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    Clinical Trial Results:
    A multi-center, randomized, open-label, Phase IV study to investigate the management of pasireotide-induced hyperglycemia with incretin based therapy or insulin in adult patients with Cushing’s disease or acromegaly

    Summary
    EudraCT number
    2012-002916-16
    Trial protocol
    DE   DK   PL   BE  
    Global end of trial date
    26 Mar 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Mar 2019
    First version publication date
    16 Mar 2019
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    CSOM230B2219
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02060383
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Manager, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Manager, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of treatment with incretin based therapy vs. insulin on the 16-week glycemic control in patients with Cushing’s disease or acromegaly who develop or worsen hyperglycemia on pasireotide, and cannot be controlled by metformin alone or other background anti-diabetic treatments
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 May 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Brazil: 25
    Country: Number of subjects enrolled
    China: 60
    Country: Number of subjects enrolled
    Denmark: 8
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    India: 21
    Country: Number of subjects enrolled
    Peru: 11
    Country: Number of subjects enrolled
    Poland: 38
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Thailand: 23
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    United States: 34
    Worldwide total number of subjects
    249
    EEA total number of subjects
    59
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    234
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    A total of 68 randomized evaluable participants with at least 8 weeks of randomized treatment without any rescue anti-diabetic medication was required. Approximately 79 participants were planned to be randomized.

    Pre-assignment
    Screening details
    A total of 249 participants were included in the study & treated with pasireotide s.c. (59 participants with Cushing's disease) or pasireotide LAR (190 participants with acromegaly). 81 participants were randomized to either incretin-based therapy or insulin (with 72 evaluable for the primary analysis) & 168 who did not qualify for randomization.

    Period 1
    Period 1 title
    Core Phase
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Incretin based therapy (randomized group)
    Arm description
    Participants randomized to the incretin based arm started with sitagliptin once daily. If sitagliptin did not control the participant's hyperglycemia, sitagliptin was stopped and participants switched to liraglutide once daily. If despite treatment with liraglutide, hyperglycemia was not controlled then the participant was eligible for rescue therapy with addition of insulin
    Arm type
    Experimental

    Investigational medicinal product name
    Pasireotide s.c.
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pasireotide s.c. was provided as solution for injection in individual one-point-cut 1 mL ampule, containing 900, 600, and 300 μg pasireotide per 1 mL of solution, b.i.d. which was self-injected by the patients. Starting dose = 600 μg b.i.d.

    Investigational medicinal product name
    Pasireotide i.m. long acting release (LAR)
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide i.m. LAR was provided as 20 mg, 40 mg, 60 mg every 28 days (q28d); Starting dose = 40 mg q28d

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Individual doses starting from 1000 mg/day to maximum dose according to the approved package insert and depending on the patient tolerability

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 or 100 mg administered orally once a day

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered s.c. once a day according to package insert

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered s.c. according to package insert, per investigator discretion. Insulin was only given as rescue therapy in the Incretin arm if required.

    Arm title
    Insulin (randomized group)
    Arm description
    Participants randomized to the insulin arm started with once daily dose of basal insulin. The dose was up or down titrated at the discretion of the investigator. If blood glucose levels remained uncontrolled on basal insulin, participant switched to basal insulin plus prandial insulin
    Arm type
    Experimental

    Investigational medicinal product name
    Pasireotide s.c.
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pasireotide s.c. was provided as solution for injection in individual one-point-cut 1 mL ampule, containing 900, 600, and 300 μg pasireotide per 1 mL of solution, b.i.d. which was self-injected by the patients. Starting dose = 600 μg b.i.d.

    Investigational medicinal product name
    Pasireotide i.m. long acting release (LAR)
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide i.m. LAR was provided as 20 mg, 40 mg, 60 mg every 28 days (q28d); Starting dose = 40 mg q28d

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Individual doses starting from 1000 mg/day to maximum dose according to the approved package insert and depending on the patient tolerability

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered s.c. according to package insert, per investigator discretion

    Arm title
    Baseline Insulin (BL) (non-randomized group)
    Arm description
    This group included participants who were receiving insulin at study entry
    Arm type
    This was an Observational arm

    Investigational medicinal product name
    Pasireotide s.c.
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pasireotide s.c. was provided as solution for injection in individual one-point-cut 1 mL ampule, containing 900, 600, and 300 μg pasireotide per 1 mL of solution, b.i.d. which was self-injected by the patients. Starting dose = 600 μg b.i.d.

    Investigational medicinal product name
    Pasireotide i.m. long acting release (LAR)
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide i.m. LAR was provided as 20 mg, 40 mg, 60 mg every 28 days (q28d); Starting dose = 40 mg q28d

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin treatment was not required for the BL Insulin group but may have been prescribed at the discretion of the investigator.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered s.c. according to package insert, per investigator discretion

    Arm title
    Oral antidiabetic drugs (OAD) (non-randomized group)
    Arm description
    This group included participants who developed hyperglycemia that was controlled by metformin and/or other background anti-diabetic treatment
    Arm type
    This was an Observational arm

    Investigational medicinal product name
    Pasireotide s.c.
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pasireotide s.c. was provided as solution for injection in individual one-point-cut 1 mL ampule, containing 900, 600, and 300 μg pasireotide per 1 mL of solution, b.i.d. which was self-injected by the patients. Starting dose = 600 μg b.i.d.

    Investigational medicinal product name
    Pasireotide i.m. long acting release (LAR)
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide i.m. LAR was provided as 20 mg, 40 mg, 60 mg every 28 days (q28d); Starting dose = 40 mg q28d

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin treatment was not required for the OAD group but may have been prescribed at the discretion of the investigator.

