Study of Long-term Safety, Efficacy Tolerability of BYM338 in Patients With Sporadic Inclusion Body Myositis

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02250443
• Collaborator: (none)
• Enrollment: 10
• Locations: 2
• Arm: 1
• Actual Duration (Months): 29.4
• Patients Per Site: 5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study is an open-label, long-term study for those patients who participated in the prior proof-of-concept protocol, in which the preliminary efficacy for BYM338 in patients with sIBM was demonstrated after a single 30 mg/kg i.v. dose of BYM338. This study is designed to confirm the efficacy, safety and tolerability of BYM338 in sIBM with long-term dosing. However due to lack of efficacy in patients with sIBM, the study was terminated early.

Condition or Disease	Intervention/Treatment	Phase
Sporadic Inclusion Body Myositis (sIBM)	Drug: BYM338 (Bimagrumab)	Phase 2/Phase 3

Detailed Description

This is a non-confirmatory, multicenter, open-label, non-randomized trial which will extend active treatment to those patients that participated in the preceding proof-of-concept study (CBYM338X2205) in order to collect long-term safety and tolerability data. Up to 14 patients with sIBM will be invited to enroll into the study to receive BYM338 open-label for a period of approximately 3 years or until BYM338 is commercially available, whichever comes first. The study consists of a maximum 28-day screening period, a 5-day baseline period, and a treatment period consisting of the site visits at 4-week intervals for treatment administration, safety and pharmacokinetic follow-up. All patients will be administered a medium level i.v. BYM338 dose regardless of their treatment allocation in the prior study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Long-term Study to Evaluate the Safety and Tolerability of BYM338 in Patients With Sporadic Inclusion Body Myositis
• Actual Study Start Date: Mar 11, 2014
• Actual Primary Completion Date: Aug 23, 2016
• Actual Study Completion Date: Aug 23, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BYM338 BYM338 Group	Drug: BYM338 (Bimagrumab)

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events as a Measure of Safety and Tolerability [Up to 29 month]

   Any Adverse Event was defined as occurrence of any symptom regardless of intensity grade, Serious Adverse Event (SAEs) assessed as medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in persistent or significant disability/incapacity

Secondary Outcome Measures

1. Changes From Baseline in Lean Body Mass (LBM) by Dual-Energy X-ray Absorptiometery (DXA) [Baseline, Day 1, 57, 113, 169, 365, 533, and day 729]

   To assess the effect of multiple doses of BYM338 on lean body mass as measured by DXA in terms of change from baseline.

2. Pharmacokinetics (PK) Parameter of Cmin From Multiple i.v. Dosing [Day 29, 85, 169, 253, 337, 421, 505, 589, 673, 757, 1177]

   To obtain pharmacokinetic data from multiple i.v. dosing of BYM338 in this patient population. Pre-dose, 30 mins & 4 hours post-dose on Day 1. Pre-dose only on each subsequent administration

3. Changes From Baseline in Physical Function Reported by Patients [Baseline, Week 104]

   Self-reported physical function was assessed by a newly developed patient reported outcome named sporadic inclusion body myositis (sIBM) functional assessment (sIFA). The sIFA consists of 11 items scored on an 11 point numerical rating scale from 0 (no difficulty) to 10 (unable to do) across 3 domains: upper body functioning, lower body functioning and general functioning. Participants completed the assessment where the recall period was the past week prior to completing the patient reported outcome (PRO). The total score on the sIFA scale ranges from 0 (minimum) to 110 (maximum). Higher values represent a worse outcome. A positive change from baseline indicates deterioration. Due to the no-signal this analysis was cancelled.

4. Changes From Baseline in Muscle Strength. [Baseline, Day 1, 113, 169, 365, 533, 729]

   Quadriceps muscle strength was measured, Quadriceps Quantitative Muscle Testing (QMT) by portable fixed dynamometry (PFD). A negative change from baseline indicates deterioration

5. Changes From Baseline in Muscle Function (Hand-grip and Pinch-grip Dynamometry) [Baseline,Day 1, 113, 169, 365, 533, 729]

   The effect of BYM338 on additional muscle function measures (hand-grip and pinch-grip dynamometry).

6. Changes From Baseline in Muscle Function 6 Minute Walking Distance [Baseline,Day 1, 113, 169, 365, 533, 729]

   The effect of BYM338 on additional muscle function measures (6 minute walking distance). The 6MWD test measured the distance (in meters) that a participant walked in a 6 minute timeframe. A positive change from baseline indicates improvement.

7. Change From Baseline of Thigh Muscle Volume (TMV) by MRI Scan [Baseline, Day 1, 57, 113]

   Thigh Muscle Volume (TMV) change was evaluated by a responder analysis. Patients whose loss of muscle TMV by MRI was equal or more than 2% at Week 8 and 16 were considered responders

8. Pharmacokinetics (PK) Parameter of Cmax [Day 1]

   To obtain pharmacokinetic data from multiple i.v. dosing of BYM338 in this patient population. Pre-dose, 30 mins & 4 hours post-dose on Day 1.

9. Time to Reach the Maximum Concentration After Drug Administration (Tmax) [Day 1]

   The time to reach the maximum concentration after drug administration

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent must be obtained before any assessment is performed.

• Patients who participated in the CBYM338X2205 study. A patient is defined as participating in the study if they were enrolled and received study medication.

• Able to communicate well with the investigator, to understand and comply with the requirements of the study.

Exclusion Criteria:

• Patients for whom the treating physician considers it inappropriate for continuation into the study, including consideration of physical and laboratory assessment of the patient at screening.

• Patients who were non-compliant or demonstrated a serious protocol deviation in the previous study.

• Use of other investigational drugs at the time of enrollment, within 30 days or 5 half-lives of enrollment, or until the expected PD effect has returned to baseline, whichever is longer; or longer if required by local regulations.

• History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes

• Swallowing difficulty or other reason that precludes adequate intake of energy and protein, defined as at least 20 kcal/kg/day and 0.6 g protein/kg/day as determined by the investigators assessment.

• On the Columbia-Suicide Severity Rating Scale, a score of 4 or 5 on the Suicidal Ideation item or any "yes" on the Suicidal Behavior item that is related to suicidal behavior occurring during the last 2 years.

• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.

• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and for 5 half-lives (14 weeks) after stopping treatment. Highly effective contraception is defined as either:

1. Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception].

2. Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.

3. Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). [For female study subjects, the vasectomized male partner should be the sole partner for that patient].

4. Use of a combination of any two of the following (a+b or a+c or b+c):

5. Use of oral, injected or implanted hormonal methods of contraception.

6. Placement of an intrauterine device (IUD) or intrauterine system (IUS).

7. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.

In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Postmenopausal females must have had no regular menstrual bleeding for at least one (1) year prior to initial dosing. Menopause will be confirmed by a plasma FSH level of > 40 IU/L (or as determined by the cut off used by the local clinical laboratory) at screening. Female patients who report surgical sterilization must have had the procedure at least six (6) months prior to initial dosing. Surgical sterilization procedures should be supported with clinical documentation made available to the sponsor and noted in the Relevant Medical History / Current Medical Conditions section of the eCRF. All female patients must have negative pregnancy test results at screening and baseline.

• Use of oral beta agonists, oral corticosteroids, androgens or androgen inhibitors (including LHRH agonists), or intravenous gamma globulin (IVIG) within the previous 6 months. Short-term corticosteroids for unrelated indications, defined as < 20 mg/d for < 30 days and ending at least 60 days prior to screening, are acceptable.

• Patients with known bleeding disorders, or who are under treatment with anti-coagulants.

• A presence or history of clinically relevant ECG abnormalities, or including but not limited to Long QT syndrome, ischemic changes that cannot be shown to be stable for at least 6 months by previous ECG, or 2nd degree Mobitz II or 3rd degree heart block.

• History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.

• Significant illness which has not resolved within two (2) weeks prior to initial dosing.

• A positive HIV, Hepatitis B surface antigen or Hepatitis C test result. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Phoenix	Arizona	United States	85013
2	Novartis Investigative Site	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02250443
• Other Study ID Numbers: CBYM338X2205E1
• First Posted: Sep 26, 2014
• Last Update Posted: Dec 30, 2020
• Last Verified: Mar 1, 2019

• Keywords provided by Novartis Pharmaceuticals: Inclusion Body Myositis (IBM)
• Additional relevant MeSH terms: Myositis; Myositis, Inclusion Body

Study Results

Participant Flow

Recruitment Details	Due to lack of efficacy in patients with sIBM, the study was terminated early.

