Neoplasms

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Acromegaly

Pituitary Neoplasms

Growth Hormone-Secreting Pituitary Adenoma

Neoplasms, Glandular and Epithelial

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All Drugs and Chemicals

Gastric Inhibitory Polypeptide

GIP-A

Placebo

Mette H Jensen, MSc

Modulation of the GIP System in Patients With Acromegaly Due to a Pituitary adenoma

Aim: To determine the importance of the GIP system in patients with acromegaly who has paradoxical growth hormone secretion during an oral glucose tolerance test (OGTT) using a GIP antagonist (GIP-A).

Thirty participants (age 18-75 years) with normal kidney and liver parameters and hemoglobin levels will be included in a placebo-controlled cross-over study. The study consists of two study days with concomitant infusions of A) GIP-A or B) saline (placebo).

A paradoxical growth hormone secretion to an OGTT is here defined as an increase in plasma growth hormone levels of ≥30% from baseline based on a mean value of the definitions in the literature.

Regazzo et al. (2017) European Journal of Endocrinology 176, 543-553 Mukai et al. (2018) The Journal of Clinical Endocrinology and Metabolism 104(5), 1637-1644 Hage et al. (2019) The Journal of Clinical Endocrinology and Metabolism 104(5), 1777-1787 Scaroni et al. (2019) J Clin Endocrinol Metab 104(3), 856-862

Modulating the GIP System in Patients With Acromegaly Due to a Pituitary Tumor

Modulating the Glucose-dependent Insulinotropic Polypeptide (GIP) System in Patients With Acromegaly Due to a Pituitary Tumor

Plasma growth hormone area under the curve (AUC)

Rigshospitalet, Denmark

Aarhus University Hospital

Aalborg University Hospital

Odense University Hospital

Herlev and Gentofte Hospital

University of Copenhagen

Industrial PhD student

Pharmaceutical Solutions

Antineoplastic Agents

Hormones

Lanreotide

Gamma knife radiosurgery (Leksell Gamma Knife, Elekta AB, Stockholm, Sweden) is used for intervention. Administration of standard medical therapy using Lanreotide 60 mg concurrently starts with radiosurgery

Without radiosurgery, standard medical therapy (Lanreotide 60Mg Solution for Injection) same with interventional group is applied

Minimum 25 Gy of marginal dose is applied for residual tumor or resection cavity. Depending on the size of tumor, the dose can be varied.

Gamma knife radiosurgery

Lanreotide 60Mg Solution for Injection

Doo-Sik Kong, MD,Ph.D

Doo0Sik Kong, MD,Ph.D

In this study, the investigators hypothesize that upfront gamma knife radiosurgery with drug therapy is superior in the treatment of growth hormone-secreting pituitary tumors after primary surgical treatment compared with the drug therapy alone. This study can provide useful clinical information in the treatment of patients with acromegaly.

Acromegaly is often caused by growth hormone (GH)-secreting pituitary adenoma and causes anatomic changes in the body and various metabolic disorders caused by increased GH and insulin-like growth factor-1 (IGF1). Surgical treatment of pituitary tumors is the preferred standard of care, but only 40-70% of patients can be treated with surgical treatment alone. In many cases, complete resection of the tumor is not possible and the hormone imbalance persists after surgery. After surgical treatment, several additional treatments are needed to prevent hypersecretion of GH and to normalize blood levels of IGF-1.

As first-line treatment after surgical resection, there are typically drug therapy and radiation therapy. The most common used drugs are octreotide and lanreotide, which are growth hormone analogues. However, according to the recent guideline, the endocrine remission rate obtained from post-operative drug therapy is only 17-35%. Although clinical trials are underway for new drugs, the burden of expensive drug costs, recurrence during drug withdrawal, and drug side effects remains major drawbacks. There is a need for therapeutic intervention to reduce the dose and duration of therapy, to prevent tumor recurrence, and to achieve rapid endocrinologic remission.

Stereotactic radiosurgery (SRS), such as gamma knife radiosurgery, has been actively introduced worldwide to control residual pituitary tumors and has been applied to more than 200 cases of intractable acromegaly. The effect of SRS on endocrine remission in patients who did not receive endocrine therapy was confirmed in the literature. In a study of 136 patients who underwent preoperative radiotherapy followed by more than 5 years of follow-up, 65.4% of patients reported endocrine remission. According to the recently published meta-analysis, SRS showed 93-100% tumor growth control and size reduction within 5 to 10 years after surgery. The endocrinologic remission rate was reported to be 40-60% at 5 years.

To date, SRS has been recommended for the treatment of growth hormone - secreting pituitary tumors in cases where surgical removal is not feasible from the beginning or if drug treatment fails after surgical removal. Only the retrospective study of SRS was performed and no prospective study was conducted at all. However, many institutions already prefer preemptive SRS treatment for residual tumor after surgery and have been practiced in many patients. Therefore, prospective clinical trials are needed to establish the basis for upfront SRS and establish the treatment strategy for patients who do not have endocrine remission after surgical treatment of GH secretory pituitary tumor.

The patients with acromegaly due to growth hormone secreting pituitary adenoma who receive primary surgical resection and fail to achieve endocrinologic remission at 3 months after surgical resection are enrolled. They are devided into two groups; One consists of patients underwent upfront stereotactic radiosurgery combinated with standard drug therapy, and another group consists of patients receiving only standard drug therapy.

Technically, the procedure of gamma knife radiosurgery includes fixating stereotactic frame on the head of patients. Therefore, It is not possible to keep masking for participants and other investigators.

Multicenter Evaluation of the Effect of Upfront Radiosurgery on Residual Growth Hormone-secreting Pituitary Adenoma

Multicenter Evaluation of the Effect of Upfront Radiosurgery on Residual Growth Hormone-secreting Pituitary Adenoma From an Endocrinological Point of View (MERGE Study): a Randomized, Phase 3 Trial

Achieving random growth hormone level below 2.5 ug/L and normalization of insulin-growth factor-1 level

daily total dose requirement (multiplied dose per injection by number of injections)

radiation induced and drug related side effects

modified Rankin scale; lower values represent a better outcome as followings: 0 - No symptoms.

1. - No significant disability. Able to carry out all usual activities, despite some symptoms.
2. - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.
3. - Moderate disability. Requires some help, but able to walk unassisted.
4. - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.
5. - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.
6. - Dead.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Modulating the GIP System in Patients With Acromegaly Due to a Pituitary Tumor	NCT03807076	Acromegaly Due ...	GIP-A Placebo	18 Years - 85 Years	University of Copenhagen
Multicenter Evaluation of the Effect of Upfront Radiosurgery on Residual Growth Hormone-secreting Pituitary Adenoma	NCT03439709	Acromegaly Due ...	Gamma knife rad... Lanreotide 60Mg...	18 Years - 70 Years	Samsung Medical Center

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