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

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ClinicalTrials.gov Identifier: NCT01137682
Recruitment Status : Completed
First Posted : June 4, 2010
Results First Posted : January 21, 2015
Last Update Posted : April 5, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acromegaly Drug: Pasireotide Drug: octreotide LAR 30mg Drug: lanreotide ATG 120mg Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 198 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : July 19, 2010
Actual Primary Completion Date : January 22, 2013
Actual Study Completion Date : February 28, 2017


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 Name: 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 Name: 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



Primary Outcome Measures :
  1. Percentage of Participants With a Reduction of Mean GH Levels to < 2.5 µg/L and Normalization of Sex- and Age-adjusted IGF-1. [ Time Frame: At 24 weeks ]
    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.


Secondary Outcome Measures :
  1. 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) [ Time Frame: Extension baseline up to approximately week 268 ]
    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)

  2. 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). [ Time Frame: Extension baseline up to approximately week 268 ]
    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)

  3. 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) [ Time Frame: Extension baseline up to approximately week 268 ]
    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)

  4. 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) [ Time Frame: Extension baseline up to approximately week 268 ]
    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

  5. 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) [ Time Frame: Extension baseline up to approximately week 268 ]
    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)

  6. 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) [ Time Frame: CORE baseline up to approximately 24 weeks ]
  7. 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) [ Time Frame: CORE and extension baseline up to approximately 268 weeks ]
    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.

  8. 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) [ Time Frame: CORE baseline up to approximately 24 weeks ]
    Standardized IGF-1 = IGF-1 value / ULN, where ULN is the upper limit of the normal range

  9. 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) [ Time Frame: CORE and extension baseline up to approximately 268 weeks ]
    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

  10. 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) [ Time Frame: CORE baseline up to approximately 268 weeks ]
    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.

  11. 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 Frame: CORE baseline up to approximately 268 weeks ]
    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.

  12. 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) [ Time Frame: CORE baseline up to approximately 24 weeks ]
    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.

  13. 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) [ Time Frame: CORE Baseline and extension baseline up to approximately 268 weeks ]
    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.

  14. 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) [ Time Frame: Extension baseline up to approximately 196 weeks ]

    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.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01137682


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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01137682     History of Changes
Other Study ID Numbers: CSOM230C2402
EUDRACT 2009-016722-13 ( Registry Identifier: EUDRACT )
First Posted: June 4, 2010    Key Record Dates
Results First Posted: January 21, 2015
Last Update Posted: April 5, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Acromegaly
hormone disorder
growth hormone
insulin like growth factor-1
pituitary tumor
pasireotide
SOM230

Additional relevant MeSH terms:
Acromegaly
Bone Diseases, Endocrine
Bone Diseases
Musculoskeletal Diseases
Hyperpituitarism
Pituitary Diseases
Hypothalamic Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Endocrine System Diseases
Octreotide
Lanreotide
Angiopeptin
Pasireotide
Somatostatin
Gastrointestinal Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs