A Study to Evaluate Safety and Efficacy of Panobinostat in Participants With Primary Myelofibrosis

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00931762
• Collaborator: (none)
• Enrollment: 35
• Locations: 9
• Arm: 1
• Actual Duration (Months): 23.9
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study assessed the safety and efficacy of Panobinostat as a single agent in the treatment of Primary Myelofibrosis, Post-Polycythemia Vera and Post-Essential Thrombocythemia. There were two cohorts - participants with JAK2 mutation and participants without JAK2 mutation.

Condition or Disease	Intervention/Treatment	Phase
Primary Myelofibrosis; Post-Polycythemia Vera; Post-Essential Thrombocytopenia	Drug: Panobinostat	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Oral Panobinostat (LBH589), a Novel Deacetylase Inhibitor (DACi) in Patients With Primary Myelofibrosis (PMF), Post Essential Thrombocythemia (ET) Myelofibrosis and Post- Polycythemia Vera (PV) Myelofibrosis
• Actual Study Start Date: Aug 31, 2009
• Actual Primary Completion Date: Aug 29, 2011
• Actual Study Completion Date: Aug 29, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Panobinostat Participants received panobinostat 40 mg, capsules, orally, with or without food, three times a week on Monday, Wednesday, and Friday for up to 6 treatment cycles (each cycle of 28-days) with dose adjustments possible.	Drug: Panobinostat; Panobinostat oral capsules; Other Names: LBH589 H-DAC Inhibitor

Outcome Measures

Primary Outcome Measures

1. Overall Response (OR) Rate Per International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) Criteria [Up to approximately 2 years]

   Overall response (OR) = Complete remission (CR) + Partial remission (PR) + Clinical improvement (CI). CR: complete resolution of disease-related symptoms and signs with hemoglobin level 110 grams per deciliter (g/L), platelet count 100 x 10^9/liter (L), and absolute neutrophil count (ANC) 1.0 x 10^9/L, all 3 blood counts < upper normal limit (UNL), normal leukocyte differential, and bone marrow histologic remission. PR= all of the criteria for CR except the requirement for bone marrow histologic remission. CI= minimum 20 g/L increase in hemoglobin for transfusion or becoming transfusion independent or reduction in splenomegaly ≥ 50% or 100% increase in platelet count and absolute platelet count of 50 x 10^9/L and 100% increase in ANC of at least 0.5 x 10^9/L.

Secondary Outcome Measures

1. Change From Baseline in Myelofibrosis Symptom Assessment Form (MF-SAF) Scale Scores At Cycle 6 [Baseline, Cycle 6 (each cycle was of 28 days)]

   The MF-SAF consists of seven questions about key symptoms and impact of MF. Questions were scored on a scale of 0-10, with higher scores indicating more severe symptoms and greater inactivity. Questions 1-6 investigate the following symptoms: night sweats, pruritus/itching, abdominal discomfort, pain under the ribs, early satiety and bone/muscle pain. Question 7 asked participants to report levels of inactivity. Negative change from baseline indicates improvement.

2. Change From Baseline in Myelofibrosis Symptom Assessment Form (MF-SAF) Scale Scores [Baseline, Cycles 2, and 4 (each cycle was of 28-days)]

   The MF-SAF consists of seven questions about key symptoms and impact of MF. Questions were scored on a scale of 0-10, with higher scores indicating more severe symptoms and greater inactivity. Questions 1-6 investigate the following symptoms: night sweats, pruritus/itching, abdominal discomfort, pain under the ribs, early satiety and bone/muscle pain. Question 7 asked participants to report levels of inactivity. Negative change from baseline indicates improvement.

3. Number of Participants With Adverse Events (AEs), and Serious Adverse Events (SAEs) [AE: From the start of treatment up to 28 days after last study dose (up to approximately 2 years); SAE: From time of informed consent up to 4 weeks after last study dose (approximately 2 years)]

   An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. SAEs was an undesirable sign, symptom or medical condition which is: life-threatening, persistent or significant disability/incapacity, congenital anomaly/birth defect, requires hospitalizations or prolongation of hospitalizations, or is medically significant

Other Outcome Measures

1. Monthly Capsule Counts to Assess Compliance to Panobinostat Treatment [Up to approximately 2 years]

2. To Compare the Response to Panobinostat in Patients With the JAK2 V617F Mutation to Those Without the JAK2 V617F Mutation [Up to approximately 2 years]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Diagnosis of myelofibrosis, either primary myelofibrosis (PMF), post- polycythemia vera (PV) or post-essential thrombocythemia (ET) myelofibrosis (MF) with international prognostic scoring system (IPSS) score of 2 (intermediate risk) or 3 (high risk) plus at least one of the following:

Symptomatic spenomegaly (≥10 centimeter [cm] below costal margin [BCM]) Hemoglobin < 10 or red cell transfusion dependent. (The presence of a janus kinase (JAK2) V617F mutation is not required for study entry).

