Study of Management of Pasireotide-induced Hyperglycemia in Adult Patients With Cushing's Disease or Acromegaly

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02060383
• Collaborator: (none)
• Enrollment: 249
• Locations: 43
• Arms: 3
• Actual Duration (Months): 46.1
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The study was designed to investigate the optimal management of hyperglycemia developed during pasireotide treatment in participants with Cushing's disease or Acromegaly, which was not manageable with metformin.

This was a Phase IV, multi-center, randomized, open-label study. Eligible patients started pasireotide subcutaneously (s.c.) for Cushing's disease and pasireotide LAR (long-acting release) for Acromegaly.

Participants being treated with pasireotide s.c or LAR at screening were eligible as long as they met protocol criteria during the screening period. If previously normo-glycemic participants experienced an increase in their fasting blood glucose and met the criteria for diabetes while on pasireotide, they started anti-diabetic treatment using metformin. If they continued to have elevated blood glucose above target on metformin within the first 16 weeks, they were randomized in a 1:1 ratio to receive treatment with incretin based therapy or insulin for approximately 16 weeks.

Participants who continued to receive clinical benefit after completing the Core Phase could enter an optional Extension Phase if pasireotide was not commercially available in their country or a local access program was not available to provide drug. Patients continued in the Extension Phase until the last participant randomized in the Core Phase completed 16 weeks of treatment post-randomization.

Condition or Disease	Intervention/Treatment	Phase
Cushing's Disease; Acromegaly	Drug: Pasireotide s.c.; Drug: Sitagliptin; Drug: Liraglutide; Drug: Insulin; Drug: Pasireotide LAR; Drug: Metformin	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 249 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: 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
• Actual Study Start Date: May 23, 2014
• Actual Primary Completion Date: Feb 5, 2018
• Actual Study Completion Date: Mar 26, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Incretin based therapy (randomized group) 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.	Drug: Pasireotide s.c.; Administered to Cushing's disease participants.; Other Names: SOM230 ; Drug: Sitagliptin; Taken for approximately 16 weeks during the core study phase or until the drug was found not to be effective; Drug: Liraglutide; Participant switched to liraglutide if sitagliptin was found not to be effective.; Drug: Insulin; Participant took insulin for 16 weeks. Insulin was also administered as rescue therapy in the incretin-based therapy arm if required. Insulin was administered to the BL-insulin group at the discretion of the Principal Investigator. Note: OAD and No OAD groups within the non-randomized arm did not take Insulin.; Drug: Pasireotide LAR; Administered to Acromegaly participants.; Other Names: SOM230 ; Drug: Metformin; If previously normo-glycemic participants experienced increase in their fasting blood glucose and meeting the criteria for diabetes while on pasireotide, they started anti-diabetic treatment using metformin. If they continued to experience increase in their fasting blood glucose within the first 16 weeks, they were randomized in a 1:1 ratio to receive treatment with incretin based therapy or insulin for approximately 16 weeks. Metformin treatment was not required for the BL Insulin and OAD groups, within the non-randomized arm, but may have been prescribed at the discretion of the investigator. Note: No OAD group within the non-randomized arm did not take metformin.
Experimental: Insulin (randomized group) 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.	Drug: Pasireotide s.c.; Administered to Cushing's disease participants.; Other Names: SOM230 ; Drug: Insulin; Participant took insulin for 16 weeks. Insulin was also administered as rescue therapy in the incretin-based therapy arm if required. Insulin was administered to the BL-insulin group at the discretion of the Principal Investigator. Note: OAD and No OAD groups within the non-randomized arm did not take Insulin.; Drug: Pasireotide LAR; Administered to Acromegaly participants.; Other Names: SOM230 ; Drug: Metformin; If previously normo-glycemic participants experienced increase in their fasting blood glucose and meeting the criteria for diabetes while on pasireotide, they started anti-diabetic treatment using metformin. If they continued to experience increase in their fasting blood glucose within the first 16 weeks, they were randomized in a 1:1 ratio to receive treatment with incretin based therapy or insulin for approximately 16 weeks. Metformin treatment was not required for the BL Insulin and OAD groups, within the non-randomized arm, but may have been prescribed at the discretion of the investigator. Note: No OAD group within the non-randomized arm did not take metformin.
Other: Non-Randomized Arm This arm represents the non-randomized participants: Cushing's Disease (CD) or Acromegaly participants, who received pasireotide s.c. or LAR (long-acting release) respectively, but who were not randomized to the Incretin or Insulin arms. For the purpose of analysis, this non-randomized arm is further split into 3 groups: Baseline insulin group (BL insulin) includes participants who were receiving insulin at study entry Oral antidiabetic drugs (OAD) group includes participants who developed hyperglycemia that was controlled by metformin and/or other background anti-diabetic treatment No OAD group includes participants who did not receive any anti-diabetic medication during the core phase of the trial	Drug: Pasireotide s.c.; Administered to Cushing's disease participants.; Other Names: SOM230 ; Drug: Insulin; Participant took insulin for 16 weeks. Insulin was also administered as rescue therapy in the incretin-based therapy arm if required. Insulin was administered to the BL-insulin group at the discretion of the Principal Investigator. Note: OAD and No OAD groups within the non-randomized arm did not take Insulin.; Drug: Pasireotide LAR; Administered to Acromegaly participants.; Other Names: SOM230 ; Drug: Metformin; If previously normo-glycemic participants experienced increase in their fasting blood glucose and meeting the criteria for diabetes while on pasireotide, they started anti-diabetic treatment using metformin. If they continued to experience increase in their fasting blood glucose within the first 16 weeks, they were randomized in a 1:1 ratio to receive treatment with incretin based therapy or insulin for approximately 16 weeks. Metformin treatment was not required for the BL Insulin and OAD groups, within the non-randomized arm, but may have been prescribed at the discretion of the investigator. Note: No OAD group within the non-randomized arm did not take metformin.