    Arm title
    No OAD (non-randomized group)
    Arm description
    This group included participants who did not receive any anti-diabetic medication during the Core Phase of the study
    Arm type
    This was an Observational arm

    Investigational medicinal product name
    Pasireotide i.m. long acting release (LAR)
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide i.m. LAR was provided as 20 mg, 40 mg, 60 mg every 28 days (q28d); Starting dose = 40 mg q28d

    Investigational medicinal product name
    Pasireotide s.c.
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pasireotide s.c. was provided as solution for injection in individual one-point-cut 1 mL ampule, containing 900, 600, and 300 μg pasireotide per 1 mL of solution, b.i.d. which was self-injected by the patients. Starting dose = 600 μg b.i.d.

    Number of subjects in period 1
    Incretin based therapy (randomized group) Insulin (randomized group) Baseline Insulin (BL) (non-randomized group) Oral antidiabetic drugs (OAD) (non-randomized group) No OAD (non-randomized group)
    Started
    38
    43
    19
    46
    103
    Completed Core/Entered Extension
    17 [1]
    17 [2]
    10 [3]
    21 [4]
    53 [5]
    Completed Core/Did not enter Extension
    18 [6]
    20 [7]
    9 [8]
    18 [9]
    42 [10]
    Completed
    35
    37
    19
    39
    95
    Not completed
    3
    6
    0
    7
    8
         Protocol deviation
    -
    -
    -
    1
    -
         Unsatisfactory therapeutic effect
    1
    5
    -
    -
    -
         Administrative problems
    -
    1
    -
    -
    -
         Adverse event, non-fatal
    2
    -
    -
    2
    6
         Consent withdrawn by subject
    -
    -
    -
    4
    2
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not everyone who completed the Core phase entered the extension phase of the study.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not everyone who completed the Core phase entered the extension phase of the study.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not everyone who completed the Core phase entered the extension phase of the study.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not everyone who completed the Core phase entered the extension phase of the study.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not everyone who completed the Core phase entered the extension phase of the study.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not everyone who completed the Core phase entered the extension phase of the study.
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not everyone who completed the Core phase entered the extension phase of the study.
    [8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not everyone who completed the Core phase entered the extension phase of the study.
    [9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not everyone who completed the Core phase entered the extension phase of the study.
    [10] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not everyone who completed the Core phase entered the extension phase of the study.
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Incretin based therapy (randomized group)
    Arm description
    Participants randomized to the incretin based arm started with sitagliptin once daily. If sitagliptin did not control the participant's hyperglycemia, sitagliptin was stopped and participants switched to liraglutide once daily. If despite treatment with liraglutide, hyperglycemia was not controlled then the participant was eligible for rescue therapy with addition of insulin
    Arm type
    Experimental

    Investigational medicinal product name
    Pasireotide s.c.
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pasireotide s.c. was provided as solution for injection in individual one-point-cut 1 mL ampule, containing 900, 600, and 300 μg pasireotide per 1 mL of solution, b.i.d. which was self-injected by the patients. Starting dose = 600 μg b.i.d.

    Investigational medicinal product name
    Pasireotide i.m. long acting release (LAR)
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide i.m. LAR was provided as 20 mg, 40 mg, 60 mg every 28 days (q28d); Starting dose = 40 mg q28d

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin may have been continued in the Extension phase at the discretion of the investigator; however, it was not provided by Novartis unless required by local regulations.

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin may have been continued in the Extension phase at the discretion of the investigator; however, it was not provided by Novartis unless required by local regulations.

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Liraglutide may have been continued in the Extension phase at the discretion of the investigator; however, it was not provided by Novartis unless required by local regulations.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin may have been continued in the Extension phase at the discretion of the investigator; however, it was not provided by Novartis unless required by local regulations.

    Arm title
    Insulin (randomized group)
    Arm description
    Participants randomized to the insulin arm started with once daily dose of basal insulin. The dose was up or down titrated at the discretion of the investigator. If blood glucose levels remained uncontrolled on basal insulin, participant switched to basal insulin plus prandial insulin.
    Arm type
    Experimental

    Investigational medicinal product name
    Pasireotide s.c.
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pasireotide s.c. was provided as solution for injection in individual one-point-cut 1 mL ampule, containing 900, 600, and 300 μg pasireotide per 1 mL of solution, b.i.d. which was self-injected by the patients. Starting dose = 600 μg b.i.d.

    Investigational medicinal product name
    Pasireotide i.m. long acting release (LAR)
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide i.m. LAR was provided as 20 mg, 40 mg, 60 mg every 28 days (q28d); Starting dose = 40 mg q28d

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin may have been continued in the Extension phase at the discretion of the investigator; however, it was not provided by Novartis unless required by local regulations.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin may have been continued in the Extension phase at the discretion of the investigator; however, it was not provided by Novartis unless required by local regulations.

    Arm title
    Baseline Insulin (BL) (non-randomized group)
    Arm description
    This group included participants who were receiving insulin at study entry and thus were not eligible for randomization.
    Arm type
    This was an Observational arm

    Investigational medicinal product name
    Pasireotide s.c.
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pasireotide s.c. was provided as solution for injection in individual one-point-cut 1 mL ampule, containing 900, 600, and 300 μg pasireotide per 1 mL of solution, b.i.d. which was self-injected by the patients. Starting dose = 600 μg b.i.d.

    Investigational medicinal product name
    Pasireotide i.m. long acting release (LAR)
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide i.m. LAR was provided as 20 mg, 40 mg, 60 mg every 28 days (q28d); Starting dose = 40 mg q28d

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin may have been continued in the Extension phase at the discretion of the investigator; however, it was not provided by Novartis unless required by local regulations.

