TY - JOUR
T1 - Maintenance of response to oral octreotide compared with injectable somatostatin receptor ligands in patients with acromegaly
T2 - a phase 3, multicentre, randomised controlled trial
AU - Fleseriu, Maria
AU - Dreval, Alexander
AU - Bondar, Irina
AU - Vagapova, Gulnar
AU - Macut, Djuro
AU - Pokramovich, Yulia G.
AU - Molitch, Mark E.
AU - Leonova, Nina
AU - Raverot, Gerald
AU - Grineva, Elena
AU - Poteshkin, Yury E.
AU - Gilgun-Sherki, Yossi
AU - Ludlam, William H.
AU - Patou, Gary
AU - Haviv, Asi
AU - Gordon, Murray B.
AU - Biermasz, Nienke R.
AU - Melmed, Shlomo
AU - Strasburger, Christian J.
N1 - Funding Information:
MF received a research grant to Oregon Health and Science University as principal investigator for Crinetics, Chiasma, Ionis, Novartis, and Recordati and served as an occasional scientific consultant or advisory board member for Crinetics, Chiasma, Ionis, Ipsen, Novartis, Pfizer, and Recordati. AD, IB, NL, YEP, and YGP received funding to the institution as an investigator in this study from Chiasma. GV has received funding as a coinvestigator from Chiasma and Novo Nordisk; as a principal investigator from Novo Nordisk and Camurus; and has received speaker honoraria from Novo Nordisk, Eli Lilly, Servier, Pfizer, Ipsen, Novartis, AstraZeneca, and Boehringer Ingelheim. DM received funding to institution and team as a principal investigator for a clinical study from Chiasma. MEM received research grants to institution from Chiasma, Novartis, Ionis, and Crinetics; and received consulting fees from Chiasma and Novartis. GR received funding as a research investigator for Chiasma, Pfizer, and Novartis; speaker honoraria from Ipsen, Novartis, Pfizer, and Recordati Rare Diseases; consulting fees from Pfizer, Recordati Rare Diseases, and Ipsen; and has served as an advisory board member for Pfizer and Recordati Rare Diseases. EG received speaker honoraria and support for attending meetings from Pfizer and Ipsen, and payment for expert testimony from Pfizer. YG-S, GP, and AH are employees of Chiasma. WHL was a previous employee of Chiasma and is a current employee of Recordati Rare Diseases. MBG received research support from Chiasma, Corcept, Crinetics, Ipsen, Novartis, Opico, Pfizer, Strongbridge, and Teva; support for attending meetings or travel from Chiasma; and consulting fees from Novo Nordisk. NRB declares no competing interests. SM has received consulting fees for Ionis, Mediatech, Crinetics, Rami, and Chiasma; grant funding from Pfizer; funding as a research investigator for Ipsen; and has served as an advisory board member for Chiasma. CJS has received consultancy fees and speaker honoraria from Chiasma, Pfizer, Ipsen, Sandoz-Hexal, Novo-Nordisk, and Crinetics, and served as an advisory board member for Chiasma.
Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2022/2
Y1 - 2022/2
N2 - Background: Despite biochemically responding to injectable somatostatin receptor ligands (iSRLs), many patients with acromegaly experience treatment burdens. We aimed to assess maintenance of biochemical response and symptomatic control with oral octreotide capsules versus iSRLs in patients with acromegaly who previously tolerated and responded to both. Methods: This global, open-label, randomised controlled phase 3 trial was done in 29 clinical sites in Austria, France, Germany, Hungary, Italy, Lithuania, Russia, Serbia, Spain, and the USA. Eligible patients were adults aged 18–75 years with acromegaly who were receiving iSRLs (long-acting octreotide or lanreotide autogel) for at least 6 months before baseline with a stable dose for at least 4 months, and were deemed to be biochemically responding (insulin-like growth factor I [IGF-I] <1·3 × upper limit of normal [ULN] and mean integrated growth hormone <2·5 ng/mL). In the 26-week run-in phase, all patients received oral octreotide (40 mg a day, optional titration to 60 or 80 mg a day). Eligibility for the randomised treatment phase was completion of the run-in phase as a biochemical responder (IGF-I <1·3 × ULN and mean integrated growth hormone <2·5 ng/mL at week 24) and investigator assessment of acromegaly being adequately controlled. Patients were randomly assigned (3:2) to oral octreotide capsules or iSRL at the same dose and interval as before enrolment. Randomisation and drug dispensing were conducted through a qualified randomisation service provider (eg, interactive web or voice response system). The primary endpoint was a non-inferiority assessment (margin −20 percentage points) of proportion of participants maintaining biochemical response throughout the randomised treatment phase (IGF-I <1·3 × ULN using time-weighted average; assessed by comparing the lower bound of the 2-sided 95% CI for the difference in biochemical response between groups). IGF-I was assessed once a month during the run-in and randomised treatment phases (single sample). Efficacy and safety assessments were performed on the randomised population. This trial is registered with ClinicalTrials.gov, NCT02685709. Findings: Between Feb 11, 2016, and Aug 20, 2020, 218 patients were assessed for eligibility. 72 patients were excluded, and 146 participants were enrolled into the run-in phase. 116 patients completed the run-in phase and 30 participants discontinued treatment. 92 participants were randomly assigned to oral octreotide (n=55) or iSRL (n=37). 50 (91%) of 55 participants who received oral octreotide (95% CI 44–53) and 37 (100%) of 37 participants who received iSRLs (34–37) maintained biochemical response. The lower bound of the 2-sided 95% CI for the adjusted difference in proportions between the two treatment groups achieved the prespecified non-inferiority criterion of −20% (95% CI −19·9 to 0·5). 19 (35%) of 55 participants in the oral octreotide group and 15 (41%) of 37 participants in the iSRL group had treatment-related adverse events; the most common of which in both groups were gastrointestinal. Interpretation: Oral octreotide was non-inferior to iSRL treatment, and might be a favourable alternative to iSRLs for many patients with acromegaly. Funding: Chiasma. Translation: For the Russian translation of the abstract see Supplementary Materials section.