Outcome Measures

Primary Outcome Measures

1. Change in HbA1c From Randomization to Approximately 16 Weeks [Randomization, 16 weeks]

   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.

Secondary Outcome Measures

1. Change in HbA1c From Randomization (R) Over Time Per Randomized Arm [Randomization (R), Week (W) 4 post R, W 8 post R, W 16 post R, end of Core phase (up to week 16 post R)]

   Absolute change in HbA1c overtime from randomization (i.e. start of randomized antidiabetic treatment) to end of core phase per randomized arm

2. Change in FPG (Fasting Plasma Glucose) From Randomization Until End of Core Phase [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]

   Absolute change in fasting glucose overtime from randomization (i.e. start of randomized antidiabetic treatment) to end of core phase per randomized arm

3. Percentage of Participants in the Incretin-based Arm Who Required Anti-diabetic Rescue Therapy With Insulin [Randomization to up to 16 weeks]

   The percentage of participants who received anti-diabetic rescue therapy in incretin based therapy is summarized.

4. Absolute Change in HbA1c From Baseline to End of Core Phase [Baseline, up to 32 weeks (end of Core phase)]

   Absolute change in HbA1c from baseline to end of core phase in the incretin based therapy arm and the insulin arm

5. Absolute Change in FPG From Baseline to End of Core Phase [Baseline, Up to 32 weeks (end of Core Phase)]

   Absolute change in FPG from baseline to end of core phase in the incretin based therapy arm and the insulin arm.

6. Percentage of Participants With ≤ 0.3% HbA1c Increase to End of Core Phase [Randomization, up to 16 weeks]

   Percentage of participants with ≤ 0.3% HbA1c increase in the incretin based therapy arm and the insulin arm.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients greater than or equal to 18 years old

• Confirmed diagnosis of Cushing's disease or acromegaly

Exclusion Criteria:

• Patients who require surgical intervention

• Patients receiving DPP-4 inhibitors or GLP-1 receptor agonists within 4 weeks prior to study entry