1. Participants must meet the following laboratory criteria:

• Participants can be either JAK2 V617F mutated or wild type.

• Serum potassium, magnesium, phosphorous, sodium, total calcium (corrected for serum albumin) or ionized calcium within normal limits (WNL) for the institution Note: Potassium, magnesium, phosphorous, sodium, and/or calcium supplements maybe given to correct values that are < lower limit of normal (LLN). Post correction values must not be deemed to be a clinically significant abnormality prior to participants being dosed.

• Creatinine < 1.5 X upper limit of normal (ULN) or calculated creatinine clearance (CrCl) ≥ 50 milliliter per minute (mL/min) (modification of diet in renal diseases [MDRD] formula).

• Aspartate aminotransferase [AST] and alanine transaminase [ALT] ≤ 2.5 x ULN.

• Serum total bilirubin ≤ 1.5 x ULN.

1. Eastern cooperative oncology group (ECOG) performance status of ≤ 2.

2. Clinically euthyroid. Note: Participants are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.

Exclusion Criteria:

1. Prior histone deacetylases (HDAC), deacetylase (DAC), heat shock protein 90 (HSP90) inhibitors or valproic acid for the treatment of cancer.

2. Previous treatment with JAK2 inhibitors.

3. Any participant who has previously received radiation therapy to ≥ 30% of the bone marrow.

4. Impaired cardiac function or clinically significant cardiac diseases.

5. Participant with unresolved diarrhoea ≥ grade 2.

6. Participants using medications that have a relative risk of prolonging the QT interval or inducing Torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug.

7. Participants who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of surgery.

8. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not using an effective method of birth control. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). Women of childbearing potential must have a negative serum pregnancy test at screening and at baseline.

9. Male participants whose sexual partners are WOCBP not using effective birth control.

10. Participants with a prior malignancy with in the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix).

11. Participants with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required.

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic - Scottsdale	Scottsdale	Arizona	United States	85259
2	City of Hope National Medical Center	Duarte	California	United States	91010
3	Stanford Comprehensive Cancer Center	Stanford	California	United States	94305
4	Medical College of Georgia	Augusta	Georgia	United States	30912
5	Northwestern University Feinberg School of Medicine	Chicago	Illinois	United States	60611
6	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
7	University of Michigan	Ann Arbor	Michigan	United States	48109
8	Mayo Clinic - Rochester	Rochester	Minnesota	United States	55905
9	New York Presbyterian Hospital - Weill Cornell Medical College	New York	New York	United States	10021

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00931762
• Other Study ID Numbers: CLBH589BUS58
• First Posted: Jul 2, 2009
• Last Update Posted: Jul 30, 2021
• Last Verified: Jul 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: Bone marrow; Myelofibrosis; JAK2mutation; Post-Polycythemia Vera; Post-Essential Thrombocytopenia
• Additional relevant MeSH terms: Polycythemia Vera; Thrombocytopenia; Primary Myelofibrosis; Polycythemia; Panobinostat

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at 9 investigative centers in the United States from 31 August 2009 to 29 August 2011.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 40 mg, capsules, orally, with or without food, three times a week on Monday, Wednesday, and Friday for up to 6 treatment cycles (each cycle of 28-days) with dose adjustments possible.
Period Title: Overall Study
STARTED	35
COMPLETED	0
NOT COMPLETED	35

Baseline Characteristics

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 40 mg, capsules, orally, with or without food, three times a week on Monday, Wednesday, and Friday for up to 6 treatment cycles (each cycle of 28-days) with dose adjustments possible.
Overall Participants	35
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68.3 (10.30)
Sex: Female, Male (Count of Participants)
Female	10 28.6%
Male	25 71.4%