Arm/Group Title	BYM338
Arm/Group Description	BYM338 Group
Period Title: Overall Study
STARTED	10
COMPLETED	0
NOT COMPLETED	10

Baseline Characteristics

Arm/Group Title	BYM338
Arm/Group Description	BYM338 Group
Overall Participants	10
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	70.1 (10.39)
Sex: Female, Male (Count of Participants)
Female	4 40%
Male	6 60%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Description	Any Adverse Event was defined as occurrence of any symptom regardless of intensity grade, Serious Adverse Event (SAEs) assessed as medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in persistent or significant disability/incapacity
Time Frame	Up to 29 month

Outcome Measure Data

Analysis Population Description

safety analysis set - included all patients that received at least one dose of study drug. No statistical analysis provided for Number of Participants Who Experienced Adverse Events (AEs) and Serious Adverse Events (SAEs) During this extension study

Arm/Group Title	BYM338
Arm/Group Description	BYM338 Group
Measure Participants	10
Death	0 0%
Serious adverse events (SAE)	2 20%
Adverse Events (AE)	10 100%

2. Secondary Outcome

Title	Changes From Baseline in Lean Body Mass (LBM) by Dual-Energy X-ray Absorptiometery (DXA)
Description	To assess the effect of multiple doses of BYM338 on lean body mass as measured by DXA in terms of change from baseline.
Time Frame	Baseline, Day 1, 57, 113, 169, 365, 533, and day 729

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set: Patients with evaluable PD parameter data

Arm/Group Title	BYM338
Arm/Group Description	BYM338 Group
Measure Participants	10
Day 1	0 (0)
Day 57	4.292 (2.7480)
Day 113	5.552 (3.6066)
Day 169	7.463 (4.5687)
Day 365	6.919 (2.9669)
Day 533	6.885 (3.7894)
Day 729	0.727 (NA)

3. Secondary Outcome

Title	Pharmacokinetics (PK) Parameter of Cmin From Multiple i.v. Dosing
Description	To obtain pharmacokinetic data from multiple i.v. dosing of BYM338 in this patient population. Pre-dose, 30 mins & 4 hours post-dose on Day 1. Pre-dose only on each subsequent administration
Time Frame	Day 29, 85, 169, 253, 337, 421, 505, 589, 673, 757, 1177

Outcome Measure Data

Analysis Population Description

Pharmacokinetics (PK) Analysis set: Patients with available PK data and no protocol deviations with relevant impact on PK data

Arm/Group Title	BYM338
Arm/Group Description	BYM338 Group
Measure Participants	10
Day 29 (n=10)	13.4 (5.01)
Day 85 (n=10)	24.1 (13.1)
Day 169 (n=10)	26.3 (15.9)
Day 253 (n=9)	28.8 (12.1)
Day 337 (n=10)	24.4 (14.6)
Day 421 (n=9)	24.5 (11.5)
Day 505 (n=8)	28.3 (10.6)
Day 589 (n=6)	39.8 (30.2)
Day 673 (n=2)	20.5 (1.98)
Day 757 (n=1)	20.3 (NA)
Day 1177 (n=1)	31.4 (NA)

4. Secondary Outcome

Title	Changes From Baseline in Physical Function Reported by Patients
Description	Self-reported physical function was assessed by a newly developed patient reported outcome named sporadic inclusion body myositis (sIBM) functional assessment (sIFA). The sIFA consists of 11 items scored on an 11 point numerical rating scale from 0 (no difficulty) to 10 (unable to do) across 3 domains: upper body functioning, lower body functioning and general functioning. Participants completed the assessment where the recall period was the past week prior to completing the patient reported outcome (PRO). The total score on the sIFA scale ranges from 0 (minimum) to 110 (maximum). Higher values represent a worse outcome. A positive change from baseline indicates deterioration. Due to the no-signal this analysis was cancelled.
Time Frame	Baseline, Week 104

Outcome Measure Data

Analysis Population Description

Due to the early study termination and the small sample size in this open-label trial, this PRO analysis was cancelled.

Arm/Group Title	BYM338
Arm/Group Description	BYM338 Group
Measure Participants	0

5. Secondary Outcome

Title	Changes From Baseline in Muscle Strength.
Description	Quadriceps muscle strength was measured, Quadriceps Quantitative Muscle Testing (QMT) by portable fixed dynamometry (PFD). A negative change from baseline indicates deterioration
Time Frame	Baseline, Day 1, 113, 169, 365, 533, 729

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set: Patients with available PD data and no protocol deviations with relevant impact on PD data

Arm/Group Title	BYM338
Arm/Group Description	BYM338 Group
Measure Participants	10
Quadriceps score left side Day 1	0 (0)
left side Day 113	-5.80 (28.160)
left side Day 169	-5.95 (26.587)
left side Day 365	-9.51 (28.149)
left side Day 533	-25.77 (21.321)
left side Day 729	178.26 (NA)
Quadriceps score Right side Day 1	0 (0)
Right side Day 113	-4.83 (29.904)
Right side Day 169	-22.81 (18.784)
Right side Day 365	-11.63 (47.141)
Right side Day 533	-31.00 (29.173)
Right side Day 729	-57.66 (NA)