• HbA1c > 10 % at screening

• Known hypersensitivity to somatostatin analogues Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Diabetes and Endocrine Associates La Mesa Location	Multiple Locations	California	United States
2	LA Biomedical Research at Harbor UCLA Medical Center SC - SOM230B2219	Torrance	California	United States	90502
3	Coastal Metabolic Research Centre SC	Ventura	California	United States	93003
4	East Coast Institute for Research East Coast Inst. for Res(ECIR)	Jacksonville	Florida	United States	32223
5	Washington University SC - SOM230B2411	Saint Louis	Missouri	United States	63110
6	Great Falls Clinic	Great Falls	Montana	United States	59405
7	Robert Wood Johnson Medical School - Rutgers SC	New Brunswick	New Jersey	United States	08901
8	The Mount Sinai Hospital SC	New York	New York	United States	10029
9	Columbia University Medical Center New York Presbyterian Neuroendocrine Unit	New York	New York	United States	10032
10	Lenox Hill Hospital/Manhattan Eye, Ear and Throat Hospital SC	New York	New York	United States	10075
11	Allegheny Endocrinology Associates SC	Pittsburgh	Pennsylvania	United States	15212
12	Vanderbilt Clinical Trials Center SOM230B2219	Nashville	Tennessee	United States	37212-8210
13	Baylor College of Medicine Ben Taub General Hosp.	Houston	Texas	United States	77030
14	Virginia Endocrinology Research SC-2	Chesapeake	Virginia	United States	23321
15	Swedish Medical Center Dept.ofSeattle Neuroscience(2)	Seattle	Washington	United States	98122-4379
16	Novartis Investigative Site	Leuven		Belgium	3000
17	Novartis Investigative Site	Wilrijk		Belgium	2610
18	Novartis Investigative Site	Rio de Janeiro	RJ	Brazil	21941-590
19	Novartis Investigative Site	Porto Alegre	RS	Brazil	90560-030
20	Novartis Investigative Site	Joinville	SC	Brazil	89201260
21	Novartis Investigative Site	São Paulo	SP	Brazil	05403 000
22	Novartis Investigative Site	Beijing	Beijing	China	100730
23	Novartis Investigative Site	Guangzhou	Guangdong	China	510000
24	Novartis Investigative Site	Chengdu	Sichuan	China	610041
25	Novartis Investigative Site	Aalborg		Denmark	9000
26	Novartis Investigative Site	Aarhus		Denmark	DK-8000
27	Novartis Investigative Site	Herlev		Denmark	DK-2730
28	Novartis Investigative Site	Odense C		Denmark	DK-5000
29	Novartis Investigative Site	Erlangen		Germany	91054
30	Novartis Investigative Site	Freiburg		Germany	79106
31	Novartis Investigative Site	Oldenburg		Germany	26122
32	Novartis Investigative Site	Bangalore	Karnataka	India	560054
33	Novartis Investigative Site	Vellore	Tamil Nadu	India	632004
34	Novartis Investigative Site	San Isidro	Lima	Peru	27
35	Novartis Investigative Site	Warszawa		Poland	00-909
36	Novartis Investigative Site	Wroclaw		Poland	50 367
37	Novartis Investigative Site	Saint Petersburg		Russian Federation	197341
38	Novartis Investigative Site	Bangkok		Thailand	10400
39	Novartis Investigative Site	Bangkok		Thailand	10700
40	Novartis Investigative Site	Songkla		Thailand	90110
41	Novartis Investigative Site	Altunizade		Turkey	34662
42	Novartis Investigative Site	Ankara		Turkey	06500
43	Novartis Investigative Site	Antalya		Turkey	07070

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Mar 17, 2017
• Statistical Analysis Plan - Jun 25, 2018

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02060383
• Other Study ID Numbers: CSOM230B2219; 2012-002916-16
• First Posted: Feb 12, 2014
• Last Update Posted: May 29, 2019
• Last Verified: May 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Cushing's disease; acromegaly; pasireotide; hyperglycemia
• Additional relevant MeSH terms: ACTH-Secreting Pituitary Adenoma; Acromegaly; Pituitary ACTH Hypersecretion; Hyperglycemia; Metformin; Sitagliptin Phosphate; Liraglutide; Pasireotide; Somatostatin

Study Results

Participant Flow

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 Detail	249 participants were included in study & treated with pasireotide s.c. (59 with Cushing's disease) or pasireotide LAR (190 with acromegaly). Following pre-randomization period (up to 16 weeks), 81 participants were randomized to either incretin-based therapy or insulin (72 evaluable for the primary analysis) & 168 not qualified for randomization.

Arm/Group Title	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)
Arm/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	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.	This group included participants who were receiving insulin at study entry.	This group included participants who developed hyperglycemia that was controlled by metformin and/or other background anti-diabetic treatment. Patients in this group did not require additional treatment with either incretin or insulin.	This group included participants who did not receive any anti-diabetic medication during the Core Phase of the study as they did not develop hyperglycemia.
Period Title: Core Phase
STARTED	38	43	19	46	103
Completed Core/Entered Extension	17	17	10	21	53
Completed Core/Did Not Enter Extension	18	20	9	18	42
COMPLETED	35	37	19	39	95
NOT COMPLETED	3	6	0	7	8
Period Title: Core Phase
STARTED	17	17	10	21	53
COMPLETED	14	14	7	19	46
NOT COMPLETED	3	3	3	2	7