Outcome Measures

1. Primary Outcome

Title	Overall Response (OR) Rate Per International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) Criteria
Description	Overall response (OR) = Complete remission (CR) + Partial remission (PR) + Clinical improvement (CI). CR: complete resolution of disease-related symptoms and signs with hemoglobin level 110 grams per deciliter (g/L), platelet count 100 x 10^9/liter (L), and absolute neutrophil count (ANC) 1.0 x 10^9/L, all 3 blood counts < upper normal limit (UNL), normal leukocyte differential, and bone marrow histologic remission. PR= all of the criteria for CR except the requirement for bone marrow histologic remission. CI= minimum 20 g/L increase in hemoglobin for transfusion or becoming transfusion independent or reduction in splenomegaly ≥ 50% or 100% increase in platelet count and absolute platelet count of 50 x 10^9/L and 100% increase in ANC of at least 0.5 x 10^9/L.
Time Frame	Up to approximately 2 years

Outcome Measure Data

Analysis Population Description

FAS population included all participants who received at least one dose of study drug.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 40 mg, capsules, orally, with or without food, three times a week on Monday, Wednesday, and Friday for up to 6 treatment cycles (each cycle of 28-days) with dose adjustments possible.
Measure Participants	35
Number (95% Confidence Interval) [percentage of participants]	2.9 8.3%

2. Secondary Outcome

Title	Change From Baseline in Myelofibrosis Symptom Assessment Form (MF-SAF) Scale Scores At Cycle 6
Description	The MF-SAF consists of seven questions about key symptoms and impact of MF. Questions were scored on a scale of 0-10, with higher scores indicating more severe symptoms and greater inactivity. Questions 1-6 investigate the following symptoms: night sweats, pruritus/itching, abdominal discomfort, pain under the ribs, early satiety and bone/muscle pain. Question 7 asked participants to report levels of inactivity. Negative change from baseline indicates improvement.
Time Frame	Baseline, Cycle 6 (each cycle was of 28 days)

Outcome Measure Data

Analysis Population Description

FAS population included all participants who received at least one dose of study drug. All 35 participants were evaluated for this Outcome. The Number Analyzed represented in each row differs from the Overall Number of Participants Analyzed as scores that are presented are for the participants who reported the measured event at the time evaluated.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 40 mg, capsules, orally, with or without food, three times a week on Monday, Wednesday, and Friday for up to 6 treatment cycles (each cycle of 28-days) with dose adjustments possible.
Measure Participants	35
Cycle 6, Day 1: Fatigue Right now	-1.5 (2.12)
Cycle 6, Day 1: Fatigue Usual Past 24 Hours	-1.0 (5.66)
Cycle 6, Day 1: Fatigue Worst Past 24 Hours	-3.0 (2.83)
Cycle 6, Day 1: General Activity	-3.5 (2.12)
Cycle 6, Day 1: Mood	-3.5 (3.54)
Cycle 6, Day 1: Walking Ability	-3.0 (5.66)
Cycle 6, Day 1: Normal Work	-4.0 (4.24)
Cycle 6, Day 1: Relations with Other People	-4.5 (2.12)
Cycle 6, Day 1: Enjoyment of Life	-5.0 (4.24)
Cycle 6, Day 1: Filling up quickly when you eat	1.0 (1.41)
Cycle 6, Day 1: Abdominal pain or Discomfort	0.5 (2.12)
Cycle 6, Day 1: Inactivity	-0.5 (3.54)
Cycle 6, Day 1: Cough	-1.5 (2.12)
Cycle 6, Day 1: Night Sweats	-0.5 (0.71)
Cycle 6, Day 1: Itching	1.5 (2.12)
Cycle 6, Day 1: Bone Pain	-2.5 (0.71)
Cycle 6, Day 1: What is Overall Quality of Life?	-2.5 (2.12)

3. Secondary Outcome

Title	Change From Baseline in Myelofibrosis Symptom Assessment Form (MF-SAF) Scale Scores
Description	The MF-SAF consists of seven questions about key symptoms and impact of MF. Questions were scored on a scale of 0-10, with higher scores indicating more severe symptoms and greater inactivity. Questions 1-6 investigate the following symptoms: night sweats, pruritus/itching, abdominal discomfort, pain under the ribs, early satiety and bone/muscle pain. Question 7 asked participants to report levels of inactivity. Negative change from baseline indicates improvement.
Time Frame	Baseline, Cycles 2, and 4 (each cycle was of 28-days)

