control will be assessed by measurement of HbA1c, expressed in mmol/mol. The outcome measure is the HbA1c value at each scheduled study assessment.

Trial sites (1)

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