Baseline Characteristics

Arm/Group Title	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
Arm/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	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.	This group included participants who were receiving insulin at study entry.	This group included participants who developed hyperglycemia that was controlled by metformin and/or other background anti-diabetic treatment. Patients in this group did not require additional treatment with either incretin or insulin.	This group included participants who did not receive any anti-diabetic medication during the Core Phase of the study as they did not develop hyperglycemia.	Total of all reporting groups
Overall Participants	38	43	19	46	103	249
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	50.6 (11.76)	46.4 (12.90)	46.7 (12.54)	40.2 (13.80)	37.8 (11.17)	42.4 (13.05)
Sex: Female, Male (Count of Participants)
Female	22 57.9%	27 62.8%	10 52.6%	31 67.4%	47 45.6%	137 55%
Male	16 42.1%	16 37.2%	9 47.4%	15 32.6%	56 54.4%	112 45%
Race/Ethnicity, Customized (Number) [Number]
Other	22 57.9%	24 55.8%	11 57.9%	25 54.3%	43 41.7%	125 50.2%
Chinese	5 13.2%	9 20.9%	1 5.3%	13 28.3%	33 32%	61 24.5%
Hispanic/Latino	7 18.4%	2 4.7%	5 26.3%	6 13%	19 18.4%	39 15.7%
Indian (Indian subcontinent)	4 10.5%	8 18.6%	2 10.5%	2 4.3%	7 6.8%	23 9.2%
Japanese	0 0%	0 0%	0 0%	0 0%	1 1%	1 0.4%

Outcome Measures

1. Primary Outcome

Title	Change in HbA1c From Randomization to Approximately 16 Weeks
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.
Time Frame	Randomization, 16 weeks

Outcome Measure Data

Analysis Population Description

Randomized Analysis Set (RAS): all patients who received at least one dose of pasireotide and were assigned to either incretin based therapy or insulin by randomization. If the patient discontinued the study or used rescue treatment within 8 weeks after randomization, it was considered missing.

Arm/Group Title	Incretin Based Therapy (Randomized Group)	Insulin (Randomized Group)
Arm/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	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.
Measure Participants	31	41
All Patients	-0.12	0.26
Cushing's Disease	0.33	0.45
Acromegaly	-0.25	0.19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Incretin Based Therapy (Randomized Group), Insulin (Randomized Group)
	Comments	All Patients
	Type of Statistical Test	Other
	Comments	There was no formal hypothesis testing planned in this study.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -0.63 to 0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments	Difference of adjusted mean change in HbA1c between the two arms based on an ANOVA model with treatment (Incretin, Insulin) and randomization stratification factors (Cushing's vs. Acromegaly; baseline HbA1c <7% vs ≥7%) as fixed effects.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Incretin Based Therapy (Randomized Group), Insulin (Randomized Group)
	Comments	Cushing's Disease
	Type of Statistical Test	Other
	Comments	There was no formal hypothesis testing planned in this study.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.96 to 0.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.45
	Estimation Comments	Difference of adjusted mean change in HbA1c between the two arms based on an ANOVA model with treatment (Incretin, Insulin) and randomization stratification factors (baseline HbA1c <7% vs ≥7%) as fixed effects.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Incretin Based Therapy (Randomized Group), Insulin (Randomized Group)
	Comments	Acromegaly
	Type of Statistical Test	Other
	Comments	There was no formal hypothesis testing planned in this study.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.36
	Confidence Interval	(2-Sided) 95%; -0.74 to 0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.19
	Estimation Comments	Difference of adjusted mean change in HbA1c between the two arms based on an ANOVA model with treatment (Incretin, Insulin) and randomization stratification factors (baseline HbA1c <7% vs ≥7%) as fixed effects.

2. Secondary Outcome

Title	Change in HbA1c From Randomization (R) Over Time Per Randomized Arm
Description	Absolute change in HbA1c overtime from randomization (i.e. start of randomized antidiabetic treatment) to end of core phase per randomized arm
Time Frame	Randomization (R), Week (W) 4 post R, W 8 post R, W 16 post R, end of Core phase (up to week 16 post R)

Outcome Measure Data

Analysis Population Description

Randomized Analysis Set (RAS): all patients who received at least one dose of pasireotide and were assigned to either incretin based therapy or insulin by randomization.

Arm/Group Title	Incretin Based Therapy (Randomized Group)	Insulin (Randomized Group)
Arm/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	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.
Measure Participants	38	43
Randomization	7.1 (1.00)	7.1 (0.75)
Change at RW4 D29	0.5 (0.73)	0.5 (0.60)
Change at RW8 D57	0.3 (0.98)	0.5 (0.86)
Change at RW12 D85	0.2 (1.03)	0.4 (0.85)
Change at RW16 D113	0.0 (0.93)	0.3 (0.87)
End of Core Phase	0.0 (0.92)	0.3 (0.84)

3. Secondary Outcome

Title	Change in FPG (Fasting Plasma Glucose) From Randomization Until End of Core Phase
Description	Absolute change in fasting glucose overtime from randomization (i.e. start of randomized antidiabetic treatment) to end of core phase per randomized arm
Time Frame	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

Outcome Measure Data

Analysis Population Description

Randomized Analysis Set (RAS): all patients who received at least one dose of pasireotide and were assigned to either incretin based therapy or insulin by randomization.