AB - Background: Despite biochemically responding to injectable somatostatin receptor ligands (iSRLs), many patients with acromegaly experience treatment burdens. We aimed to assess maintenance of biochemical response and symptomatic control with oral octreotide capsules versus iSRLs in patients with acromegaly who previously tolerated and responded to both. Methods: This global, open-label, randomised controlled phase 3 trial was done in 29 clinical sites in Austria, France, Germany, Hungary, Italy, Lithuania, Russia, Serbia, Spain, and the USA. Eligible patients were adults aged 18–75 years with acromegaly who were receiving iSRLs (long-acting octreotide or lanreotide autogel) for at least 6 months before baseline with a stable dose for at least 4 months, and were deemed to be biochemically responding (insulin-like growth factor I [IGF-I] <1·3 × upper limit of normal [ULN] and mean integrated growth hormone <2·5 ng/mL). In the 26-week run-in phase, all patients received oral octreotide (40 mg a day, optional titration to 60 or 80 mg a day). Eligibility for the randomised treatment phase was completion of the run-in phase as a biochemical responder (IGF-I <1·3 × ULN and mean integrated growth hormone <2·5 ng/mL at week 24) and investigator assessment of acromegaly being adequately controlled. Patients were randomly assigned (3:2) to oral octreotide capsules or iSRL at the same dose and interval as before enrolment. Randomisation and drug dispensing were conducted through a qualified randomisation service provider (eg, interactive web or voice response system). The primary endpoint was a non-inferiority assessment (margin −20 percentage points) of proportion of participants maintaining biochemical response throughout the randomised treatment phase (IGF-I <1·3 × ULN using time-weighted average; assessed by comparing the lower bound of the 2-sided 95% CI for the difference in biochemical response between groups). IGF-I was assessed once a month during the run-in and randomised treatment phases (single sample). Efficacy and safety assessments were performed on the randomised population. This trial is registered with ClinicalTrials.gov, NCT02685709. Findings: Between Feb 11, 2016, and Aug 20, 2020, 218 patients were assessed for eligibility. 72 patients were excluded, and 146 participants were enrolled into the run-in phase. 116 patients completed the run-in phase and 30 participants discontinued treatment. 92 participants were randomly assigned to oral octreotide (n=55) or iSRL (n=37). 50 (91%) of 55 participants who received oral octreotide (95% CI 44–53) and 37 (100%) of 37 participants who received iSRLs (34–37) maintained biochemical response. The lower bound of the 2-sided 95% CI for the adjusted difference in proportions between the two treatment groups achieved the prespecified non-inferiority criterion of −20% (95% CI −19·9 to 0·5). 19 (35%) of 55 participants in the oral octreotide group and 15 (41%) of 37 participants in the iSRL group had treatment-related adverse events; the most common of which in both groups were gastrointestinal. Interpretation: Oral octreotide was non-inferior to iSRL treatment, and might be a favourable alternative to iSRLs for many patients with acromegaly. Funding: Chiasma. Translation: For the Russian translation of the abstract see Supplementary Materials section.
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U2 - 10.1016/S2213-8587(21)00296-5
DO - 10.1016/S2213-8587(21)00296-5
M3 - Article
C2 - 34953531
AN - SCOPUS:85123362039
VL - 10
SP - 102
EP - 111
JO - The Lancet Diabetes and Endocrinology
JF - The Lancet Diabetes and Endocrinology
SN - 2213-8587
IS - 2
ER -