Extension Study to Assess the Safety and Efficacy of Pasireotide in Participants With Cushing's Disease

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00171951
• Collaborator: (none)
• Enrollment: 19
• Locations: 8
• Arm: 1
• Actual Duration (Months): 106.8
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Cushing's disease is a rare serious condition that is caused by an adrenocorticotropic hormone (ACTH) secreting pituitary adenoma. This study assessed the long-term safety and efficacy of pasireotide in participants with Cushing's disease.

Condition or Disease	Intervention/Treatment	Phase
Cushing Disease	Drug: Pasireotide	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Extension to a Multicenter, Open-label Study to Assess the Safety and Efficacy of 600 μg SOM230, Administered Subcutaneously, Bid in Patients With Cushing's Disease
• Actual Study Start Date: Aug 13, 2004
• Actual Primary Completion Date: Jul 8, 2013
• Actual Study Completion Date: Jul 8, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC Participants received pasireotide 600 micrograms (μg) twice daily (BID) subcutaneously (SC) to achieve or maintain urinary free cortisol (UFC) normalization. If UFC levels were increased at any time, participants received 900 μg BID SC, until no safety or tolerability concerns were observed as per investigators assessment. If the participant was unable to tolerate the 900 μg BID, dosing of 600 μg three times a day was given.

Drug: Pasireotide; Pasireotide 600 μg or 900 μg was administered as an SC injection.; Other Names: SOM230

Outcome Measures

Primary Outcome Measures

1. Percentage of Responders With Mean Urinary Free Cortisol (UFC) Within Normal Limits [Month 6]

   A participant was considered a responder if the mean UFC from the two 24-hour urine samples collected at Month 6 was within normal limits. The normal range for UFC is 55 to 276 nmol/day.

2. Change From Baseline in Mean Urinary Free Cortisol (UFC) [Core Baseline, Days 14/15 (Core study), Months 6, 12, 24 and 102]

   24-hour urine samples were collected to obtain mean UFC measurements. A negative mean change from baseline indicates improvement.

Secondary Outcome Measures

1. Number of Participants Who Had At Least One Adverse Event (AE) [Up to approximately 106 months]

   An AE was any undesirable sign, symptom or medical condition occurring after starting study drug even if the event is not considered to be related to study drug. AEs were assessed according to incident dose group: Pasireotide 1200 μg sc total daily dose (TDD), Pasireotide 1800 μg SC TDD and Pasireotide SC Any Dose. The incident dose for an AE was the last total daily dose administered on or prior to the AE onset date.

2. Change From Baseline in Serum Cortisol Levels [Core Baseline, Day 15 (Core study), Months 6, 12, 24, and Month 105 (end of the study)]

   Blood samples were withdrawn to obtain the serum cortisol levels. A negative change from baseline indicates improvement.

3. Plasma Trough Concentrations (Ctrough) of Pasireotide in UFC Responders [Day 15 (Core study) and Month 6]

   Participants with Cushing's disease were considered responders if mean UFC levels from the 24-hour urine collections at Day 15 (Core study) and at extension Month 6, were within normal limits. Ctrough levels of pasireotide were measured at Day 15 of Core study and Month 6.

4. Change From Baseline in Plasma Adrenocorticotropic Hormone (ACTH) Levels [Core Baseline, Day 15 (Core study), Months 6, 12, 24 and Month 105 (end of the study)]

   Blood samples were withdrawn to obtain the ACTH levels. A negative change from baseline indicates improvement.

5. Change From Baseline in Gene-expression and Protein in Blood and Urine for Biomarker Development [Baseline to end of the study]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Participants who have completed the 15 days of Pasireotide treatment in the CSOM230B2208 study and have achieved normalization of 24-hour urinary free cortisol. Participants who did not achieve normalization of 24 -hour urinary free cortisol may be enrolled if in the opinion of the investigator the participant is getting significant clinical benefits from treatment with Pasireotide .

• The participant did not experience any unacceptable adverse events of tolerability issues during the original 15 day treatment.

• Female participants of childbearing potential who have not undergone clinically documented total hysterectomy and/or ovariectomy or tubal ligation must agree to use barrier contraception throughout the course of the extension study, and for one month after the study has ended.