Arm/Group Title	Incretin Based Therapy (Randomized Group)	Insulin (Randomized Group)
Arm/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	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.
Measure Participants	38	43
Randomization	172.2 (60.78)	167.9 (40.77)
Change at RW2 D15	4.6 (51.01)	-31.1 (41.19)
Change at RW4 D29	-15.0 (47.95)	-28.3 (41.14)
Change at RW6 D43	-17.7 (57.97)	-37.5 (52.39)
Change at RW8 D57	-25.7 (53.32)	-38.3 (44.10)
Change at RW10 D71	-28.8 (61.14)	-36.9 (50.82)
Change at RW12 D85	-33.4 (50.17)	-41.1 (51.68)
Change at RW14 D99	-35.1 (55.83)	-35.6 (47.43)
Change at RW16 D113	-38.8 (53.69)	-33.4 (47.63)
End of Core Phase	-40.1 (56.35)	-36.0 (46.90)

4. Secondary Outcome

Title	Percentage of Participants in the Incretin-based Arm Who Required Anti-diabetic Rescue Therapy With Insulin
Description	The percentage of participants who received anti-diabetic rescue therapy in incretin based therapy is summarized.
Time Frame	Randomization to up to 16 weeks

Outcome Measure Data

Analysis Population Description

Safety set - All participants randomized to the incretin-based therapy who received at least one dose of pasireotide and had at least one post-baseline safety assessment. Randomized participants within the safety set were analyzed according to the anti-diabetic study treatment first received.

Arm/Group Title	Incretin Based Therapy (Randomized Group)
Arm/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
Measure Participants	38
Number (95% Confidence Interval) [Percentage of participants]	31.6 83.2%

5. Secondary Outcome

Title	Absolute Change in HbA1c From Baseline to End of Core Phase
Description	Absolute change in HbA1c from baseline to end of core phase in the incretin based therapy arm and the insulin arm
Time Frame	Baseline, up to 32 weeks (end of Core phase)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): Participants who received at least 1 dose of pasireotide. Randomized participants were analyzed according to the anti-diabetic treatment assigned to at randomization. Non-randomized participants were analyzed by the anti-diabetic treatment received during the core phase (insulin at baseline, oral antidiabetics (OAD), none).

Arm/Group Title	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)
Arm/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	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.	This group included participants who were receiving insulin at study entry.	This group included participants who developed hyperglycemia that was controlled by metformin and/or other background anti-diabetic treatment. Patients in this group did not require additional treatment with either incretin or insulin.	This group included participants who did not receive any anti-diabetic medication during the Core Phase of the study as they did not develop hyperglycemia.
Measure Participants	38	43	19	46	103
Baseline: All Patients	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	0.8 (0.97)	1.1 (0.94)	1.3 (1.40)	0.8 (0.64)	0.4 (0.32)
Baseline: Cushing's	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	1.3 (1.19)	1.7 (1.05)	1.4 (1.58)	0.9 (0.95)	0.5 (0.51)
Baseline: Acromegaly	6.1 (0.71)	6.3 (0.65)	8.0 (1.61)	5.6 (0.36)	5.4 (0.32)
Change at EOP: Acromegaly	0.6 (0.78)	0.8 (0.78)	1.2 (1.37)	0.7 (0.47)	0.4 (0.28)

6. Secondary Outcome

Title	Absolute Change in FPG From Baseline to End of Core Phase
Description	Absolute change in FPG from baseline to end of core phase in the incretin based therapy arm and the insulin arm.
Time Frame	Baseline, Up to 32 weeks (end of Core Phase)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All participants who received at least one dose of pasireotide. Randomized patients were analyzed according to the anti-diabetic treatment assigned to at randomization. Non-randomized patients were analyzed by the anti-diabetic treatment received during the core phase (insulin at baseline, oral antidiabetics (OAD), none).