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin may have been continued in the Extension phase at the discretion of the investigator; however, it was not provided by Novartis unless required by local regulations.

    Arm title
    Oral antidiabetic drugs (OAD) (non-randomized group)
    Arm description
    This group included participants who developed hyperglycemia that was controlled by metformin and/or other background anti-diabetic treatment and thus were not randomized.
    Arm type
    This was an Observational arm

    Investigational medicinal product name
    Pasireotide s.c.
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pasireotide s.c. was provided as solution for injection in individual one-point-cut 1 mL ampule, containing 900, 600, and 300 μg pasireotide per 1 mL of solution, b.i.d. which was self-injected by the patients. Starting dose = 600 μg b.i.d.

    Investigational medicinal product name
    Pasireotide i.m. long acting release (LAR)
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide i.m. LAR was provided as 20 mg, 40 mg, 60 mg every 28 days (q28d); Starting dose = 40 mg q28d

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin may have been continued in the Extension phase at the discretion of the investigator; however, it was not provided by Novartis unless required by local regulations.

    Arm title
    No OAD (non-randomized group)
    Arm description
    This group included participants who did not receive any anti-diabetic medication during the Core Phase of the study and thus were not randomized.
    Arm type
    This was an Observational arm

    Investigational medicinal product name
    Pasireotide i.m. long acting release (LAR)
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide i.m. LAR was provided as 20 mg, 40 mg, 60 mg every 28 days (q28d); Starting dose = 40 mg q28d

    Investigational medicinal product name
    Pasireotide s.c.
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pasireotide s.c. was provided as solution for injection in individual one-point-cut 1 mL ampule, containing 900, 600, and 300 μg pasireotide per 1 mL of solution, b.i.d. which was self-injected by the patients. Starting dose = 600 μg b.i.d.

    Number of subjects in period 2 [11]
    Incretin based therapy (randomized group) Insulin (randomized group) Baseline Insulin (BL) (non-randomized group) Oral antidiabetic drugs (OAD) (non-randomized group) No OAD (non-randomized group)
    Started
    17
    17
    10
    21
    53
    Completed
    14
    14
    7
    19
    46
    Not completed
    3
    3
    3
    2
    7
         Protocol deviation
    -
    -
    -
    -
    1
         Unsatisfactory therapeutic effect
    1
    1
    -
    2
    2
         Adverse event, serious fatal
    -
    -
    1
    -
    1
         Administrative problems
    1
    -
    -
    -
    -
         Adverse event, non-fatal
    1
    1
    2
    -
    1
         Consent withdrawn by subject
    -
    1
    -
    -
    2
    Notes
    [11] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not everyone who completed the Core phase entered the extension phase of the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Incretin based therapy (randomized group)
    Reporting group description
    Participants randomized to the incretin based arm started with sitagliptin once daily. If sitagliptin did not control the participant's hyperglycemia, sitagliptin was stopped and participants switched to liraglutide once daily. If despite treatment with liraglutide, hyperglycemia was not controlled then the participant was eligible for rescue therapy with addition of insulin

    Reporting group title
    Insulin (randomized group)
    Reporting group description
    Participants randomized to the insulin arm started with once daily dose of basal insulin. The dose was up or down titrated at the discretion of the investigator. If blood glucose levels remained uncontrolled on basal insulin, participant switched to basal insulin plus prandial insulin

    Reporting group title
    Baseline Insulin (BL) (non-randomized group)
    Reporting group description
    This group included participants who were receiving insulin at study entry

    Reporting group title
    Oral antidiabetic drugs (OAD) (non-randomized group)
    Reporting group description
    This group included participants who developed hyperglycemia that was controlled by metformin and/or other background anti-diabetic treatment

    Reporting group title
    No OAD (non-randomized group)
    Reporting group description
    This group included participants who did not receive any anti-diabetic medication during the Core Phase of the study

    Reporting group values
    Incretin based therapy (randomized group) Insulin (randomized group) Baseline Insulin (BL) (non-randomized group) Oral antidiabetic drugs (OAD) (non-randomized group) No OAD (non-randomized group) Total
    Number of subjects
    38 43 19 46 103 249
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    32 40 18 43 101 234
        From 65-84 years
    6 3 1 3 2 15
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    50.6 ± 11.76 46.4 ± 12.90 46.7 ± 12.54 40.2 ± 13.80 37.8 ± 11.17 -
    Sex: Female, Male
    Units: Subjects
        Female
    22 27 10 31 47 137
        Male
    16 16 9 15 56 112
    Race/Ethnicity, Customized
    Units: Subjects
        Other
    22 24 11 25 43 125
        Chinese
    5 9 1 13 33 61
        Hispanic/Latino
    7 2 5 6 19 39
        Indian (Indian subcontinent)
    4 8 2 2 7 23
        Japanese
    0 0 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Incretin based therapy (randomized group)
    Reporting group description
    Participants randomized to the incretin based arm started with sitagliptin once daily. If sitagliptin did not control the participant's hyperglycemia, sitagliptin was stopped and participants switched to liraglutide once daily. If despite treatment with liraglutide, hyperglycemia was not controlled then the participant was eligible for rescue therapy with addition of insulin

    Reporting group title
    Insulin (randomized group)
    Reporting group description
    Participants randomized to the insulin arm started with once daily dose of basal insulin. The dose was up or down titrated at the discretion of the investigator. If blood glucose levels remained uncontrolled on basal insulin, participant switched to basal insulin plus prandial insulin

    Reporting group title
    Baseline Insulin (BL) (non-randomized group)
    Reporting group description
    This group included participants who were receiving insulin at study entry

