Efficacy and Safety of Pasireotide Long Acting Release (LAR) Versus Octreotide LAR or Lanreotide Autogel (ATG) in Patients With Inadequately Controlled Acromegaly (PAOLA)

A Phase III, Multicenter, Randomized, Parallel-group Study to Assess the Efficacy and Safety of Double-blind Pasireotide LAR 40 mg and Pasireotide LAR 60 mg Versus Open-label Octreotide LAR or Lanreotide ATG in Patients With Inadequately Controlled Acromegaly

This study will evaluate the efficacy and safety of pasireotide LAR 40 and 60 mg versus octreotide LAR or lanreotide ATG in patients with inadequately controlled acromegaly.

Study Overview

• Status: Completed
• Conditions: Acromegaly
• Intervention / Treatment: Drug: Pasireotide; Drug: octreotide LAR 30mg; Drug: lanreotide ATG 120mg

• Study Type: Interventional
• Enrollment (Actual): 198
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1405BCH
      • Novartis Investigative Site
• Belgium
  • Brussels, Belgium, BE-B-1200
    • Novartis Investigative Site
  • Gent, Belgium, 9000
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Antwerpen
    • Edegem, Antwerpen, Belgium, 2650
      • Novartis Investigative Site
• Brazil
  • CE
    • Fortaleza, CE, Brazil, 60430 370
      • Novartis Investigative Site
  • MA
    • Sao Luis, MA, Brazil, 65020-070
      • Novartis Investigative Site
  • RJ
    • Rio de Janeiro, RJ, Brazil, 21941-913
      • Novartis Investigative Site
  • SC
    • Joinville, SC, Brazil, 89201260
      • Novartis Investigative Site
  • SP
    • Botucatu, SP, Brazil, 18618-970
      • Novartis Investigative Site
    • Campinas, SP, Brazil, 13083-970
      • Novartis Investigative Site
    • Sao Paulo, SP, Brazil, 05403 000
      • Novartis Investigative Site
    • São Paulo, SP, Brazil, 04038-002
      • Novartis Investigative Site
• Canada
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Novartis Investigative Site
• Colombia
  • Bogotá, Colombia, 00000
    • Novartis Investigative Site
  • Cali, Colombia
    • Novartis Investigative Site
  • Cundinamarca
    • Bogota, Cundinamarca, Colombia, 111411
      • Novartis Investigative Site
• France
  • Dijon, France, 21034
    • Novartis Investigative Site
  • Le Kremlin Bicetre, France, 94275
    • Novartis Investigative Site
  • Lille, France, 59037
    • Novartis Investigative Site
  • Marseille, France, 13005
    • Novartis Investigative Site
  • Paris, France, 75571
    • Novartis Investigative Site
  • Pessac Cedex, France, 33604
    • Novartis Investigative Site
  • Rennes Cedex, France, 35022
    • Novartis Investigative Site
  • Saint Herblain - Nantes, France, 44093
    • Novartis Investigative Site
  • Cedex
    • Bron, Cedex, France, 69677
      • Novartis Investigative Site
  • Cedex 9
    • Toulouse, Cedex 9, France, 31000
      • Novartis Investigative Site
• Germany
  • Erlangen, Germany, 91054
    • Novartis Investigative Site
  • Hamburg, Germany, 22587
    • Novartis Investigative Site
  • Muenchen, Germany, 80336
    • Novartis Investigative Site
  • Wurzburg, Germany, 97080
    • Novartis Investigative Site
• Israel
  • Petach Tikva, Israel, 49100
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • GE
    • Genova, GE, Italy, 16132
      • Novartis Investigative Site
  • ME
    • Messina, ME, Italy, 98125
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00168
      • Novartis Investigative Site
  • TO
    • Torino, TO, Italy, 10126
      • Novartis Investigative Site
• Norway
  • Bergen, Norway, NO-5021
    • Novartis Investigative Site
  • Oslo, Norway, NO-0379
    • Novartis Investigative Site
• Poland
  • Gdansk, Poland, 80-952
    • Novartis Investigative Site
  • Poznan, Poland, 60-355
    • Novartis Investigative Site
  • Wroclaw, Poland, 50 367
    • Novartis Investigative Site
• Romania
  • Bucuresti, Romania, 011863
    • Novartis Investigative Site
• Russian Federation
  • Barnaul, Russian Federation, 656024
    • Novartis Investigative Site
  • Moscow, Russian Federation, 117036
    • Novartis Investigative Site
  • Moscow, Russian Federation, 101990
    • Novartis Investigative Site
  • Tyumen, Russian Federation, 625023
    • Novartis Investigative Site
• Saudi Arabia
  • Jeddah, Saudi Arabia, 21423
    • Novartis Investigative Site
  • Riyadh, Saudi Arabia, 11211
    • Novartis Investigative Site
• Spain
  • Andalucia
    • Sevilla, Andalucia, Spain, 41013
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Alicante, Comunidad Valenciana, Spain, 03010
      • Novartis Investigative Site
• Turkey
  • Altunizade, Turkey, 34662
    • Novartis Investigative Site
  • Antalya, Turkey, 07070
    • Novartis Investigative Site
  • Izmir, Turkey, 35340
    • Novartis Investigative Site
• United Kingdom
  • Plymouth, United Kingdom, PL6 8DH
    • Novartis Investigative Site
• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center Division of Hematology/Oncolog
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Neuroscience Institute 550 17th Avenue, Suite 500