Exclusion Criteria:

• Participant who have developed poorly controlled diabetes mellitus as indicated by ketoacidosis or hemoglobin (Hgb) A1C (HgbA1C) > 10 since starting [study CSOM230B2208].

• Participant with persistent alanine aminotransferase (ALT)/ aspartate transaminase (AST) or alkaline phosphatase levels more than 2.5X upper limit of normal (ULN), serum creatinine > 2.0 X ULN, serum bilirubin > 2 X ULN.

• Participant with abnormal coagulation (Prothrombin time (PT) and partial thromboplastin time (PTT) elevated by 30% above normal limits), white blood cells (WBC) <3.0x1'000'000'000/L; Hgb <12.0g/dL for females, Hgb <13.0g/dL for males; PLT <100x1'000'000'000/L.

Other protocol-defined inclusion / exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Oregon Health & Sciences University Dept.ofOregonHealth&SciencesU.	Portland	Oregon	United States	97239
3	University of Pennsylvania Medical Center	Philadelphia	Pennsylvania	United States	19104-6149
4	Novartis Investigative Site	Paris		France	75006
5	Novartis Investigative Site	Essen		Germany	45122
6	Novartis Investigative Site	Muenchen		Germany	80336
7	Novartis Investigative Site	Ancona	AN	Italy	60126
8	Novartis Investigative Site	Belfast		United Kingdom	BT12 6BA

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticlas, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00171951
• Other Study ID Numbers: CSOM230B2208E1; 2004-002407-32
• First Posted: Sep 15, 2005
• Last Update Posted: Jun 2, 2021
• Last Verified: May 1, 2021

• 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; ACTH; Cortisol; ACTH dependent Cushing's disease
• Additional relevant MeSH terms: ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion; Pasireotide

Study Results

Participant Flow

Pre-assignment Detail	The study included participants with Cushing's disease who received 15 days of pasireotide treatment in the Core Study CSOM230B2208 (NCT00088608). This study was an extension study of the Core Study.

Arm/Group Title	Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC
Arm/Group Description	Participants received pasireotide 600 micrograms (μg) twice daily (BID) subcutaneously (SC) to achieve or maintain urinary free cortisol (UFC) normalization. If UFC levels were increased at any time, participants received 900 μg BID SC, until no safety or tolerability concerns were observed as per investigators assessment. If the participant was unable to tolerate the 900 μg BID, dosing of 600 μg three times a day was given.
Period Title: Overall Study
STARTED	19
COMPLETED	3
NOT COMPLETED	16

Baseline Characteristics

Arm/Group Title	Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC
Arm/Group Description	Participants received pasireotide 600 μg BID SC to achieve or maintain UFC normalization. If UFC levels were increased at any time, participants received 900 μg BID SC, until no safety or tolerability concerns were observed as per investigators assessment. If the participant was unable to tolerate the 900 μg BID, dosing of 600 μg three times a day was given.
Overall Participants	19
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.0 (11.62)
Sex: Female, Male (Count of Participants)
Female	17 89.5%
Male	2 10.5%

Outcome Measures

1. Primary Outcome

Title	Percentage of Responders With Mean Urinary Free Cortisol (UFC) Within Normal Limits
Description	A participant was considered a responder if the mean UFC from the two 24-hour urine samples collected at Month 6 was within normal limits. The normal range for UFC is 55 to 276 nmol/day.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

Primary Efficacy Population included participants from ITT whose mean UFC at core-baseline, based on at least 2 UFC samples, was >1.0x upper limit of normal (ULN) or for whom the one and only UFC sample available at baseline was >2.0xULN.

