TY - JOUR
T1 - Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA)
T2 - A randomised, phase 3 trial
AU - on behalf of the Pasireotide C2402 Study Group
AU - Gadelha, Mônica R.
AU - Bronstein, Marcello D.
AU - Brue, Thierry
AU - Coculescu, Mihail
AU - Fleseriu, Maria
AU - Guitelman, Mirtha
AU - Pronin, Vyacheslav
AU - Raverot, Gérald
AU - Shimon, Ilan
AU - Lievre, Kayo Kodama
AU - Fleck, Juergen
AU - Aout, Mounir
AU - Pedroncelli, Alberto M.
AU - Colao, Annamaria
N1 - Funding Information:
MRG has received research grants from Novartis and Pfizer and served as a principal investigator for clinical trials and speaker for Novartis and Ipsen. MDB has received grants and personal fees as a principal investigator for clinical trials, speaker and steering committee member from Ipsen; grants, personal fees, and non-financial support as a principal investigator for clinical trials, speaker and steering committee member, and for the use of drugs on a compassionate basis from Novartis; grants and personal fees as a principal investigator for clinical trials, speaker and advisory board member from Pfizer; and personal fees as an advisory board member from Chiasma. TB has received funding as a co-investigator in clinical trials and advisory board member from Novartis. MC has received non-financial support for the conduct of this clinical trial from Novartis, and personal fees from Novartis. MF has received grants for research support to her institution from Ipsen and personal fees for scientific consulting from Novartis, Ipsen, Pfizer, and Genentech. MG has received honoraria as a principal researcher on this clinical trial from Novartis. GR has received grants and personal fees as a speaker and to his institution for data monitoring from Novartis, and grants and personal fees as a speaker from Ipsen. IS has received grants from Novartis and Pfizer; personal fees from Novartis, Pfizer, Novo Nordisk, Teva, and Neopharm; and non-financial support from Novartis. AC has received grants and honoraria as a speaker and for research in neuroendocrinology from Novartis. KKL, JF, MA, and AMP are employees of Novartis. VP declares no competing interests.
Funding Information:
This study was funded by Novartis Pharma AG. We thank all the investigators who contributed to the study, the study nurses and coordinators, and the patients who participated in the study. We also thank Andrew Jones for medical editorial assistance with this report.
PY - 2014
Y1 - 2014
N2 - Background: Many patients with acromegaly do not achieve biochemical control despite receiving high doses of the first-generation somatostatin analogues octreotide or lanreotide. In the PAOLA trial, we aimed to assess the efficacy and safety of two different doses of the somatostatin analogue pasireotide long-acting release compared with active control (octreotide or lanreotide) in patients with inadequately controlled acromegaly. Methods: In a multicentre, randomised, phase 3 trial, we enrolled eligible patients aged 18 years or older with acromegaly who were inadequately controlled (5-point, 2 h mean growth hormone concentration >2˙5 μg/L and insulin-like growth factor 1 [IGF-1] concentration >1˙3 times the upper normal limit) and had received 30 mg octreotide long-acting repeatable or 120 mg lanreotide (Somatuline Autogel; Ipsen, UK) as monotherapy for 6 months or longer. We randomly assigned patients in a 1:1:1 ratio with an interactive voice-web response system to receive 40 mg pasireotide long-acting release once every 28 days for 24 weeks, 60 mg pasireotide long-acting release once every 28 days for 24 weeks, or continued treatment with octreotide or lanreotide (active control). Patients were stratified according to previous treatment (octreotide or lanreotide) and growth hormone concentrations at screening (2˙5-10 μg/L and >10 μg/L). Patients and study investigators were not masked to study drug assignment but were masked to pasireotide dose allocation. The primary endpoint was number of patients achieving biochemical control, defined as mean growth hormone concentration less than 2˙5 μg/L and normalised IGF-1 concentration. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01137682. Findings: Between Dec 17, 2010, and Aug 6, 2012, 198 patients were enrolled and randomly assigned to pasireotide 40 mg (n=65), pasireotide 60 mg (n=65), or active control (n=68) groups. At 24 weeks, ten (15%) patients in the pasireotide 40 mg group and 13 (20%) patients in the pasireotide 60 mg group achieved biochemical control, compared with no patients in the active control group (absolute difference from control group 15˙4%, 95% CI 7˙6-26˙5, p=0˙0006 for pasireotide 40 mg group, 20˙0%, 11˙1-31˙8, p<0˙0001 for pasireotide 60 mg group). The most common adverse events were hyperglycaemia (21 [33%] for treatment with 40 mg pasireotide, 19 [31%] with 60 mg pasireotide, and nine [14%] with active control), diabetes (13 [21%], 16 [26%], and five [8%]), and diarrhoea (ten [16%], 12 [19%], and three [5%]); most were grade 1 or 2 in severity. Serious adverse events were reported in six (10%) patients in the pasireotide 40 mg group, two (3%) in the pasireotide 60 mg group, and three (5%) in the active control group. Interpretation: Pasireotide provides superior efficacy compared with continued treatment with octreotide or lanreotide, and could become the new standard pituitary-directed treatment in patients with acromegaly who are inadequately controlled using first-generation somatostatin analogues. Funding: Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.