    Reporting group title
    Oral antidiabetic drugs (OAD) (non-randomized group)
    Reporting group description
    This group included participants who developed hyperglycemia that was controlled by metformin and/or other background anti-diabetic treatment

    Reporting group title
    No OAD (non-randomized group)
    Reporting group description
    This group included participants who did not receive any anti-diabetic medication during the Core Phase of the study
    Reporting group title
    Incretin based therapy (randomized group)
    Reporting group description
    Participants randomized to the incretin based arm started with sitagliptin once daily. If sitagliptin did not control the participant's hyperglycemia, sitagliptin was stopped and participants switched to liraglutide once daily. If despite treatment with liraglutide, hyperglycemia was not controlled then the participant was eligible for rescue therapy with addition of insulin

    Reporting group title
    Insulin (randomized group)
    Reporting group description
    Participants randomized to the insulin arm started with once daily dose of basal insulin. The dose was up or down titrated at the discretion of the investigator. If blood glucose levels remained uncontrolled on basal insulin, participant switched to basal insulin plus prandial insulin.

    Reporting group title
    Baseline Insulin (BL) (non-randomized group)
    Reporting group description
    This group included participants who were receiving insulin at study entry and thus were not eligible for randomization.

    Reporting group title
    Oral antidiabetic drugs (OAD) (non-randomized group)
    Reporting group description
    This group included participants who developed hyperglycemia that was controlled by metformin and/or other background anti-diabetic treatment and thus were not randomized.

    Reporting group title
    No OAD (non-randomized group)
    Reporting group description
    This group included participants who did not receive any anti-diabetic medication during the Core Phase of the study and thus were not randomized.

    Primary: Change in HbA1c from randomization to approximately 16 weeks

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    End point title
    Change in HbA1c from randomization to approximately 16 weeks [1]
    End point description
    Absolute change in HbA1c from randomization to end of core phase (16 weeks) in incretin based therapy arm and insulin arm, and mean difference of change in HbA1c between the two treatment groups based on an ANOVA model using treatment (Incretin, Insulin) and the two randomization stratification factors (Disease: Cushing’s disease vs Acromegaly; Baseline glycemic status: HbA1c <7% vs HbA1c ≥ 7%) as fixed effects. For Participants who discontinued the study or required rescue treatment before the time of assessing the primary endpoint, the last HbA1c assessment collected 8 weeks (56 days) after randomization (and prior to or on the date of start of rescue treatment) was carried forward. If the participant discontinued the study or used rescue treatment within 8 weeks after randomization, it was considered missing.
    End point type
    Primary
    End point timeframe
    Randomization, 16 weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics analysis was done only within these 3 groups
    End point values
    Incretin based therapy (randomized group) Insulin (randomized group)
    Number of subjects analysed
    38
    43
    Units: HbA1c percentage
    arithmetic mean (confidence interval 95%)
        All Patients (n = 31, 41)
    -0.12 (-0.36 to 0.13)
    0.26 (-0.01 to 0.53)
        Cushing's Disease (n = 7, 11)
    0.33 (-0.41 to 1.07)
    0.45 (-0.20 to 1.09)
        Acromegaly (n = 24, 30)
    -0.25 (-0.49 to -0.00)
    0.19 (-0.12 to 0.49)
    Statistical analysis title
    All Patients
    Statistical analysis description
    Incretin based therapy (randomized group) vs. Insulin (randomized group)
    Comparison groups
    Incretin based therapy (randomized group) v Insulin (randomized group)
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    [2]
    Method
    Parameter type
    Mean difference (net)
    Point estimate
    -0.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.63
         upper limit
    0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.18
    Notes
    [2] - There was no formal hypothesis testing planned in this study.
    Statistical analysis title
    Cushing's Disease
    Statistical analysis description
    Incretin based therapy (randomized group) vs. Insulin (randomized group)
    Comparison groups
    Incretin based therapy (randomized group) v Insulin (randomized group)
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    [3]
    Method
    Parameter type
    Mean difference (net)
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.96
         upper limit
    0.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.45
    Notes
    [3] - There was no formal hypothesis testing planned in this study.
    Statistical analysis title
    Acromegaly
    Statistical analysis description
    Incretin based therapy (randomized group) vs. Insulin (randomized group)
    Comparison groups
    Incretin based therapy (randomized group) v Insulin (randomized group)
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    [4]
    Method
    Parameter type
    Mean difference (net)
    Point estimate
    -0.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.74
         upper limit
    0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.19
    Notes
    [4] - There was no formal hypothesis testing planned in this study.

    Secondary: Change in HbA1c from randomization over time per randomized arm

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    End point title
    Change in HbA1c from randomization over time per randomized arm [5]
    End point description
    Absolute change in HbA1c overtime from randomization to end of core phase per randomized arm
    End point type
    Secondary
    End point timeframe
    R, R - Week 4, R - Week 8, R - Week 12, R - Week 16, end of Core phase
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    Incretin based therapy (randomized group) Insulin (randomized group)
    Number of subjects analysed
    38
    43
    Units: HbA1c percentage
    arithmetic mean (standard deviation)
        Baseline (Randomization)
    7.1 ± 1.00
    7.1 ± 0.75
        Change at RW4 D29 (n = 37, 43)
    0.5 ± 0.73
    0.5 ± 0.60
        Change at RW8 D57 (n = 37, 43)
    0.3 ± 0.98
    0.5 ± 0.86
        Change at RW12 D85 (n = 37, 40)
    0.2 ± 1.03
    0.4 ± 0.85
        Change at RW16 D113 (n = 35, 37)
    0.0 ± 0.93
    0.3 ± 0.87
        End of Core Phase (n = 37, 42)
    0.0 ± 0.92
    0.3 ± 0.84
    No statistical analyses for this end point