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with written informed consent prior to any study related activity
2. Patients who had inadequately controlled acromegaly as defined by a mean GH concentration of a 5-point profile over a 2-hour period > 2.5 µg/L and sex- and age-adjusted IGF-1 > 1.3 x upper limit of normal (ULN)
3. Patients who had been treated with maximum indicated doses of octreotide LAR or lanreotide ATG for at least 6 months prior to visit 1 (screening). The maximum indicated dose for octreotide LAR was 30mg and for lanreotide ATG iwas120 mg
4. Patients who had a diagnosis of pituitary micro- or macro adenoma. Patients could have been previously submitted to surgery
5. Patients who completed the 24-week treatment period in core according to the requirements of the core study protocol or corresponding amendments could enter extension

Exclusion Criteria:

1. Patients who had received pasireotide (SOM 230) prior to enrolment
2. Concomitant treatment with Growth Hormone Receptor (GHR)-antagonist or dopamine agonists unless concomitant treatment was discontinued 8 weeks prior to visit 1 (screening)(8 weeks wash out period). Such patients must have been treated with octreotide LAR 30 mg or lanreotide ATG 120 mg monotherapy continuously for a minimum of 6 months prior to starting combination therapy and they should have been inadequately controlled on monotherapy.
3. Patients who had compression of the optic chiasm causing acute clinically significant visual field defects
4. Patients who required a surgical intervention for relief of any sign or symptom associated with tumor compression
5. Patients who had received pituitary irradiation within 10 years prior to visit 1 (screening).
6. Patients who had undergone major surgery/surgical therapy for any cause within 4 weeks prior to visit 1 (screening).
7. Patients who were hypothyroid and not adequately treated with a stable dose of thyroid hormone replacement therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pasireotide LAR 40 mg; Supplied in blinded fashion as 20 and 40 mg powder in vials and 2 mL vehicle in ampoule (for reconstitution)	Drug: Pasireotide; Double-blind pasireotide LAR 40 mg i.m. injection once every 28 ± 2 days for 24 weeks or; Double-blind pasireotide LAR 60 mg i.m. injection once every 28 ± 2 days for 24 weeks; Other Names: SOM230
Experimental: Pasireotide LAR 60 mg; Supplied in blinded fashion as 20 and 40 mg powder in vials and 2 mL vehicle in ampoule (for reconstitution)	Drug: Pasireotide; Double-blind pasireotide LAR 40 mg i.m. injection once every 28 ± 2 days for 24 weeks or; Double-blind pasireotide LAR 60 mg i.m. injection once every 28 ± 2 days for 24 weeks; Other Names: SOM230
Active Comparator: Control arm (octreotide or lanreotide); If a patient is randomized to the open label arm the investigator will either: be instructed to contact a Novartis delegate to initiate shipment of either octreotide LAR 30 mg or lanreotide ATG 120 mg from a Novartis or designee depot to the site, or; continue to dispense either octreotide LAR 30 mg or lanreotide ATG 120 mg available at the institution to the patient if permitted by local regulations.	Drug: octreotide LAR 30mg; In an open-label, active control arm, continue on the same treatment with octreotide LAR 30 mg every 28 ± 2 days as received for at least 6 months prior to randomization; Drug: lanreotide ATG 120mg; In an open-label, active control arm, continue on the same treatment with lanreotide ATG 120 mg every 28 ± 2 days as received for at least 6 months prior to randomization

