Pasireotide LAR maintains inhibition of GH and IGF-1 in patients with acromegaly for up to 25 months: results from the blinded extension phase of a randomized, double-blind, multicenter, Phase III study

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Abstract

Purpose

A large, randomized, double-blind, Phase III core study demonstrated that pasireotide LAR was significantly superior to octreotide LAR at providing GH <2.5 μg/L and normalized IGF-1 after 12 months’ treatment in patients with acromegaly. We report the efficacy and safety of pasireotide LAR and octreotide LAR after up to 26 months’ treatment.

Methods

Patients with GH <2.5 μg/L and IGF-1 ≤1× ULN at month 12, or patients considered to be experiencing clinical benefit, were eligible to continue receiving their randomized therapy in the extension. Efficacy and safety in the pasireotide LAR and octreotide LAR groups were evaluated for up to 26 months.

Results

Overall, 120 patients who completed the core study continued receiving pasireotide LAR (n = 74) or octreotide LAR (n = 46) in the extension. At month 25, biochemical control (GH <2.5 μg/L and normal IGF-1) was achieved by 48.6 % (36/74) and 45.7 % (21/46) of patients in the pasireotide LAR and octreotide LAR arms [60.8 % (45/74) and 52.2 % (24/46) when including patients with IGF-1 < LLN], respectively. In total, 74.7 % of pasireotide LAR and 71.6 % of octreotide LAR patients had tumor volume decrease ≥20 % from baseline to month 26. Most AEs were mild or moderate. Hyperglycemia-related AEs were seen in 62.9 and 25.0 % of pasireotide LAR and octreotide LAR patients, respectively. No new safety signals were observed in the extension compared with the core study.

Conclusions

GH and IGF-1 suppression is maintained for up to 25 months during pasireotide LAR treatment. The safety profile of pasireotide LAR is typical of a somatostatin analogue, except for the frequency and degree of hyperglycemia.

Electronic supplementary material

The online version of this article (doi:10.1007/s11102-014-0585-6) contains supplementary material, which is available to authorized users.

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Most cited references 19

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Systemic complications of acromegaly: epidemiology, pathogenesis, and management.

Annamaria Colao, Diego Ferone, Paolo Marzullo … (2004)

This review focuses on the systemic complications of acromegaly. Mortality in this disease is increased mostly because of cardiovascular and respiratory diseases, although currently neoplastic complications have been questioned as a relevant cause of increased risk of death. Biventricular hypertrophy, occurring independently of hypertension and metabolic complications, is the most frequent cardiac complication. Diastolic and systolic dysfunction develops along with disease duration; and other cardiac disorders, such as arrhythmias, valve disease, hypertension, atherosclerosis, and endothelial dysfunction, are also common in acromegaly. Control of acromegaly by surgery or pharmacotherapy, especially somatostatin analogs, improves cardiovascular morbidity. Respiratory disorders, sleep apnea, and ventilatory dysfunction are also important contributors in increasing mortality and are advantageously benefitted by controlling GH and IGF-I hypersecretion. An increased risk of colonic polyps, which more frequently recur in patients not controlled after treatment, has been reported by several independent investigations, although malignancies in other organs have also been described, but less convincingly than at the gastrointestinal level. Finally, the most important cause of morbidity and functional disability of the disease is arthropathy, which can be reversed at an initial stage, but not if the disease is left untreated for several years.

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Guidelines for acromegaly management: an update.

D Clemmons, Güliz Barkan, Gillian M Vance … (2009)

The Acromegaly Consensus Group reconvened in November 2007 to update guidelines for acromegaly management. The meeting participants comprised 68 pituitary specialists, including neurosurgeons and endocrinologists with extensive experience treating patients with acromegaly. EVIDENCE/CONSENSUS PROCESS: Goals of treatment and the appropriate imaging and biochemical and clinical monitoring of patients with acromegaly were enunciated, based on the available published evidence. The group developed a consensus on the approach to managing acromegaly including appropriate roles for neurosurgery, medical therapy, and radiation therapy in the management of these patients.

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Factors influencing mortality in acromegaly.