    Secondary: Change in FPG (Fasting Plasma Glucose) from randomization until end of Core phase

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    End point title
    Change in FPG (Fasting Plasma Glucose) from randomization until end of Core phase [6]
    End point description
    Absolute change in fasting glucose overtime from randomization to end of core phase per randomized arm
    End point type
    Secondary
    End point timeframe
    Randomization, R(randomization) Week 2, R-Week 4, R-Week 6, R-Week 8, R-Week 10, R-Week 12, R-Week 14, R-Week 16, end of Core phase
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    Incretin based therapy (randomized group) Insulin (randomized group)
    Number of subjects analysed
    38
    43
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline (Randomization)
    172.2 ± 60.78
    167.9 ± 40.77
        Change at RW2 D15 (n = 36, 42)
    4.6 ± 51.01
    -31.1 ± 41.19
        Change at RW4 D29 (n = 38, 43)
    -15.0 ± 47.95
    -28.3 ± 41.14
        Change at RW6 D43 (n = 36, 41)
    -17.7 ± 57.97
    -37.5 ± 52.39
        Change at RW8 D57 (n = 36, 42)
    -25.7 ± 53.32
    -38.3 ± 44.10
        Change at RW10 D71 (n = 37, 37)
    -28.8 ± 61.14
    -36.9 ± 50.82
        Change at RW12 D85 (n = 37, 40)
    -33.4 ± 50.17
    -41.1 ± 51.68
        Change at RW14 D99 (n = 36, 36)
    -35.1 ± 55.83
    -35.6 ± 47.43
        Change at RW16 D113 (n = 35, 34)
    -38.8 ± 53.69
    -33.4 ± 47.63
        End of Core Phase (n = 37, 41)
    -40.1 ± 56.35
    -36.0 ± 46.90
    No statistical analyses for this end point

    Secondary: Percentage of participants in the incretin-based arm who required anti-diabetic rescue therapy with insulin

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    End point title
    Percentage of participants in the incretin-based arm who required anti-diabetic rescue therapy with insulin [7]
    End point description
    The percentage of participants who received anti-diabetic rescue therapy in incretin based therapy is summarized.
    End point type
    Secondary
    End point timeframe
    Randomization to up to 16 weeks
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    Incretin based therapy (randomized group)
    Number of subjects analysed
    38
    Units: Percentage of participants
        number (confidence interval 95%)
    31.6 (17.5 to 48.7)
    No statistical analyses for this end point

    Secondary: Absolute change in HbA1c from baseline to end of Core phase

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    End point title
    Absolute change in HbA1c from baseline to end of Core phase
    End point description
    Absolute change in HbA1c from baseline to end of core phase in the incretin based therapy arm and the insulin arm
    End point type
    Secondary
    End point timeframe
    Baseline, up to 32 weeks (end of Core phase)
    End point values
    Incretin based therapy (randomized group) Insulin (randomized group) Baseline Insulin (BL) (non-randomized group) Oral antidiabetic drugs (OAD) (non-randomized group) No OAD (non-randomized group)
    Number of subjects analysed
    38
    43
    19
    46
    103
    Units: HbA1c percentage
    arithmetic mean (standard deviation)
        Baseline: All Patients (n = 38, 43, 19, 46,102)
    6.3 ± 0.80
    6.3 ± 0.63
    7.7 ± 1.51
    5.7 ± 0.41
    5.4 ± 0.33
        Change at EOP: All Patients (n = 37,42, 19,45,100)
    0.8 ± 0.97
    1.1 ± 0.94
    1.3 ± 1.40
    0.8 ± 0.64
    0.4 ± 0.32
        Baseline: Cushing's (n = 12, 13, 6, 13, 15)
    6.6 ± 0.87
    6.5 ± 0.58
    6.9 ± 0.92
    5.9 ± 0.49
    5.5 ± 0.41
        Change at EOP: Cushing's (n = 12, 13, 6, 13, 14)
    1.3 ± 1.19
    1.7 ± 1.05
    1.4 ± 1.58
    0.9 ± 0.95
    0.5 ± 0.51
        Baseline: Acromegaly (n = 26, 30, 13, 33, 87)
    6.1 ± 0.71
    6.3 ± 0.65
    8.0 ± 1.61
    5.6 ± 0.36
    5.4 ± 0.32
        Change at EOP: Acromegaly (n = 25, 29, 13, 32, 86)
    0.6 ± 0.78
    0.8 ± 0.78
    1.2 ± 1.37
    0.7 ± 0.47
    0.4 ± 0.28
    No statistical analyses for this end point

    Secondary: Absolute change in FPG from baseline to end of Core Phase

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    End point title
    Absolute change in FPG from baseline to end of Core Phase
    End point description
    Absolute change in FPG from baseline to end of core phase in the incretin based therapy arm and the insulin arm.
    End point type
    Secondary
    End point timeframe
    Baseline, Up to 32 weeks (end of Core Phase)
    End point values
    Incretin based therapy (randomized group) Insulin (randomized group) Baseline Insulin (BL) (non-randomized group) Oral antidiabetic drugs (OAD) (non-randomized group) No OAD (non-randomized group)
    Number of subjects analysed
    38
    43
    19
    46
    103
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline: All Patients (n = 38, 43, 19, 46, 103)
    111.1 ± 18.95
    111.8 ± 18.20
    157.7 ± 66.50
    97.2 ± 14.24
    92.2 ± 8.58
        Change at EOP: All Patients (n = 37,41,19,45,101)
    22.2 ± 31.67
    22.5 ± 34.05
    9.8 ± 75.67
    22.9 ± 23.40
    16.3 ± 13.63
        Baseline: Cushing's (n = 12, 13, 6, 13, 15)
    117.9 ± 20.99
    106.3 ± 15.71
    147.2 ± 68.38
    93.3 ± 10.98
    85.5 ± 6.92
        Change at EOP: Cushing's (n = 12, 12, 6, 13, 14)
    13.4 ± 34.92
    36.4 ± 33.11
    21.3 ± 72.01
    15.8 ± 18.43
    11.7 ± 22.11
        Baseline: Acromegaly (n = 26, 30, 13, 33, 88)
    107.9 ± 17.46
    114.2 ± 18.91
    162.5 ± 67.85
    98.8 ± 15.20
    93.4 ± 8.32
        Change at EOP: Acromegaly (n = 25, 29, 13, 32, 87)
    26.5 ± 29.79
    16.7 ± 33.29
    4.6 ± 79.57
    25.8 ± 24.82
    17.0 ± 11.75
    No statistical analyses for this end point