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With a Reduction of Mean GH Levels to < 2.5 µg/L and Normalization of Sex- and Age-adjusted IGF-1.	The primary objective of this study was to compare the percentage of patients achieving biochemical control (defined as mean GH levels <2.5 µg/L and normalization of sex- and age- adjusted IGF-1) at 24 weeks with pasireotide LAR 40 mg and pasireotide LAR 60 mg separately versus continued treatment with octreotide LAR 30 mg or lanreotide autogel (ATG) 120 mg. The primary efficacy variable is the proportion of patients with a reduction of mean GH levels to < 2.5 µg/L and normalization of sex- and age-adjusted IGF-1 at 24 weeks.	At 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With Mean GH < 2.5 μg/L and Normalization of IGF-1, Treated With Pasireotide LAR Alone or With Concomitant Medications Used to Treat Acromegaly (Extension Full Analysis Set)	The percentage of patients achieving mean growth hormone (GH) levels < 2.5 μg/L and normalization of sex and age-adjusted IGF-1 was calculated with two sided 95% confidence interval. All GH assessments were based on a 5-point mean growth hormone (GH) assessed from a 2-hour profile. Scheduled time points for blood sampling were pre-dose at 0, 30, 60, 90 and 120 minutes. Total insulin-like growth factor (IGF-1) levels were assessed with one pre-dose sample at the same visits as GH. Concomitant medication known to affect GH or IGF-1 levels were allowed in patients who were not biochemically controlled after at least one year treatment with pasireotide LAR monotherapy: dopamine agonists and growth hormone receptor antagonists (extension full analysis set)	Extension baseline up to approximately week 268
Percentage of Participants With Normalization of Sex- and Age-adjusted IGF-1treated With Pasireotide LAR Alone or With Concomitant Medications Used to Treat Acromegaly (Extension Full Analysis Set).	The percentage of patients achieving normalization of sex and age-adjusted IGF-1 was calculated with two sided 95% confidence interval. Total insulin-like growth factor (IGF-1) levels were assessed with one pre-dose sample at the same visits as GH. Concomitant medication known to affect IGF-1 levels were allowed in patients who were not biochemically controlled after at least one year treatment with pasireotide LAR monotherapy: dopamine agonists and growth hormone receptor antagonists (Extension full analysis set)	Extension baseline up to approximately week 268
Percentage of Patients With Mean GH < 2.5 μg/L Treated With Pasireotide LAR Alone or With Concomitant Medications Used to Treat Acromegaly (Extension Full Analysis Set)	The percentage of patients achieving mean growth hormone (GH) levels < 2.5 μg/L was calculated with two sided 95% confidence interval. All GH assessments were based on a 5-point mean growth hormone (GH) assessed from a 2-hour profile. Scheduled time points for blood sampling were pre-dose at 0, 30, 60, 90 and 120 minutes. Concomitant medication known to affect GH levels were allowed in patients who were not biochemically controlled after at least one year treatment with pasireotide LAR monotherapy: dopamine agonists and growth hormone receptor antagonists (Extension full analysis set)	Extension baseline up to approximately week 268
Percentage of Patients With Mean GH < 1.0 μg/L and Normalization of IGF-1, Treated With Pasireotide LAR Alone or With Concomitant Medications Used to Treat Acromegaly (Extension Full Analysis Set)	The percentage of patients achieving mean growth hormone (GH) levels < 1.0 μg/L and normalization of sex and age-adjusted IGF-1 was calculated with two sided 95% confidence interval. All GH assessments were based on a 5-point mean growth hormone (GH) assessed from a 2-hour profile. Scheduled time points for blood sampling were pre-dose at 0, 30, 60, 90 and 120 minutes. Total insulin-like growth factor (IGF-1) levels were assessed with one pre-dose sample at the same visits as GH. Concomitant medication known to affect GH or IGF-1 levels were allowed in patients who were not biochemically controlled after at least one year treatment with pasireotide LAR monotherapy: dopamine agonists and growth hormone receptor antagonists (Extension full analysis set	Extension baseline up to approximately week 268