6. Secondary Outcome

Title	Changes From Baseline in Muscle Function (Hand-grip and Pinch-grip Dynamometry)
Description	The effect of BYM338 on additional muscle function measures (hand-grip and pinch-grip dynamometry).
Time Frame	Baseline,Day 1, 113, 169, 365, 533, 729

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set: Patients with available PD data and no protocol deviations with relevant impact on PD data

Arm/Group Title	BYM338
Arm/Group Description	BYM338 Group
Measure Participants	10
Left hand-grip day 1	0 (0)
Left hand-grip day 113	25.58 (37.544)
Left hand-grip day 169	21.36 (43.815)
Left hand-grip day 365	-1.42 (47.973)
Left hand-grip day 533	2.78 (16.934)
Left hand-grip day 729	8.95 (24.034)
Right hand-grip day 1	0 (0)
Right hand-grip day 113	99.59 (184.472)
Right hand-grip day 169	109.05 (214.248)
Right hand-grip day 365	77.46 (160.133)
Right hand-grip day 533	53.99 (127.776)
Right hand-grip day 729	163.66 (237.402)
Left hand pinch grip day 1	0 (0)
Left hand pinch grip day 113	7.82 (27.292)
Left hand pinch grip day 169	-4.74 (20.210)
Left hand pinch grip day 365	-7.30 (35.224)
Left hand pinch grip day 533	-11.40 (21.204)
Left hand pinch grip day 729	-8.41 (46.672)
Right hand pinch grip day 1	0 (0)
Right hand pinch grip day 113	-7.55 (26.792)
Right hand pinch grip day 169	-9.35 (30.942)
Right hand pinch grip day 365	0.59 (32.094)
Right hand pinch grip day 533	-8.65 (21.491)
Right hand pinch grip day 729	-35.40 (44.820)

7. Secondary Outcome

Title	Changes From Baseline in Muscle Function 6 Minute Walking Distance
Description	The effect of BYM338 on additional muscle function measures (6 minute walking distance). The 6MWD test measured the distance (in meters) that a participant walked in a 6 minute timeframe. A positive change from baseline indicates improvement.
Time Frame	Baseline,Day 1, 113, 169, 365, 533, 729

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set: Patients with available PD data and no protocol deviations with relevant impact on PD data

Arm/Group Title	BYM338
Arm/Group Description	BYM338 Group
Measure Participants	10
Day 1	0 (0)
Day 113	-1.56 (13.685)
Day 169	-7.41 (12.463)
Day 365	-8.97 (15.763)
Day 533	-16.99 (22.382)
Day 729	-17.86 (NA)

8. Secondary Outcome

Title	Change From Baseline of Thigh Muscle Volume (TMV) by MRI Scan
Description	Thigh Muscle Volume (TMV) change was evaluated by a responder analysis. Patients whose loss of muscle TMV by MRI was equal or more than 2% at Week 8 and 16 were considered responders
Time Frame	Baseline, Day 1, 57, 113

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set: Patients with available PD data and no protocol deviations with relevant impact on PD data

Arm/Group Title	BYM338
Arm/Group Description	BYM338 Group
Measure Participants	10
Day 1	0 (0)
Day 57	4.14 (4.250)
Day 113	4.51 (6.300)

9. Secondary Outcome

Title	Pharmacokinetics (PK) Parameter of Cmax
Description	To obtain pharmacokinetic data from multiple i.v. dosing of BYM338 in this patient population. Pre-dose, 30 mins & 4 hours post-dose on Day 1.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetics (PK) Analysis set: Patients with available PK data and no protocol deviations with relevant impact on PK data

Arm/Group Title	BYM338
Arm/Group Description	BYM338 Group
Measure Participants	9
Mean (Standard Deviation) [ug/mL]	278 (62.6)

10. Secondary Outcome

Title	Time to Reach the Maximum Concentration After Drug Administration (Tmax)
Description	The time to reach the maximum concentration after drug administration
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetics (PK) Analysis set: Patients with available PK data and no protocol deviations with relevant impact on PK data

Arm/Group Title	BYM338
Arm/Group Description	BYM338 Group
Measure Participants	9
Median (Full Range) [hr]	0.744 (NA)

