Maintenance of Acromegaly Control in Patients Switching From Injectable Somatostatin Receptor Ligands to Oral Octreotide
Susan L Samson, Lisa B Nachtigall, Maria Fleseriu, Murray B Gordon, Marek Bolanowski, Artak Labadzhyan, Ehud Ur, Mark Molitch, William H Ludlam, Gary Patou, Asi Haviv, Nienke Biermasz, Andrea Giustina, Peter J Trainer, Christian J Strasburger, Laurence Kennedy, Shlomo Melmed, Susan L Samson, Lisa B Nachtigall, Maria Fleseriu, Murray B Gordon, Marek Bolanowski, Artak Labadzhyan, Ehud Ur, Mark Molitch, William H Ludlam, Gary Patou, Asi Haviv, Nienke Biermasz, Andrea Giustina, Peter J Trainer, Christian J Strasburger, Laurence Kennedy, Shlomo Melmed
Abstract
Purpose: The phase 3 CHIASMA OPTIMAL trial (NCT03252353) evaluated efficacy and safety of oral octreotide capsules (OOCs) in patients with acromegaly who previously demonstrated biochemical control while receiving injectable somatostatin receptor ligands (SRLs).
Methods: In this double-blind study, patients (N = 56) stratified by prior SRL dose were randomly assigned 1:1 to OOC or placebo for 36 weeks. The primary end point was maintenance of biochemical control at the end of treatment (mean insulin-like growth factor 1 [IGF-1] ≤ 1.0 × upper limit of normal [ULN]; weeks 34 and 36). Time to loss of IGF-1 response and proportion requiring reversion to injectable SRLs were assessed as broader control measures.
Results: Mean IGF-1 measurements were 0.80 and 0.97 × ULN for OOC and 0.84 and 1.69 × ULN for placebo, at baseline and end of treatment, respectively. Mean growth hormone (GH) changed from 0.66 to 0.60 ng/mL for OOCs and 0.90 to 2.57 ng/mL for placebo. Normalization of IGF-1 levels (≤ 1.0 × ULN) was maintained in 58.2% for OOCs vs 19.4% for placebo (P = .008); GH levels were maintained (< 2.5 ng/mL) in 77.7% for OOC vs 30.4% for placebo (P = .0007). Median time to loss of response (IGF-1 > 1.0 or ≥ 1.3 × ULN definitions) for patients receiving placebo was 16 weeks; for patients receiving OOCs, it was not reached for both definitions during the 36-week trial (P < .0001). Of the patients in the OOC group, 75% completed the trial on oral therapy. The OOC safety profile was consistent with previous SRL experience.
Conclusions: OOCs may be an effective therapy for patients with acromegaly who previously were treated with injectable SRLs.
Keywords: oral octreotide; IGF-1; acromegaly; growth hormone; somatostatin analogues; somatostatin receptor ligands.
© Endocrine Society 2020.
Figures
References
- Colao A, Grasso LFS, Giustina A, et al. Acromegaly. Nat Rev Dis Primers. 2019;5(1):20.
- Giustina A, Barkan A, Beckers A, et al. A consensus on the diagnosis and treatment of acromegaly comorbidities: an update. J Clin Endocrinol Metab. 2019;105(4):e937-e946.
- Melmed S, Bronstein MD, Chanson P, et al. A consensus statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol. 2018;14(9):552-561.
- Devesa J, Almengló C, Devesa P. Multiple effects of growth hormone in the body: is it really the hormone for growth? Clin Med Insights Endocrinol Diabetes. 2016;9:47-71.
- Freda PU. Monitoring of acromegaly: what should be performed when GH and IGF-1 levels are discrepant? Clin Endocrinol (Oxf). 2009;71(2):166-170.
- Melmed S. Pituitary-tumor endocrinopathies. N Engl J Med. 2020;382(10):937-950.
- Gadelha MR, Kasuki L, Lim DST, Fleseriu M. Systemic complications of acromegaly and the impact of the current treatment landscape: an update. Endocr Rev. 2019;40(1):268-332.
- Chen CJ, Ironside N, Pomeraniec IJ, et al. Microsurgical versus endoscopic transsphenoidal resection for acromegaly: a systematic review of outcomes and complications. Acta Neurochir (Wien). 2017;159(11):2193-2207.