Arm/Group Title	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)
Arm/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	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.	This group included participants who were receiving insulin at study entry.	This group included participants who developed hyperglycemia that was controlled by metformin and/or other background anti-diabetic treatment. Patients in this group did not require additional treatment with either incretin or insulin.	This group included participants who did not receive any anti-diabetic medication during the Core Phase of the study as they did not develop hyperglycemia.
Measure Participants	38	43	19	46	103
Baseline: All Patients	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	22.2 (31.67)	22.5 (34.05)	9.8 (75.67)	22.9 (23.40)	16.3 (13.63)
Baseline: Cushing's	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	13.4 (34.92)	36.4 (33.11)	21.3 (72.01)	15.8 (18.43)	11.7 (22.11)
Baseline: Acromegaly	107.9 (17.46)	114.2 (18.91)	162.5 (67.85)	98.8 (15.20)	93.4 (8.32)
Change at EOP: Acromegaly	26.5 (29.79)	16.7 (33.29)	4.6 (79.57)	25.8 (24.82)	17.0 (11.75)

7. Secondary Outcome

Title	Percentage of Participants With ≤ 0.3% HbA1c Increase to End of Core Phase
Description	Percentage of participants with ≤ 0.3% HbA1c increase in the incretin based therapy arm and the insulin arm.
Time Frame	Randomization, up to 16 weeks

Outcome Measure Data

Analysis Population Description

Randomized Analysis Set (RAS): all participants who received at least one dose of pasireotide and were assigned to either incretin based therapy or insulin by randomization.

Arm/Group Title	Incretin Based Therapy (Randomized Group)	Insulin (Randomized Group)
Arm/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	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.
Measure Participants	38	43
Number (95% Confidence Interval) [Percentage of participants]	73.7 193.9%	65.1 151.4%