Adverse Events

Time Frame	period up to 104 weeks
Arm/Group Title	BYM338 10mg/kg i.v.
Arm/Group Description	BYM338 10mg/kg i.v.
All Cause Mortality
	BYM338 10mg/kg i.v.
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	BYM338 10mg/kg i.v.
	Affected / at Risk (%)	# Events
Total	2/10 (20%)
Blood and lymphatic system disorders
Anaemia	1/10 (10%)
Cardiac disorders
Myocardial infarction	1/10 (10%)
Tachyarrhythmia	1/10 (10%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	1/10 (10%)
Haemorrhoidal haemorrhage	1/10 (10%)
Metabolism and nutrition disorders
Dehydration	1/10 (10%)
Iron deficiency	1/10 (10%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung adenocarcinoma	1/10 (10%)
Oesophageal carcinoma	1/10 (10%)
Other (Not Including Serious) Adverse Events
	BYM338 10mg/kg i.v.
	Affected / at Risk (%)	# Events
Total	10/10 (100%)
Blood and lymphatic system disorders
Lymphadenopathy	1/10 (10%)
Cardiac disorders
Atrial fibrillation	1/10 (10%)
Myocardial infarction	1/10 (10%)
Ear and labyrinth disorders
Tinnitus	1/10 (10%)
Gastrointestinal disorders
Abdominal pain	1/10 (10%)
Diarrhoea	6/10 (60%)
Frequent bowel movements	1/10 (10%)
Haemorrhoidal haemorrhage	1/10 (10%)
Inguinal hernia	1/10 (10%)
Nausea	2/10 (20%)
Vomiting	1/10 (10%)
General disorders
Oedema peripheral	3/10 (30%)
Peripheral swelling	1/10 (10%)
Infections and infestations
Cellulitis	1/10 (10%)
Fungal skin infection	1/10 (10%)
Influenza	1/10 (10%)
Nasopharyngitis	1/10 (10%)
Upper respiratory tract infection	1/10 (10%)
Urinary tract infection	3/10 (30%)
Injury, poisoning and procedural complications
Avulsion fracture	1/10 (10%)
Bone contusion	1/10 (10%)
Concussion	1/10 (10%)
Contusion	1/10 (10%)
Corneal abrasion	1/10 (10%)
Fall	9/10 (90%)
Laceration	1/10 (10%)
Ligament sprain	3/10 (30%)
Limb injury	1/10 (10%)
Scratch	1/10 (10%)
Skin abrasion	5/10 (50%)
Tibia fracture	1/10 (10%)
Investigations
Mammogram abnormal	1/10 (10%)
Natural killer cell count increased	1/10 (10%)
Vitamin D decreased	1/10 (10%)
Weight decreased	1/10 (10%)
Metabolism and nutrition disorders
Abnormal loss of weight	1/10 (10%)
Decreased appetite	2/10 (20%)
Glucose tolerance impaired	1/10 (10%)
Gout	2/10 (20%)
Iron deficiency	1/10 (10%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/10 (30%)
Back pain	1/10 (10%)
Bursitis	1/10 (10%)
Muscle spasms	9/10 (90%)
Muscular weakness	1/10 (10%)
Musculoskeletal pain	2/10 (20%)
Myalgia	1/10 (10%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/10 (10%)
Squamous cell carcinoma of skin	1/10 (10%)
Nervous system disorders
Dementia	1/10 (10%)
Dizziness	1/10 (10%)
Dysgeusia	1/10 (10%)
Headache	2/10 (20%)
Hypogeusia	1/10 (10%)
Psychiatric disorders
Depression	1/10 (10%)
Insomnia	1/10 (10%)
Renal and urinary disorders
Nephrolithiasis	1/10 (10%)
Urinary incontinence	1/10 (10%)
Urinary retention	1/10 (10%)
Reproductive system and breast disorders
Breast hyperplasia	1/10 (10%)
Cervical polyp	1/10 (10%)
Respiratory, thoracic and mediastinal disorders
Cough	1/10 (10%)
Dysphonia	1/10 (10%)
Productive cough	1/10 (10%)
Upper-airway cough syndrome	1/10 (10%)
Skin and subcutaneous tissue disorders
Acne	5/10 (50%)
Blister	1/10 (10%)
Night sweats	1/10 (10%)
Papule	1/10 (10%)
Pruritus	1/10 (10%)
Rash	3/10 (30%)
Skin hypertrophy	1/10 (10%)
Vascular disorders
Thrombophlebitis superficial	1/10 (10%)

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 (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.