Arm/Group Title	Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC
Arm/Group Description	Participants received pasireotide 600 μg BID SC to achieve or maintain UFC normalization. If UFC levels were increased at any time, participants received 900 μg BID SC, until no safety or tolerability concerns were observed as per investigators assessment. If the participant was unable to tolerate the 900 μg BID, dosing of 600 μg three times a day was given.
Measure Participants	18
Number (95% Confidence Interval) [percentage of responders]	22.2

2. Primary Outcome

Title	Change From Baseline in Mean Urinary Free Cortisol (UFC)
Description	24-hour urine samples were collected to obtain mean UFC measurements. A negative mean change from baseline indicates improvement.
Time Frame	Core Baseline, Days 14/15 (Core study), Months 6, 12, 24 and 102

Outcome Measure Data

Analysis Population Description

Primary Efficacy Population included participants from ITT whose mean UFC at core-baseline, based on at least 2 UFC samples, was >1.0x ULN or for whom the one and only UFC sample available at baseline was >2.0xULN. Number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC
Arm/Group Description	Participants received pasireotide 600 μg BID SC to achieve or maintain UFC normalization. If UFC levels were increased at any time, participants received 900 μg BID SC, until no safety or tolerability concerns were observed as per investigators assessment. If the participant was unable to tolerate the 900 μg BID, dosing of 600 μg three times a day was given.
Measure Participants	18
Core Baseline	1219.74 (752.9)
Change from Core Baseline to Day 14/Day 15	-710.57 (740.6)
Change from Core Baseline to Month 6	-801.85 (819.4)
Change from Core Baseline to Month 12	-1202.1 (1084.1)
Change from Core Baseline to Month 24	-1241.1 (925.6)
Change from Core Baseline to Month 102	-2417.0 (NA)

3. Secondary Outcome

Title	Number of Participants Who Had At Least One Adverse Event (AE)
Description	An AE was any undesirable sign, symptom or medical condition occurring after starting study drug even if the event is not considered to be related to study drug. AEs were assessed according to incident dose group: Pasireotide 1200 μg sc total daily dose (TDD), Pasireotide 1800 μg SC TDD and Pasireotide SC Any Dose. The incident dose for an AE was the last total daily dose administered on or prior to the AE onset date.
Time Frame	Up to approximately 106 months

Outcome Measure Data

Analysis Population Description

Safety Population included participants from ITT Population. ITT Population included participants who completed 15 days of treatment in the Core study, experienced significant clinical benefit without any unacceptable AEs, and received at least 1 dose in the extension period.

Arm/Group Title	Pasireotide 600 μg BID SC	Pasireotide 900 μg BID SC
Arm/Group Description	Participants received pasireotide 600 μg BID SC, to achieve or maintain UFC normalization.	Participants received 900 μg BID SC if UFC levels were increased at any time, until no safety or tolerability concerns were observed as per investigators assessment. If the participant was unable to tolerate the 900 μg BID, dosing of 600 μg three times a day was given.
Measure Participants	19	8
Count of Participants [Participants]	19 100%	8 NaN

4. Secondary Outcome

Title	Change From Baseline in Serum Cortisol Levels
Description	Blood samples were withdrawn to obtain the serum cortisol levels. A negative change from baseline indicates improvement.
Time Frame	Core Baseline, Day 15 (Core study), Months 6, 12, 24, and Month 105 (end of the study)

Outcome Measure Data

Analysis Population Description

Primary Efficacy Population included participants from ITT whose mean UFC at core-baseline, based on at least 2 UFC samples, was >1.0x ULN or for whom the one and only UFC sample available at baseline was >2.0xULN. Number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC
Arm/Group Description	Participants received pasireotide 600 μg BID SC to achieve or maintain UFC normalization. If UFC levels were increased at any time, participants received 900 μg BID SC, until no safety or tolerability concerns were observed as per investigators assessment. If the participant was unable to tolerate the 900 μg BID, dosing of 600 μg three times a day was given.
Measure Participants	18
Core Baseline	723.60 (221.5)
Change from Core Baseline to Day 15	-25.96 (125.1)
Change from Core Baseline to Month 6	-150.60 (308.9)
Change from Core Baseline to Month 12	-66.06 (301.9)
Change from Core Baseline to Month 24	-227.53 (283.1)
Change from Core Baseline to Month 105	-166.00 (NA)

5. Secondary Outcome

Title	Plasma Trough Concentrations (Ctrough) of Pasireotide in UFC Responders
Description	Participants with Cushing's disease were considered responders if mean UFC levels from the 24-hour urine collections at Day 15 (Core study) and at extension Month 6, were within normal limits. Ctrough levels of pasireotide were measured at Day 15 of Core study and Month 6.
Time Frame	Day 15 (Core study) and Month 6

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population included participants from ITT who had at least one post dosing PK assessment up to the implementation of Amendment 2 when no further blood samples were collected for PK assessment (24 May 2007).

