title: Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.
authors.affiliation: Endocrine Unit, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: mgadelha@hucff.ufrj.br.
authors.forename: Mônica R
authors.initials: MR
authors.lastname: Gadelha
authors.affiliation: Neuroendocrine Unit, Division of Endocrinology and Metabolism, University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: Marcello D
authors.initials: MD
authors.lastname: Bronstein
authors.affiliation: Department of Endocrinology, Hôpital de la Timone, Aix-Marseille University, Centre National de la Recherche Scientifique, and Assistance Publique-Hôpitaux de Marseille, Marseille, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Brue
authors.affiliation: Academy of Medical Sciences of Romania, University of Medicine and Pharmacy 'Carol Davila', National Institute of Endocrinology 'CI Parhon', Bucharest, Romania.
authors.forename: Mihail
authors.initials: M
authors.lastname: Coculescu
authors.affiliation: Northwest Pituitary Center, Departments of Medicine and Neurological Surgery, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Fleseriu
authors.affiliation: División Endocrinología, Hospital Carlos G Durand, Buenos Aires, Argentina.
authors.forename: Mirtha
authors.initials: M
authors.lastname: Guitelman
authors.affiliation: IM Sechenov First Moscow State Medical University, Moscow, Russian Federation.
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Pronin
authors.affiliation: Fédération d'Endocrinologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Raverot
authors.affiliation: Institute of Endocrinology and Metabolism, Rabin Medical Center, and Sackler School of Medicine, Tel-Aviv University, Petah-Tiqva, Israel.
authors.forename: Ilan
authors.initials: I
authors.lastname: Shimon
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Kayo Kodama
authors.initials: KK
authors.lastname: Lievre
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Juergen
authors.initials: J
authors.lastname: Fleck
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Mounir
authors.initials: M
authors.lastname: Aout
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Pedroncelli
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Naples, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colao
mesh_terms: D000172:Acromegaly / Q000188:drug therapy*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D008875:Middle Aged; D015282:Octreotide / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D013004:Somatostatin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D010456:Peptides, Cyclic; C060347:lanreotide; D019382:Human Growth Hormone; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; C517782:pasireotide; D015282:Octreotide