- Katznelson L, Laws ER Jr, Melmed S, et al. ; Endocrine Society . Acromegaly: an Endocrine Society Clinical Practice guideline. J Clin Endocrinol Metab. 2014;99(11):3933-3951.
- Strasburger CJ, Karavitaki N, Störmann S, et al. Patient-reported outcomes of parenteral somatostatin analogue injections in 195 patients with acromegaly. Eur J Endocrinol. 2016;174(3):355-362.
- Fleseriu M, Fogelfeld L, Gordon MB, et al. An evaluation of the Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ) in adult patients with acromegaly, including correlations with other patient-reported outcome measures: data from two large multicenter international studies. Pituitary. 2020;23(4):347-358.
- Bevan JS, Newell-Price J, Wass JA, et al. Home administration of lanreotide Autogel by patients with acromegaly, or their partners, is safe and effective. Clin Endocrinol (Oxf). 2008;68(3):343-349.
- Salvatori R, Nachtigall LB, Cook DM, et al. ; SALSA Study Group . Effectiveness of self- or partner-administration of an extended-release aqueous-gel formulation of lanreotide in lanreotide-naïve patients with acromegaly. Pituitary. 2010;13(2):115-122.
- Neggers SJ, Pronin V, Balcere I, et al. ; LEAD Study Group . Lanreotide Autogel 120 mg at extended dosing intervals in patients with acromegaly biochemically controlled with octreotide LAR: the LEAD study. Eur J Endocrinol. 2015;173(3):313-323.
- Geer E, Sisco J, Adelman D, et al. Relationship between responses from acromegaly patients treated with a stable dose of injectable somatostatin analogues in routine clinical practice and their endocrinology health care professional regarding treatment outcomes: preliminary findings. J Endocr Soc. 2019;3(Suppl 1):SUN-LB077.
- Geer E, Sisco J, Adelman D, et al. Patient reported outcome data from acromegaly patients treated with injectable somatostatin analogues in routine clinical practice: preliminary results. J Endocr Soc. 2019;3(Suppl 1):SAT-434.
- Melmed S, Popovic V, Bidlingmaier M, et al. Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial. J Clin Endocrinol Metab. 2015;100(4):1699-1708.
- Tuvia S, Pelled D, Marom K, et al. A novel suspension formulation enhances intestinal absorption of macromolecules via transient and reversible transport mechanisms. Pharm Res. 2014;31(8):2010-2021.
- Tuvia S, Atsmon J, Teichman SL, et al. Oral octreotide absorption in human subjects: comparable pharmacokinetics to parenteral octreotide and effective growth hormone suppression. J Clin Endocrinol Metab. 2012;97(7):2362-2369.
- Chanson P, Borson-Chazot F, Kuhn JM, Blumberg J, Maisonobe P, Delemer B; Lanreotide Acromegaly Study Group . Control of IGF-I levels with titrated dosing of lanreotide Autogel over 48 weeks in patients with acromegaly. Clin Endocrinol (Oxf). 2008;69(2):299-305.
- Lancranjan I, Atkinson AB. Results of a European multicentre study with Sandostatin LAR in acromegalic patients. Sandostatin LAR Group. Pituitary. 1999;1(2):105-114.
- Lancranjan I, Bruns C, Grass P, et al. Sandostatin LAR: a promising therapeutic tool in the management of acromegalic patients. Metabolism. 1996;45(8 Suppl 1):67-71.
- Melmed S, Cook D, Schopohl J, Goth MI, Lam KS, Marek J. Rapid and sustained reduction of serum growth hormone and insulin-like growth factor-1 in patients with acromegaly receiving lanreotide Autogel therapy: a randomized, placebo-controlled, multicenter study with a 52 week open extension. Pituitary. 2010;13(1):18-28.
- Carmichael JD, Bonert VS, Nuño M, Ly D, Melmed S. Acromegaly clinical trial methodology impact on reported biochemical efficacy rates of somatostatin receptor ligand treatments: a meta-analysis. J Clin Endocrinol Metab. 2014;99(5):1825-1833.