    Secondary: Percentage of participants with ≤ 0.3% HbA1c increase to end of Core Phase

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    End point title
    Percentage of participants with ≤ 0.3% HbA1c increase to end of Core Phase [8]
    End point description
    Percentage of participants with ≤ 0.3% HbA1c increase in the incretin based therapy arm and the insulin arm.
    End point type
    Secondary
    End point timeframe
    Randomization, up to 16 weeks
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    Incretin based therapy (randomized group) Insulin (randomized group)
    Number of subjects analysed
    38
    43
    Units: Percentage of participants
        number (confidence interval 95%)
    73.7 (56.9 to 86.6)
    65.1 (49.1 to 79.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse Events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit up to approximately 46 months.
    Adverse event reporting additional description
    There are different safety follow-up period for Cushing's and for acromegaly patients: On-treatment period: from day of first dose of study medication to 28 days after last dose of pasireotide s.c. and 84 days after last dose of pasireotide long acting, or the follow-up visit, whichever comes later.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Incretin based therapy (randomized group)
    Reporting group description
    Participants randomized to the incretin based arm started with sitagliptin once daily. If sitagliptin did not control the participant's hyperglycemia, sitagliptin was stopped and participants switched to liraglutide once daily. If despite treatment with liraglutide, hyperglycemia was not controlled then the participant was eligible for rescue therapy with addition of insulin

    Reporting group title
    Insulin (randomized group)
    Reporting group description
    Participants randomized to the insulin arm started with once daily dose of basal insulin. The dose was up or down titrated at the discretion of the investigator. If blood glucose levels remained uncontrolled on basal insulin, participant switched to basal insulin plus prandial insulin.

    Reporting group title
    Baseline Insulin (BL) (non-randomized group)
    Reporting group description
    This group included participants who were receiving insulin at study entry and thus were not eligible for randomization.

    Reporting group title
    Oral antidiabetic drugs (OAD) (non-randomized group)
    Reporting group description
    This group included participants who developed hyperglycemia that was controlled by metformin and/or other background antidiabetic treatment and thus were not randomized.

    Reporting group title
    No OAD (non-randomized group)
    Reporting group description
    This group included participants who did not receive any antidiabetic medication during the Core Phase of the study and thus were not randomized.