Percentage of Patients With Mean GH <1.0 μg/L Treated With Pasireotide LAR Alone or With Concomitant Medications Used to Treat Acromegaly (Extension Full Analysis Set)	The percentage of patients achieving mean growth hormone (GH) levels < 1.0 μg/L was calculated with two sided 95% confidence interval. All GH assessments were based on a 5-point mean growth hormone (GH) assessed from a 2-hour profile. Scheduled time points for blood sampling were pre-dose at 0, 30, 60, 90 and 120 minutes. Concomitant medication known to affect GH levels were allowed in patients who were not biochemically controlled after at least one year treatment with pasireotide LAR monotherapy: dopamine agonists and growth hormone receptor antagonists (Extension full analysis set)	Extension baseline up to approximately week 268
Change From Baseline in Mean GH Values for Patients Treated With Pasireotide LAR Alone or With Concomitant Medications Used to Treat Acromegaly for CORE Visits (Extension Full Analysis Set)		CORE baseline up to approximately 24 weeks
Change From Baseline in Mean GH Values for Patients Treated With Pasireotide LAR Alone or With Concomitant Medications Used to Treat Acromegaly for Extension Visits (Extension Full Analysis Set)	Change from CORE baseline at each scheduled assessment was performed for patients randomized to pasireotide arms. Change from extension baseline at each scheduled assessment was performed for patients randomized to active control arm.	CORE and extension baseline up to approximately 268 weeks
Change From Baseline in Standardized IGF-1 Values for Patients Treated With Pasireotide LAR Alone or With Concomitant Medications Used to Treat Acromegaly for CORE Visits (Extension Full Analysis Set)	Standardized IGF-1 = IGF-1 value / ULN, where ULN is the upper limit of the normal range	CORE baseline up to approximately 24 weeks
Change From Baseline in Standardized IGF-1 Values for Patients Treated With Pasireotide LAR Alone or With Concomitant Medications Used to Treat Acromegaly for Extension Visits (Extension Full Analysis Set)	Change from CORE baseline at each scheduled assessment was performed for patients randomized to pasireotide arms. Change from extension baseline at each scheduled assessment was performed for patients randomized to active control arm. Standardized IGF-1 = IGF-1 value / ULN, where ULN is the upper limit of the normal range	CORE and extension baseline up to approximately 268 weeks
Duration of the First Response for Patients Achieving a Reduction of Mean GH Level to < 2.5 μg/L and Normalization of IGF-1 and Treated With Pasireotide LAR Alone or With Concomitant Medications Used to Treat Acromegaly (Extension Full Analysis Set)	n is the number of patients achieving response criteria. The weeks correspond to duration of first response (in weeks) for patients achieving biomedical control. Median and 95% CI are derived from Kaplan-Meier curves. Kaplan-Meier estimates [95% CI] at each time point are estimates of probability of response.	CORE baseline up to approximately 268 weeks
Time to First Response (Weeks) by Treatment for Patients Achieving a Reduction of Mean GH Level to < 2.5 µg/L and Normalization of IGF-1 and Treated With Pasireotide LAR Alone or With Concomitant Medications Used to Treat Acromegaly	Time to first response is defined as the time from the date of first dose to the date of first occurrence of a reduction of mean GH < 2.5 µg/L and the normalization of IGF-1. The weeks correspond to time taken to achieve first mean GH < 2.5 µg/L and the normalization of IGF-1.	CORE baseline up to approximately 268 weeks
Change From Baseline in AcroQoL Total Scores for Patients Treated With Pasireotide LAR Alone or With Concomitant Medications Used to Treat Acromegaly for CORE Visits(Extension Full Analysis Set)	Acromegaly Quality of Life questionnaire (AcroQoL) is a validated disease specific questionnaire. It contains 22 items divided into two scales: physical aspects (8 items) and psychological aspects (14 items) which is divided in two sub-scales: physical appearance and personal relationships of the patient (seven items each). The total score and sub-scores were calculated using the following formula: ((X -Y) / 4Y) x 100, X=sum of the scores for individual items (between 1 and 5 for each item), Y=number of individual items included in above sum (i.e. 22 for the total score, 8 for the physical sub-score, 14 for the psychological sub-score, 7 for the sub-score 'appearance' and 'personal relations'). The scoring of the questionnaire was performed as specified by the instrument developers. Total scores range from 0 to 100. Higher scores represent better quality of life. If more than 25% of items are not completed, results were considered invalid.	CORE baseline up to approximately 24 weeks