I Holdaway, C. Rajasoorya, G Gamble (2004)

Studies of acromegaly have shown a doubling of mortality compared with the general population. With the development of new modalities of treatment, it has become important to identify prognostic factors relating to mortality. Between 1964 and 2000, 208 acromegalic patients were followed for a mean of 13 yr at Auckland Hospital. Treatment was by surgery or radionuclide pituitary implantation, and all except 27 patients received pituitary radiation. Over the duration of the study, 72 patients died at a mean age of 61 +/- 12.8 yr. Those dying were significantly older at diagnosis, had a higher prevalence of hypertension and diabetes, and were more likely to have hypopituitarism. The observed to expected mortality ratio (O/E ratio) fell from 2.6 (95% confidence interval, 1.9-3.6) in those with last follow-up GH greater than 5 microg/liter to 2.5 (1.6-3.8), 1.6 (0.9-3), and 1.1 (0.5-2.1) for those with GH less than 5, less than 2, and less than 1 microg/liter, respectively (P < 0.001). Serum IGF-I, expressed as an SD score, was significantly associated with mortality, with O/E mortality ratios of 3.5 (95% confidence interval, 2.8-4.2) for those with an SD score greater than 2, 1.6 (0.6-2.6) for those with an SD score less than 2 (normal or low levels), and 1.0 (0.1-3) for those with an SD score less than zero. When assessed by multivariate analysis, last serum GH (P < 0.001), age, duration of symptoms before diagnosis (P < 0.03), and hypertension (P < 0.04) were independent predictors of survival. If IGF-I was substituted for GH, then survival was independently related to last IGF-I SD score (P < 0.02), indicating that GH and IGF-I act equivalently as predictors of mortality. These findings indicate that reduction of GH to less than 1 microg/liter or normalization of serum IGF-I reduces mortality to expected levels.

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Author and article information

Contributors

Michael Sheppard: +44 (0)121 414 4538 , m.c.sheppard@bham.ac.uk

Journal

Journal ID (nlm-ta): Pituitary

Journal ID (iso-abbrev): Pituitary

Title: Pituitary

Publisher: Springer US (New York )

ISSN (Print): 1386-341X

ISSN (Electronic): 1573-7403

Publication date (Electronic): 8 August 2014

Publication date PMC-release: 8 August 2014

Publication date (Print): 2015

Volume: 18

Issue: 3

Pages: 385-394

Affiliations

[ ]Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Edgbaston, Birmingham, B15 2TT UK

[ ]Neuroendocrine Unit, Division of Endocrinology and Metabolism, University of São Paulo Medical School, São Paulo, Brazil

[ ]Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY USA

[ ]Service of Endocrinology, Centre Hospitalier de l’Université de Montréal, Notre-Dame Hospital, University of Montreal, Montreal, Canada

[ ]Section of Endocrinology, Department of Internal Medicine, Università Cattolica del Sacro Cuore, Rome, Italy

[ ]Unit of Endocrinology, Department of Internal Medicine, University of Brasilia, Brasilia, Brazil

[ ]Endocrinology Research Center, Moscow, Russia

[ ]Clinical Development, Novartis Pharmaceuticals Corporation, Florham Park, NJ USA

[ ]Clinical Development, Oncology Business Unit, Novartis Pharma AG, Basel, Switzerland

[ ]Novartis Pharmaceuticals Corporation, East Hanover, NJ USA

[ ]Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Naples, Italy

Article

Publisher ID: 585

DOI: 10.1007/s11102-014-0585-6

PMC ID: 4424273

PubMed ID: 25103549

SO-VID: ea9da3a6-f4a0-40e3-9a8f-14aee3c42f10

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

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ScienceOpen disciplines: Medicine

Keywords: pasireotide,octreotide,acromegaly,extension

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ScienceOpen disciplines: Medicine

Keywords: pasireotide, octreotide, acromegaly, extension

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Pasireotide LAR maintains inhibition of GH and IGF-1 in patients with acromegaly for up to 25 months: results from the blinded extension phase of a randomized, double-blind, multicenter, Phase III study

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Abstract

Purpose

Methods

Results

Conclusions

Electronic supplementary material

Related collections

JMIR: Research Protocols

Most cited references 19

Systemic complications of acromegaly: epidemiology, pathogenesis, and management.

Guidelines for acromegaly management: an update.

Factors influencing mortality in acromegaly.

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Contributors

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Cited by 29

Most referenced authors 285