    Serious adverse events
    Incretin based therapy (randomized group) Insulin (randomized group) Baseline Insulin (BL) (non-randomized group) Oral antidiabetic drugs (OAD) (non-randomized group) No OAD (non-randomized group)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 38 (15.79%)
    3 / 43 (6.98%)
    4 / 19 (21.05%)
    2 / 46 (4.35%)
    7 / 103 (6.80%)
         number of deaths (all causes)
    0
    0
    1
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Vascular disorders
    Shock
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubular breast carcinoma
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Wound
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery stenosis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Cushing's syndrome
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 46 (2.17%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 43 (2.33%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Breast abscess
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 46 (2.17%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Incretin based therapy (randomized group) Insulin (randomized group) Baseline Insulin (BL) (non-randomized group) Oral antidiabetic drugs (OAD) (non-randomized group) No OAD (non-randomized group)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 38 (97.37%)
    40 / 43 (93.02%)
    18 / 19 (94.74%)
    38 / 46 (82.61%)
    87 / 103 (84.47%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 46 (2.17%)
    2 / 103 (1.94%)
         occurrences all number
    2
    0
    0
    1
    3
    Fatigue
         subjects affected / exposed
    4 / 38 (10.53%)
    4 / 43 (9.30%)
    0 / 19 (0.00%)
    1 / 46 (2.17%)
    5 / 103 (4.85%)
         occurrences all number
    4
    4
    0
    1
    5
    Peripheral swelling
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    1 / 46 (2.17%)
    1 / 103 (0.97%)
         occurrences all number
    1
    0
    1
    2
    1
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 43 (2.33%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Polycystic ovaries
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 43 (4.65%)
    1 / 19 (5.26%)
    1 / 46 (2.17%)
    2 / 103 (1.94%)
         occurrences all number
    4
    4
    1
    1
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 43 (6.98%)
    1 / 19 (5.26%)
    1 / 46 (2.17%)
    2 / 103 (1.94%)
         occurrences all number
    2
    4
    1
    1
    2
    Bacterial test positive
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    1 / 46 (2.17%)
    5 / 103 (4.85%)
         occurrences all number
    3
    0
    3
    1
    5
    Blood creatinine increased
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Blood glucose increased
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    3 / 46 (6.52%)
    9 / 103 (8.74%)
         occurrences all number
    2
    5
    0
    3
    11
    Blood insulin increased
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences all number
    1
    0
    1
    0
    1
    Blood urea increased
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Blood uric acid increased
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 43 (4.65%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Carbon dioxide decreased
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 38 (5.26%)
    4 / 43 (9.30%)
    0 / 19 (0.00%)
    2 / 46 (4.35%)
    0 / 103 (0.00%)
         occurrences all number
    2
    6
    0
    2
    0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences all number
    3
    1
    0
    0
    1
    Lipase increased
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 43 (4.65%)
    0 / 19 (0.00%)
    1 / 46 (2.17%)
    5 / 103 (4.85%)
         occurrences all number
    4
    2
    0
    1
    6
    Weight decreased
         subjects affected / exposed
    10 / 38 (26.32%)
    4 / 43 (9.30%)
    0 / 19 (0.00%)
    5 / 46 (10.87%)
    2 / 103 (1.94%)
         occurrences all number
    11
    5
    0
    5
    2
    Weight increased
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 43 (2.33%)
    1 / 19 (5.26%)
    2 / 46 (4.35%)
    0 / 103 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences all number
    0
    0
    1
    0
    1
    Sinus bradycardia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 46 (2.17%)
    6 / 103 (5.83%)
         occurrences all number
    0
    0
    0
    1
    6
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences all number
    0
    0
    1
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 43 (4.65%)
    1 / 19 (5.26%)
    2 / 46 (4.35%)
    3 / 103 (2.91%)
         occurrences all number
    0
    2
    1
    2
    3
    Leukopenia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    1 / 46 (2.17%)
    3 / 103 (2.91%)
         occurrences all number
    0
    0
    1
    1
    3
    Neutropenia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    2 / 19 (10.53%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences all number
    0
    0
    3
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 38 (13.16%)
    5 / 43 (11.63%)
    0 / 19 (0.00%)
    3 / 46 (6.52%)
    6 / 103 (5.83%)
         occurrences all number
    5
    5
    0
    3
    6
    Dysgeusia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    4 / 38 (10.53%)
    4 / 43 (9.30%)
    0 / 19 (0.00%)
    2 / 46 (4.35%)
    12 / 103 (11.65%)
         occurrences all number
    5
    4
    0
    2
    29
    Syncope
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 43 (4.65%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    Abdominal distension
         subjects affected / exposed
    4 / 38 (10.53%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 46 (2.17%)
    4 / 103 (3.88%)
         occurrences all number
    5
    0
    0
    1
    4
    Abdominal pain
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    2 / 46 (4.35%)
    1 / 103 (0.97%)
         occurrences all number
    2
    1
    0
    2
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 43 (4.65%)
    1 / 19 (5.26%)
    1 / 46 (2.17%)
    2 / 103 (1.94%)
         occurrences all number
    1
    2
    1
    1
    2
    Constipation
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    3 / 103 (2.91%)
         occurrences all number
    3
    0
    0
    0
    3
    Diarrhoea
         subjects affected / exposed
    11 / 38 (28.95%)
    12 / 43 (27.91%)
    2 / 19 (10.53%)
    10 / 46 (21.74%)
    21 / 103 (20.39%)
         occurrences all number
    14
    17
    3
    13
    49
    Erosive duodenitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gingival hypertrophy
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    13 / 38 (34.21%)
    7 / 43 (16.28%)
    0 / 19 (0.00%)
    5 / 46 (10.87%)
    11 / 103 (10.68%)
         occurrences all number
    15
    7
    0
    7
    12
    Vomiting
         subjects affected / exposed
    5 / 38 (13.16%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    2 / 46 (4.35%)
    1 / 103 (0.97%)
         occurrences all number
    6
    0
    0
    4
    1
    Renal and urinary disorders
    Glycosuria
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 43 (2.33%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Haematuria
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences all number
    3
    0
    0
    0
    1
    Nephrolithiasis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 43 (2.33%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    5 / 38 (13.16%)
    8 / 43 (18.60%)
    0 / 19 (0.00%)
    4 / 46 (8.70%)
    9 / 103 (8.74%)
         occurrences all number
    5
    9
    0
    5
    9
    Hepatic steatosis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 43 (2.33%)
    1 / 19 (5.26%)
    3 / 46 (6.52%)
    1 / 103 (0.97%)
         occurrences all number
    0
    1
    1
    3
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    3 / 103 (2.91%)