Change From Baseline in AcroQoL Total Scores for Patients Treated With Pasireotide LAR Alone or With Concomitant Medications Used to Treat Acromegaly for Extension Visits (Extension Full Analysis Set)	Acromegaly Quality of Life questionnaire (AcroQoL) is a validated disease specific questionnaire. It contains 22 items divided into two scales: physical aspects (8 items) and psychological aspects (14 items) which is divided in two sub-scales: physical appearance and personal relationships of the patient (seven items each). The total score and sub-scores were calculated using the following formula: ((X -Y) / 4Y) x 100, X=sum of the scores for individual items (between 1 and 5 for each item), Y=number of individual items included in above sum (i.e. 22 for the total score, 8 for the physical sub-score, 14 for the psychological sub-score, 7 for the sub-score 'appearance' and 'personal relations'). The scoring of the questionnaire was performed as specified by the instrument developers. Total scores range from 0 to 100. Higher scores represent better quality of life. If more than 25% of items are not completed, results were considered invalid.	CORE Baseline and extension baseline up to approximately 268 weeks
Summary of Pasireotide Trough Concentrations in Acromegaly Patients Following Monthly i.m. Injections of Pasireotide LAR by Incident Dose From Start of Extension Phase up to Week 196 of the Extension Phase (PK Set)	PK samples were collected for those patients treated with pasireotide LAR in the core study and who continued on pasireotide LAR in the extension phase. PK samples were collected before the injection of pasireotide LAR only at weeks 112 and 196. PK samples were also collected at weeks 48 and 132 only for all patients treated with octreotide LAR 30 mg or lanreotide ATG 120 mg in the core study who started treatment with pasireotide LAR in the extension study. Blood samples (2.5 mL each sample) were collected to yield 1-mL plasma for analysis of pasireotide LAR oncentration.	Extension baseline up to approximately 196 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Colao A, Bronstein MD, Brue T, De Marinis L, Fleseriu M, Guitelman M, Raverot G, Shimon I, Fleck J, Gupta P, Pedroncelli AM, Gadelha MR. Pasireotide for acromegaly: long-term outcomes from an extension to the Phase III PAOLA study. Eur J Endocrinol. 2020 Jun;182(6):583. doi: 10.1530/EJE-19-0762.
• Gadelha MR, Bronstein MD, Brue T, Coculescu M, Fleseriu M, Guitelman M, Pronin V, Raverot G, Shimon I, Lievre KK, Fleck J, Aout M, Pedroncelli AM, Colao A; Pasireotide C2402 Study Group. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2014 Nov;2(11):875-84. doi: 10.1016/S2213-8587(14)70169-X. Epub 2014 Sep 24.

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2010
• Primary Completion (Actual): January 22, 2013
• Study Completion (Actual): February 28, 2017

Study Registration Dates

• First Submitted: May 27, 2010
• First Submitted That Met QC Criteria: June 3, 2010
• First Posted (Estimate): June 4, 2010

Study Record Updates

• Last Update Posted (Actual): April 5, 2018
• Last Update Submitted That Met QC Criteria: April 2, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Acromegaly; growth hormone; SOM230; pituitary tumor; hormone disorder; insulin like growth factor-1; pasireotide
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Musculoskeletal Diseases; Hypothalamic Diseases; Bone Diseases; Bone Diseases, Endocrine; Hyperpituitarism; Pituitary Diseases; Acromegaly; Physiological Effects of Drugs; Antineoplastic Agents; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Octreotide; Lanreotide; Pasireotide
• Other Study ID Numbers: CSOM230C2402; EUDRACT 2009-016722-13 (Registry Identifier: EUDRACT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No