- Bidlingmaier M, Friedrich N, Emeny RT, et al. Reference intervals for insulin-like growth factor-1 (IGF-I) from birth to senescence: results from a multicenter study using a new automated chemiluminescence IGF-I immunoassay conforming to recent international recommendations. J Clin Endocrinol Metab. 2014;99(5):1712-1721.
- Manolopoulou J, Alami Y, Petersenn S, et al. Automated 22-kD growth hormone-specific assay without interference from pegvisomant. Clin Chem. 2012;58(10):1446-1456.
- Giustina A, Barkan A, Casanueva FF, et al. Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab. 2000;85(2):526-529.
- Giustina A, Chanson P, Bronstein MD, et al. ; Acromegaly Consensus Group . A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab. 2010;95(7):3141-3148.
- van Esdonk MJ, van Zutphen EJM, Roelfsema F, et al. How are growth hormone and insulin-like growth factor-1 reported as markers for drug effectiveness in clinical acromegaly research? A comprehensive methodologic review. Pituitary. 2018;21(3):310-322.
- AlDallal S. Acromegaly: a challenging condition to diagnose. Int J Gen Med. 2018;11:337-343.
- Katznelson L, Atkinson JL, Cook DM, Ezzat SZ, Hamrahian AH, Miller KK; AACE Acromegaly Task Force . American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Acromegaly–2011 update: executive summary. Endocr Pract. 2011;17(4):636-646.
- Milani D, Carmichael JD, Welkowitz J, et al. Variability and reliability of single serum IGF-I measurements: impact on determining predictability of risk ratios in disease development. J Clin Endocrinol Metab. 2004;89(5):2271-2274.
- Giustina A, Chanson P, Kleinberg D, et al. ; Acromegaly Consensus Group . Expert consensus document: a consensus on the medical treatment of acromegaly. Nat Rev Endocrinol. 2014;10(4):243-248.
- Ramírez C, Vargas G, González B, et al. Discontinuation of octreotide LAR after long term, successful treatment of patients with acromegaly: is it worth trying? Eur J Endocrinol. 2012;166(1):21-26.
- Stewart PM, James RA. The future of somatostatin analogue therapy. Baillieres Best Pract Res Clin Endocrinol Metab. 1999;13(3):409-418.
- Vilar L, Fleseriu M, Naves LA, et al. Can we predict long-term remission after somatostatin analog withdrawal in patients with acromegaly? Results from a multicenter prospective trial. Endocrine. 2014;46(3):577-584.
- Colao A, Bronstein MD, Freda P, et al. ; Pasireotide C2305 Study Group . Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J Clin Endocrinol Metab. 2014;99(3):791-799.
- Baldelli R, Colao A, Razzore P, et al. Two-year follow-up of acromegalic patients treated with slow release lanreotide (30 mg). J Clin Endocrinol Metab. 2000;85(11):4099-4103.
- Chieffo C, Cook D, Xiang Q, Frohman LA. Efficacy and safety of an octreotide implant in the treatment of patients with acromegaly. J Clin Endocrinol Metab. 2013;98(10):4047-4054.
- Sheppard M, Bronstein MD, Freda P, et al. 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. Pituitary. 2015;18(3):385-394.
- Tutuncu Y, Berker D, Isik S, et al. Comparison of octreotide LAR and lanreotide autogel as post-operative medical treatment in acromegaly. Pituitary. 2012;15(3):398-404.
- Fleseriu M, Melmed S, Mangal B, Strasburger CJ, Biermasz NR. Longitudinal assessment of response to treatment with oral octreotide capsules in patients with acromegaly: post-hoc analysis of a phase 3 trial. Poster presented at: European Congress of Endocrinology; May 28–31, 2016, Munich, Germany.
- Biermasz NR, van Dulken H, Roelfsema F. Ten-year follow-up results of transsphenoidal microsurgery in acromegaly. J Clin Endocrinol Metab. 2000;85(12):4596-4602.
- Marquez Y, Tuchman A, Zada G. Surgery and radiosurgery for acromegaly: a review of indications, operative techniques, outcomes, and complications. Int J Endocrinol. 2012;2012:386401.
- Geer EB, Sisco J, Adelman DT, et al. Observed discordance between outcomes reported by acromegaly patients and their treating endocrinology medical provider. Pituitary. 2020;23(2):140-148.
Source: PubMed