Adverse Events

Time Frame	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 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.
Arm/Group Title	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)
Arm/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		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.		This group included participants who were receiving insulin at study entry.		This group included participants who developed hyperglycemia that was controlled by metformin and/or other background anti-diabetic treatment. Patients in this group did not require additional treatment with either incretin or insulin.		This group included participants who did not receive any anti-diabetic medication during the Core Phase of the study as they did not develop hyperglycemia.
All Cause Mortality
	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)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		1/103 (1%)
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)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/38 (15.8%)		3/43 (7%)		4/19 (21.1%)		2/46 (4.3%)		7/103 (6.8%)
Blood and lymphatic system disorders
Febrile neutropenia	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Cardiac disorders
Coronary artery stenosis	0/38 (0%)		1/43 (2.3%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Endocrine disorders
Cushing's syndrome	0/38 (0%)		0/43 (0%)		0/19 (0%)		1/46 (2.2%)		0/103 (0%)
Gastrointestinal disorders
Diarrhoea	1/38 (2.6%)		1/43 (2.3%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Pancreatitis acute	0/38 (0%)		1/43 (2.3%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Vomiting	1/38 (2.6%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
General disorders
Fatigue	0/38 (0%)		1/43 (2.3%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Hepatobiliary disorders
Cholecystitis acute	1/38 (2.6%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Infections and infestations
Breast abscess	0/38 (0%)		1/43 (2.3%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Cellulitis	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Epiglottitis	0/38 (0%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		1/103 (1%)
Infectious pleural effusion	1/38 (2.6%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Paronychia	0/38 (0%)		0/43 (0%)		0/19 (0%)		1/46 (2.2%)		0/103 (0%)
Sepsis	2/38 (5.3%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Upper respiratory tract infection	1/38 (2.6%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Urinary tract infection	1/38 (2.6%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Injury, poisoning and procedural complications
Subdural haematoma	0/38 (0%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		1/103 (1%)
Wound	0/38 (0%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		1/103 (1%)
Investigations
Glycosylated haemoglobin increased	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Metabolism and nutrition disorders
Dehydration	1/38 (2.6%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Diabetes mellitus inadequate control	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Hyperglycaemia	1/38 (2.6%)		1/43 (2.3%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Hypoglycaemia	1/38 (2.6%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Hypovolaemia	1/38 (2.6%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Lactic acidosis	1/38 (2.6%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Papillary thyroid cancer	0/38 (0%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		1/103 (1%)
Pituitary tumour benign	0/38 (0%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		1/103 (1%)
Tubular breast carcinoma	1/38 (2.6%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Nervous system disorders
Seizure	1/38 (2.6%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/38 (0%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		2/103 (1.9%)
Pregnancy	0/38 (0%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		1/103 (1%)
Psychiatric disorders
Mental status changes	1/38 (2.6%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Renal and urinary disorders
Acute kidney injury	1/38 (2.6%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Renal injury	0/38 (0%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		1/103 (1%)
Vascular disorders
Shock	1/38 (2.6%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Other (Not Including 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)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/38 (97.4%)		40/43 (93%)		18/19 (94.7%)		38/46 (82.6%)		87/103 (84.5%)
Blood and lymphatic system disorders
Anaemia	0/38 (0%)		2/43 (4.7%)		1/19 (5.3%)		2/46 (4.3%)		3/103 (2.9%)
Leukopenia	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		1/46 (2.2%)		3/103 (2.9%)
Neutropenia	0/38 (0%)		0/43 (0%)		2/19 (10.5%)		0/46 (0%)		1/103 (1%)
Cardiac disorders
Bradycardia	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		1/103 (1%)
Sinus bradycardia	0/38 (0%)		0/43 (0%)		0/19 (0%)		1/46 (2.2%)		6/103 (5.8%)
Ear and labyrinth disorders
Vertigo	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Endocrine disorders
Adrenal insufficiency	2/38 (5.3%)		0/43 (0%)		0/19 (0%)		1/46 (2.2%)		1/103 (1%)
Hypothyroidism	0/38 (0%)		1/43 (2.3%)		0/19 (0%)		3/46 (6.5%)		1/103 (1%)
Gastrointestinal disorders
Abdominal discomfort	2/38 (5.3%)		2/43 (4.7%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Abdominal distension	4/38 (10.5%)		0/43 (0%)		0/19 (0%)		1/46 (2.2%)		4/103 (3.9%)
Abdominal pain	2/38 (5.3%)		1/43 (2.3%)		0/19 (0%)		2/46 (4.3%)		1/103 (1%)
Abdominal pain upper	1/38 (2.6%)		2/43 (4.7%)		1/19 (5.3%)		1/46 (2.2%)		2/103 (1.9%)
Constipation	3/38 (7.9%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		3/103 (2.9%)