Arm/Group Title	Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC
Arm/Group Description	Participants received pasireotide 600 μg BID SC to achieve or maintain UFC normalization. If UFC levels were increased at any time, participants received 900 μg BID SC, until no safety or tolerability concerns were observed as per investigators assessment. If the participant was unable to tolerate the 900 μg BID, dosing of 600 μg three times a day was given.
Measure Participants	4
Day 15 (Core Study)	7.0 (4.3)
Month 6	17.4 (11.6)

6. Secondary Outcome

Title	Change From Baseline in Plasma Adrenocorticotropic Hormone (ACTH) Levels
Description	Blood samples were withdrawn to obtain the ACTH levels. A negative change from baseline indicates improvement.
Time Frame	Core Baseline, Day 15 (Core study), Months 6, 12, 24 and Month 105 (end of the study)

Outcome Measure Data

Analysis Population Description

Primary Efficacy Population included participants from ITT whose mean UFC at core-baseline, based on at least 2 UFC samples, was >1.0x ULN or for whom the one and only UFC sample available at baseline was >2.0xULN. Number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC
Arm/Group Description	Participants received pasireotide 600 μg BID SC to achieve or maintain UFC normalization. If UFC levels were increased at any time, participants received 900 μg BID SC, until no safety or tolerability concerns were observed as per investigators assessment. If the participant was unable to tolerate the 900 μg BID, dosing of 600 μg three times a day was given.
Measure Participants	18
Core Baseline	13.72 (11.0)
Change from Core Baseline to Day 15	-1.28 (7.1)
Change from Core Baseline to Month 6	-3.36 (9.4)
Change from Core Baseline to Month 12	-3.60 (15.2)
Change from Core Baseline to Month 24	-4.50 (8.3)
Change from Core Baseline to Month 105	0.00 (NA)

7. Secondary Outcome

Title	Change From Baseline in Gene-expression and Protein in Blood and Urine for Biomarker Development
Time Frame	Baseline to end of the study

Outcome Measure Data

Analysis Population Description

We have exhausted all efforts to locate this data and it has since been destroyed, therefore no data is available to report for this outcome measure.

Arm/Group Title	Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC
Arm/Group Description	Participants received pasireotide 600 μg BID SC to achieve or maintain UFC normalization. If UFC levels were increased at any time, participants received 900 μg BID SC, until no safety or tolerability concerns were observed as per investigators assessment. If the participant was unable to tolerate the 900 μg BID, dosing of 600 μg three times a day was given.
Measure Participants	0