         occurrences all number
    2
    1
    0
    0
    3
    Pruritus generalised
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 43 (4.65%)
    1 / 19 (5.26%)
    1 / 46 (2.17%)
    2 / 103 (1.94%)
         occurrences all number
    3
    2
    1
    1
    2
    Rash generalised
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Skin ulcer
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 46 (2.17%)
    8 / 103 (7.77%)
         occurrences all number
    0
    0
    0
    1
    17
    Back pain
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 43 (6.98%)
    0 / 19 (0.00%)
    2 / 46 (4.35%)
    5 / 103 (4.85%)
         occurrences all number
    0
    3
    0
    2
    6
    Muscular weakness
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 43 (4.65%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    3
    3
    0
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 43 (4.65%)
    1 / 19 (5.26%)
    4 / 46 (8.70%)
    1 / 103 (0.97%)
         occurrences all number
    1
    2
    1
    4
    1
    Osteopenia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    1 / 46 (2.17%)
    1 / 103 (0.97%)
         occurrences all number
    2
    0
    0
    1
    1
    Hypothyroidism
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    3 / 46 (6.52%)
    1 / 103 (0.97%)
         occurrences all number
    0
    1
    0
    3
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 43 (6.98%)
    0 / 19 (0.00%)
    1 / 46 (2.17%)
    2 / 103 (1.94%)
         occurrences all number
    3
    3
    0
    1
    2
    Diabetes mellitus
         subjects affected / exposed
    5 / 38 (13.16%)
    9 / 43 (20.93%)
    2 / 19 (10.53%)
    14 / 46 (30.43%)
    4 / 103 (3.88%)
         occurrences all number
    5
    9
    2
    14
    4
    Dyslipidaemia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 43 (2.33%)
    1 / 19 (5.26%)
    3 / 46 (6.52%)
    2 / 103 (1.94%)
         occurrences all number
    0
    1
    1
    3
    2
    Hyperglycaemia
         subjects affected / exposed
    14 / 38 (36.84%)
    11 / 43 (25.58%)
    6 / 19 (31.58%)
    9 / 46 (19.57%)
    13 / 103 (12.62%)
         occurrences all number
    51
    21
    34
    10
    13
    Hypertriglyceridaemia
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences all number
    3
    1
    0
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    5 / 38 (13.16%)
    10 / 43 (23.26%)
    8 / 19 (42.11%)
    5 / 46 (10.87%)
    4 / 103 (3.88%)
         occurrences all number
    8
    25
    32
    7
    7
    Hypokalaemia
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    2 / 46 (4.35%)
    0 / 103 (0.00%)
         occurrences all number
    3
    0
    1
    3
    0
    Impaired fasting glucose
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 43 (4.65%)
    0 / 19 (0.00%)
    2 / 46 (4.35%)
    14 / 103 (13.59%)
         occurrences all number
    0
    2
    0
    2
    16
    Type 2 diabetes mellitus
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 43 (2.33%)
    0 / 19 (0.00%)
    1 / 46 (2.17%)
    1 / 103 (0.97%)
         occurrences all number
    2
    1
    0
    1
    1
    Infections and infestations
    Bone abscess
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 38 (7.89%)
    4 / 43 (9.30%)
    0 / 19 (0.00%)
    3 / 46 (6.52%)
    16 / 103 (15.53%)
         occurrences all number
    3
    6
    0
    3
    27
    Onychomycosis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 43 (2.33%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    4 / 103 (3.88%)
         occurrences all number
    0
    0
    1
    0
    5
    Pneumonia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Respiratory tract infection viral
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 43 (0.00%)
    0 / 19 (0.00%)
    0 / 46 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 43 (0.00%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    1 / 103 (0.97%)
         occurrences all number
    0
    0
    1
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 43 (6.98%)
    3 / 19 (15.79%)
    6 / 46 (13.04%)
    15 / 103 (14.56%)
         occurrences all number
    2
    6
    3
    9
    16
    Urinary tract infection
         subjects affected / exposed
    3 / 38 (7.89%)
    5 / 43 (11.63%)
    1 / 19 (5.26%)
    0 / 46 (0.00%)
    4 / 103 (3.88%)
         occurrences all number
    6
    9
    1
    0
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Aug 2014
    Changes were introduced upon Health Authorities (HA) request: An additional LFT monitoring at Week 1 for the cohort of patients with Cushing’s disease (pasireotide s.c. formulation) was included in line with the approved Signifor SmPC; Additional ECG monitoring at Week 1 in line with the approved Signifor SmPC for the cohort of patients on the s.c. formulation of pasireotide; and at Week 3 in line with the proposed EU SmPC for pasireotide LAR in Acromegaly were included; In line with the Adverse Drug Report profile described in the approved labels of anti-diabetic medications used in this study, the following changes were implemented: Exclusion #13 to exclude patients with cholelithiasis and acute and chronic pancreatitis; A new exclusion criterion for patients with a family history of MTC or MEN2 was added; Exclusion #18 to exclude patients with renal dysfunction as defined by local metformin label (e.g. As per SmPC, creatinine clearance < 60 mL/min); Additional pancreatic safety monitoring (lipase and amylase) was added for all patients; Patients in Denmark on pasireotide long acting were to participate in the overall study for up to a maximum of 1 year; To ensure that patients were followed for at least 5 times the t1/2 of study drug, the safety follow-up monitoring was extended to 84 days in patients who received the pasireotide LAR; To account for gender differences in QTcF as acknowledged by HA, the exclusion criterion at screening was modified to QTcF > 450 ms for males and > 460 ms for females; To clarify the washout period for other SSAs, 8 weeks washout for octreotide long acting and lanreotide autogel was specified; Wash-out period for previous exposure to pasireotide s.c. has been updated to 1 week to minimize unnecessary interruption of pasireotide based on the 16-hour t1/2 of pasireotide s.c.; The suggested insulin titration schedule was updated to align with the study defined glycemic control (mean -consecutive daily SMBG < 126 mg/dL).
    29 Sep 2016
    The rationale of amendment 2 was to remove the protocol requirement to randomize the equal number of patients with Cushing’s disease and Acromegaly (a total of 79 patients). In protocol amendment 1, the target was to randomize 79 patients (42 in Cushing’s disease and 37 in acromegaly) to obtain 68 randomized patients (34 with Cushing’s disease and 34 with acromegaly, who completed at least 8-week randomized treatment without any rescue medication).
    17 Mar 2017
    Clarification regarding the protocol visits included in the 28-day Safety follow-up for Cushing’s disease patients who received pasireotide s.c and the 84-day Safety follow-up for acromegaly patients who received pasireotide long acting as follows: Eligible patients as per protocol who are transitioning to a roll-over study or local access program were not be required to perform the safety follow-up visit (779) as patients were continued to be monitored for safety; Eligible patients as per protocol who were transitioning to commercial drug were required to perform the safety follow-up visit (779); Re-insertion of the missing figure related to QT Prolongation Safety Management; Allow a ± 3 day visit window for Cushing’s patients. Visit windows for Acromegaly patients remained unchanged.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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