Diarrhoea	11/38 (28.9%)		12/43 (27.9%)		2/19 (10.5%)		10/46 (21.7%)		21/103 (20.4%)
Erosive duodenitis	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Gingival hypertrophy	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Nausea	13/38 (34.2%)		7/43 (16.3%)		0/19 (0%)		5/46 (10.9%)		11/103 (10.7%)
Vomiting	5/38 (13.2%)		0/43 (0%)		0/19 (0%)		2/46 (4.3%)		1/103 (1%)
General disorders
Asthenia	2/38 (5.3%)		0/43 (0%)		0/19 (0%)		1/46 (2.2%)		2/103 (1.9%)
Fatigue	4/38 (10.5%)		4/43 (9.3%)		0/19 (0%)		1/46 (2.2%)		5/103 (4.9%)
Peripheral swelling	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Pyrexia	1/38 (2.6%)		0/43 (0%)		1/19 (5.3%)		1/46 (2.2%)		1/103 (1%)
Hepatobiliary disorders
Cholelithiasis	5/38 (13.2%)		8/43 (18.6%)		0/19 (0%)		4/46 (8.7%)		9/103 (8.7%)
Hepatic steatosis	0/38 (0%)		1/43 (2.3%)		1/19 (5.3%)		3/46 (6.5%)		1/103 (1%)
Infections and infestations
Bone abscess	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Nasopharyngitis	3/38 (7.9%)		4/43 (9.3%)		0/19 (0%)		3/46 (6.5%)		16/103 (15.5%)
Onychomycosis	0/38 (0%)		1/43 (2.3%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Pharyngitis	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		4/103 (3.9%)
Pneumonia	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Respiratory tract infection viral	2/38 (5.3%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Subcutaneous abscess	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		1/103 (1%)
Upper respiratory tract infection	2/38 (5.3%)		3/43 (7%)		3/19 (15.8%)		6/46 (13%)		15/103 (14.6%)
Urinary tract infection	3/38 (7.9%)		5/43 (11.6%)		1/19 (5.3%)		0/46 (0%)		4/103 (3.9%)
Injury, poisoning and procedural complications
Laceration	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Investigations
Alanine aminotransferase increased	3/38 (7.9%)		2/43 (4.7%)		1/19 (5.3%)		1/46 (2.2%)		2/103 (1.9%)
Aspartate aminotransferase increased	2/38 (5.3%)		3/43 (7%)		1/19 (5.3%)		1/46 (2.2%)		2/103 (1.9%)
Bacterial test positive	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Blood creatine phosphokinase increased	2/38 (5.3%)		0/43 (0%)		1/19 (5.3%)		1/46 (2.2%)		5/103 (4.9%)
Blood creatinine increased	2/38 (5.3%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Blood glucose increased	2/38 (5.3%)		1/43 (2.3%)		0/19 (0%)		3/46 (6.5%)		9/103 (8.7%)
Blood insulin increased	1/38 (2.6%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		1/103 (1%)
Blood urea increased	1/38 (2.6%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Blood uric acid increased	0/38 (0%)		2/43 (4.7%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Carbon dioxide decreased	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Gamma-glutamyltransferase increased	2/38 (5.3%)		4/43 (9.3%)		0/19 (0%)		2/46 (4.3%)		0/103 (0%)
Glycosylated haemoglobin increased	3/38 (7.9%)		1/43 (2.3%)		0/19 (0%)		0/46 (0%)		1/103 (1%)
Lipase increased	3/38 (7.9%)		2/43 (4.7%)		0/19 (0%)		1/46 (2.2%)		5/103 (4.9%)
Weight decreased	10/38 (26.3%)		4/43 (9.3%)		0/19 (0%)		5/46 (10.9%)		2/103 (1.9%)
Weight increased	0/38 (0%)		1/43 (2.3%)		1/19 (5.3%)		2/46 (4.3%)		0/103 (0%)
Metabolism and nutrition disorders
Decreased appetite	3/38 (7.9%)		3/43 (7%)		0/19 (0%)		1/46 (2.2%)		2/103 (1.9%)
Diabetes mellitus	5/38 (13.2%)		9/43 (20.9%)		2/19 (10.5%)		14/46 (30.4%)		4/103 (3.9%)
Dyslipidaemia	0/38 (0%)		1/43 (2.3%)		1/19 (5.3%)		3/46 (6.5%)		2/103 (1.9%)
Hyperglycaemia	14/38 (36.8%)		11/43 (25.6%)		6/19 (31.6%)		9/46 (19.6%)		13/103 (12.6%)
Hypertriglyceridaemia	3/38 (7.9%)		1/43 (2.3%)		0/19 (0%)		0/46 (0%)		1/103 (1%)
Hypoglycaemia	5/38 (13.2%)		10/43 (23.3%)		8/19 (42.1%)		5/46 (10.9%)		4/103 (3.9%)
Hypokalaemia	3/38 (7.9%)		0/43 (0%)		1/19 (5.3%)		2/46 (4.3%)		0/103 (0%)
Impaired fasting glucose	0/38 (0%)		2/43 (4.7%)		0/19 (0%)		2/46 (4.3%)		14/103 (13.6%)
Type 2 diabetes mellitus	2/38 (5.3%)		1/43 (2.3%)		0/19 (0%)		1/46 (2.2%)		1/103 (1%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/38 (0%)		0/43 (0%)		0/19 (0%)		1/46 (2.2%)		8/103 (7.8%)
Back pain	0/38 (0%)		3/43 (7%)		0/19 (0%)		2/46 (4.3%)		5/103 (4.9%)
Muscular weakness	3/38 (7.9%)		2/43 (4.7%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Myalgia	1/38 (2.6%)		2/43 (4.7%)		1/19 (5.3%)		4/46 (8.7%)		1/103 (1%)
Osteopenia	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Nervous system disorders
Dizziness	5/38 (13.2%)		5/43 (11.6%)		0/19 (0%)		3/46 (6.5%)		6/103 (5.8%)
Dysgeusia	2/38 (5.3%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Headache	4/38 (10.5%)		4/43 (9.3%)		0/19 (0%)		2/46 (4.3%)		12/103 (11.7%)
Syncope	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Renal and urinary disorders
Glycosuria	0/38 (0%)		1/43 (2.3%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Haematuria	3/38 (7.9%)		0/43 (0%)		0/19 (0%)		0/46 (0%)		1/103 (1%)
Nephrolithiasis	0/38 (0%)		1/43 (2.3%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Reproductive system and breast disorders
Amenorrhoea	0/38 (0%)		1/43 (2.3%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Polycystic ovaries	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Respiratory, thoracic and mediastinal disorders
Rhinitis allergic	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		1/103 (1%)
Skin and subcutaneous tissue disorders
Alopecia	2/38 (5.3%)		1/43 (2.3%)		0/19 (0%)		0/46 (0%)		3/103 (2.9%)
Pruritus generalised	2/38 (5.3%)		1/43 (2.3%)		0/19 (0%)		0/46 (0%)		0/103 (0%)
Rash	3/38 (7.9%)		2/43 (4.7%)		1/19 (5.3%)		1/46 (2.2%)		2/103 (1.9%)
Rash generalised	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Skin ulcer	0/38 (0%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)
Vascular disorders
Hypotension	2/38 (5.3%)		0/43 (0%)		1/19 (5.3%)		0/46 (0%)		0/103 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.