Adverse Events

Time Frame	Up to approximately 106 months
Adverse Event Reporting Description	Safety Population included participants from ITT Population. ITT Population included participants who completed 15 days of treatment in the Core study, experienced significant clinical benefit without any unacceptable AEs, and received at least 1 dose in the extension period.
Arm/Group Title	Pasireotide 600 μg BID SC		Pasireotide 900 μg BID SC
Arm/Group Description	Participants received pasireotide 600 μg BID SC, to achieve or maintain UFC normalization.		Participants received 900 μg BID SC if UFC levels were increased at any time, until no safety or tolerability concerns were observed as per investigators assessment. If the participant was unable to tolerate the 900 μg BID, dosing of 600 μg three times a day was given.
All Cause Mortality
	Pasireotide 600 μg BID SC		Pasireotide 900 μg BID SC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/8 (0%)
Serious Adverse Events
	Pasireotide 600 μg BID SC		Pasireotide 900 μg BID SC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/19 (10.5%)		2/8 (25%)
Infections and infestations
Urinary tract infection	0/19 (0%)		1/8 (12.5%)
Injury, poisoning and procedural complications
Skin injury	0/19 (0%)		1/8 (12.5%)
Metabolism and nutrition disorders
Type 2 diabetes mellitus	0/19 (0%)		1/8 (12.5%)
Nervous system disorders
Convulsion	1/19 (5.3%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax	1/19 (5.3%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Pasireotide 600 μg BID SC		Pasireotide 900 μg BID SC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/19 (100%)		8/8 (100%)
Blood and lymphatic system disorders
Iron deficiency anaemia	2/19 (10.5%)		1/8 (12.5%)
Anaemia	1/19 (5.3%)		0/8 (0%)
Bone marrow oedema	1/19 (5.3%)		0/8 (0%)
Cardiac disorders
Palpitations	0/19 (0%)		1/8 (12.5%)
Congenital, familial and genetic disorders
Homocystinaemia	1/19 (5.3%)		0/8 (0%)
Ear and labyrinth disorders
Vertigo	2/19 (10.5%)		0/8 (0%)
Endocrine disorders
Hypogonadism	1/19 (5.3%)		0/8 (0%)
Eye disorders
Eye irritation	1/19 (5.3%)		0/8 (0%)
Retinopathy hypertensive	1/19 (5.3%)		0/8 (0%)
Ulcerative keratitis	1/19 (5.3%)		0/8 (0%)
Gastrointestinal disorders
Diarrhoea	12/19 (63.2%)		2/8 (25%)
Nausea	12/19 (63.2%)		1/8 (12.5%)
Abdominal pain	8/19 (42.1%)		2/8 (25%)
Constipation	4/19 (21.1%)		0/8 (0%)
Flatulence	4/19 (21.1%)		0/8 (0%)
Abdominal pain upper	1/19 (5.3%)		1/8 (12.5%)
Dyspepsia	1/19 (5.3%)		0/8 (0%)
Infrequent bowel movements	0/19 (0%)		1/8 (12.5%)
Oesophageal pain	1/19 (5.3%)		0/8 (0%)
Rectal haemorrhage	1/19 (5.3%)		0/8 (0%)
Tongue disorder	1/19 (5.3%)		0/8 (0%)
Umbilical hernia	1/19 (5.3%)		0/8 (0%)
Vomiting	1/19 (5.3%)		0/8 (0%)
General disorders
Injection site pain	6/19 (31.6%)		0/8 (0%)
Asthenia	4/19 (21.1%)		1/8 (12.5%)
Fatigue	5/19 (26.3%)		0/8 (0%)
Injection site pruritus	5/19 (26.3%)		0/8 (0%)
Oedema peripheral	3/19 (15.8%)		0/8 (0%)
Influenza like illness	2/19 (10.5%)		0/8 (0%)
Injection site erythema	2/19 (10.5%)		0/8 (0%)
Injection site oedema	2/19 (10.5%)		0/8 (0%)
Oedema	2/19 (10.5%)		0/8 (0%)
Chills	1/19 (5.3%)		0/8 (0%)
Cyst	1/19 (5.3%)		0/8 (0%)
Hepatobiliary disorders
Cholelithiasis	0/19 (0%)		3/8 (37.5%)
Hepatic cyst	1/19 (5.3%)		0/8 (0%)
Infections and infestations
Fungal skin infection	2/19 (10.5%)		0/8 (0%)
Influenza	1/19 (5.3%)		1/8 (12.5%)