AB - Background: Many patients with acromegaly do not achieve biochemical control despite receiving high doses of the first-generation somatostatin analogues octreotide or lanreotide. In the PAOLA trial, we aimed to assess the efficacy and safety of two different doses of the somatostatin analogue pasireotide long-acting release compared with active control (octreotide or lanreotide) in patients with inadequately controlled acromegaly. Methods: In a multicentre, randomised, phase 3 trial, we enrolled eligible patients aged 18 years or older with acromegaly who were inadequately controlled (5-point, 2 h mean growth hormone concentration >2˙5 μg/L and insulin-like growth factor 1 [IGF-1] concentration >1˙3 times the upper normal limit) and had received 30 mg octreotide long-acting repeatable or 120 mg lanreotide (Somatuline Autogel; Ipsen, UK) as monotherapy for 6 months or longer. We randomly assigned patients in a 1:1:1 ratio with an interactive voice-web response system to receive 40 mg pasireotide long-acting release once every 28 days for 24 weeks, 60 mg pasireotide long-acting release once every 28 days for 24 weeks, or continued treatment with octreotide or lanreotide (active control). Patients were stratified according to previous treatment (octreotide or lanreotide) and growth hormone concentrations at screening (2˙5-10 μg/L and >10 μg/L). Patients and study investigators were not masked to study drug assignment but were masked to pasireotide dose allocation. The primary endpoint was number of patients achieving biochemical control, defined as mean growth hormone concentration less than 2˙5 μg/L and normalised IGF-1 concentration. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01137682. Findings: Between Dec 17, 2010, and Aug 6, 2012, 198 patients were enrolled and randomly assigned to pasireotide 40 mg (n=65), pasireotide 60 mg (n=65), or active control (n=68) groups. At 24 weeks, ten (15%) patients in the pasireotide 40 mg group and 13 (20%) patients in the pasireotide 60 mg group achieved biochemical control, compared with no patients in the active control group (absolute difference from control group 15˙4%, 95% CI 7˙6-26˙5, p=0˙0006 for pasireotide 40 mg group, 20˙0%, 11˙1-31˙8, p<0˙0001 for pasireotide 60 mg group). The most common adverse events were hyperglycaemia (21 [33%] for treatment with 40 mg pasireotide, 19 [31%] with 60 mg pasireotide, and nine [14%] with active control), diabetes (13 [21%], 16 [26%], and five [8%]), and diarrhoea (ten [16%], 12 [19%], and three [5%]); most were grade 1 or 2 in severity. Serious adverse events were reported in six (10%) patients in the pasireotide 40 mg group, two (3%) in the pasireotide 60 mg group, and three (5%) in the active control group. Interpretation: Pasireotide provides superior efficacy compared with continued treatment with octreotide or lanreotide, and could become the new standard pituitary-directed treatment in patients with acromegaly who are inadequately controlled using first-generation somatostatin analogues. Funding: Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.
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U2 - 10.1016/S2213-8587(14)70169-X
DO - 10.1016/S2213-8587(14)70169-X
M3 - Article
C2 - 25260838
AN - SCOPUS:84922576956
VL - 2
SP - 875
EP - 884
JO - The Lancet Diabetes and Endocrinology
JF - The Lancet Diabetes and Endocrinology
SN - 2213-8587
IS - 11
ER -