Upper respiratory tract infection	0/19 (0%)		2/8 (25%)
Bronchitis	0/19 (0%)		1/8 (12.5%)
Gastroenteritis	1/19 (5.3%)		0/8 (0%)
Nasopharyngitis	1/19 (5.3%)		0/8 (0%)
Oral herpes	1/19 (5.3%)		0/8 (0%)
Pharyngitis	0/19 (0%)		1/8 (12.5%)
Tinea versicolour	1/19 (5.3%)		0/8 (0%)
Tooth abscess	1/19 (5.3%)		0/8 (0%)
Tooth infection	1/19 (5.3%)		0/8 (0%)
Vulvovaginitis	1/19 (5.3%)		0/8 (0%)
Injury, poisoning and procedural complications
Foot fracture	2/19 (10.5%)		0/8 (0%)
Infusion related reaction	2/19 (10.5%)		0/8 (0%)
Procedural nausea	2/19 (10.5%)		0/8 (0%)
Ankle fracture	0/19 (0%)		1/8 (12.5%)
Joint injury	1/19 (5.3%)		0/8 (0%)
Sunburn	1/19 (5.3%)		0/8 (0%)
Investigations
Alanine aminotransferase increased	2/19 (10.5%)		1/8 (12.5%)
Gamma-glutamyltransferase increased	3/19 (15.8%)		1/8 (12.5%)
Glycosylated haemoglobin increased	1/19 (5.3%)		1/8 (12.5%)
Aspartate aminotransferase increased	1/19 (5.3%)		0/8 (0%)
Blood cortisol increased	0/19 (0%)		1/8 (12.5%)
Blood creatine increased	1/19 (5.3%)		0/8 (0%)
Blood glucose increased	1/19 (5.3%)		0/8 (0%)
Blood pressure increased	1/19 (5.3%)		0/8 (0%)
Blood sodium increased	1/19 (5.3%)		0/8 (0%)
Blood uric acid increased	0/19 (0%)		1/8 (12.5%)
Cardiac murmur	1/19 (5.3%)		0/8 (0%)
Heart rate increased	1/19 (5.3%)		0/8 (0%)
Liver function test abnormal	1/19 (5.3%)		0/8 (0%)
Weight decreased	1/19 (5.3%)		0/8 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	11/19 (57.9%)		3/8 (37.5%)
Hypercholesterolaemia	2/19 (10.5%)		0/8 (0%)
Hypertriglyceridaemia	2/19 (10.5%)		0/8 (0%)
Decreased appetite	1/19 (5.3%)		0/8 (0%)
Dehydration	0/19 (0%)		1/8 (12.5%)
Hypoglycaemia	1/19 (5.3%)		0/8 (0%)
Hypomagnesaemia	0/19 (0%)		1/8 (12.5%)
Polydipsia	1/19 (5.3%)		0/8 (0%)
Vitamin B12 deficiency	1/19 (5.3%)		0/8 (0%)
Vitamin D deficiency	1/19 (5.3%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/19 (15.8%)		0/8 (0%)
Back pain	2/19 (10.5%)		1/8 (12.5%)
Tendonitis	0/19 (0%)		2/8 (25%)
Bunion	0/19 (0%)		1/8 (12.5%)
Bursitis	0/19 (0%)		1/8 (12.5%)
Neck pain	1/19 (5.3%)		0/8 (0%)
Osteoarthritis	0/19 (0%)		1/8 (12.5%)
Osteopenia	1/19 (5.3%)		0/8 (0%)
Osteoporosis	1/19 (5.3%)		0/8 (0%)
Pain in extremity	0/19 (0%)		1/8 (12.5%)
Nervous system disorders
Headache	7/19 (36.8%)		0/8 (0%)
Dizziness	4/19 (21.1%)		1/8 (12.5%)
Presyncope	1/19 (5.3%)		0/8 (0%)
Psychiatric disorders
Depression	1/19 (5.3%)		1/8 (12.5%)
Anxiety	1/19 (5.3%)		1/8 (12.5%)
Insomnia	1/19 (5.3%)		0/8 (0%)
Renal and urinary disorders
Nephrolithiasis	2/19 (10.5%)		0/8 (0%)
Polyuria	1/19 (5.3%)		0/8 (0%)
Reproductive system and breast disorders
Amenorrhoea	2/19 (10.5%)		0/8 (0%)
Vaginal haemorrhage	0/19 (0%)		1/8 (12.5%)
Vulvovaginal pruritus	1/19 (5.3%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional	1/19 (5.3%)		0/8 (0%)
Epistaxis	1/19 (5.3%)		0/8 (0%)
Lung disorder	1/19 (5.3%)		0/8 (0%)
Skin and subcutaneous tissue disorders
Alopecia	4/19 (21.1%)		0/8 (0%)
Hyperhidrosis	3/19 (15.8%)		0/8 (0%)
Pruritus	2/19 (10.5%)		1/8 (12.5%)
Dry skin	1/19 (5.3%)		0/8 (0%)
Erythema	2/19 (10.5%)		0/8 (0%)
Rash	2/19 (10.5%)		0/8 (0%)
Ecchymosis	1/19 (5.3%)		1/8 (12.5%)
Skin discolouration	1/19 (5.3%)		0/8 (0%)
Vascular disorders
Hypertension	2/19 (10.5%)		2/8 (25%)
Hypotension	4/19 (21.1%)		0/8 (0%)
Hot flush	1/19 (5.3%)		0/8 (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 the pooled data (ie, data from all sites) in the clinical trial.