Outcome Measure Data

Analysis Population Description

FAS population included all participants who received at least one dose of study drug. All 35 participants were evaluated for this Outcome. The Number Analyzed represented in each row differs from the Overall Number of Participants Analyzed as scores that are presented are for the participants who reported the measured event at the time evaluated.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 40 mg, capsules, orally, with or without food, three times a week on Monday, Wednesday, and Friday for up to 6 treatment cycles (each cycle of 28-days) with dose adjustments possible.
Measure Participants	35
Cycle 2, Day 1: Fatigue Right now	0.0 (2.00)
Cycle 2, Day 1: Fatigue Usual Past 24 Hours	0.5 (1.83)
Cycle 2, Day 1: Fatigue Worst Past 24 Hours	0.7 (1.98)
Cycle 2, Day 1: General Activity	0.0 (2.03)
Cycle 2, Day 1: Mood	0.5 (2.15)
Cycle 2, Day 1: Walking Ability	-0.6 (2.86)
Cycle 2, Day 1: Normal Work	0.2 (2.87)
Cycle 2, Day 1: Relations with Other People	-0.1 (2.71)
Cycle 2, Day 1: Enjoyment of Life	0.3 (3.30)
Cycle 2, Day 1: Filling up quickly when you eat	0.7 (2.38)
Cycle 2, Day 1: Abdominal Pain or Discomfort	-0.0 (2.64)
Cycle 2, Day 1: Inactivity	0.8 (2.45)
Cycle 2, Day 1: Cough	-0.1 (2.07)
Cycle 2, Day 1: Night Sweats	-1.0 (2.36)
Cycle 2, Day 1: Itching	-1.5 (2.89)
Cycle 2, Day 1: Bone Pain	-1.0 (2.79)
Cycle 2, Day 1: What is Overall Quality of Life?	-0.4 (2.24)
Cycle 4, Day 1: Fatigue Right now	0.0 (1.93)
Cycle 4, Day 1: Fatigue Usual Past 24 Hours	0.8 (1.91)
Cycle 4, Day 1: Fatigue Worst Past 24 Hours	1.0 (1.31)
Cycle 4, Day 1: General Activity	-0.5 (3.07)
Cycle 4, Day 1: Mood	0.3 (2.75)
Cycle 4, Day 1: Walking Ability	-0.6 (3.26)
Cycle 4, Day 1: Normal Work	0.9 (2.53)
Cycle 4, Day 1: Relations with Other People	-0.6 (2.20)
Cycle 4, Day 1: Enjoyment of Life	0.4 (3.62)
Cycle 4, Day 1: Filling up quickly when you eat	-0.1 (4.42)
Cycle 4, Day 1: Abdominal Pain or Discomfort	1.0 (2.67)
Cycle 4, Day 1: Inactivity	0.6 (3.25)
Cycle 4, Day 1: Cough	-0.9 (1.36)
Cycle 4, Day 1: Night Sweats	-1.1 (3.52)
Cycle 4, Day 1: Itching	-0.1 (0.90)
Cycle 4, Day 1: Bone Pain	-1.8 (3.41)
Cycle 4, Day 1: What is Overall Quality of Life?	-0.3 (1.60)

4. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs), and Serious Adverse Events (SAEs)
Description	An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. SAEs was an undesirable sign, symptom or medical condition which is: life-threatening, persistent or significant disability/incapacity, congenital anomaly/birth defect, requires hospitalizations or prolongation of hospitalizations, or is medically significant
Time Frame	AE: From the start of treatment up to 28 days after last study dose (up to approximately 2 years); SAE: From time of informed consent up to 4 weeks after last study dose (approximately 2 years)

Outcome Measure Data

Analysis Population Description

Safety set population included all participants who received at least one dose of study drug and had at least one post-baseline safety assessment.

Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 40 mg, capsules, orally, with or without food, three times a week on Monday, Wednesday, and Friday for up to 6 treatment cycles (each cycle of 28-days) with dose adjustments possible.
Measure Participants	35
AEs	35 100%
SAEs	19 54.3%

5. Other Pre-specified Outcome

Title	Monthly Capsule Counts to Assess Compliance to Panobinostat Treatment
Time Frame	Up to approximately 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	To Compare the Response to Panobinostat in Patients With the JAK2 V617F Mutation to Those Without the JAK2 V617F Mutation
Time Frame	Up to approximately 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	AE: From the start of treatment up to 28 days after last study dose (up to approximately 2 years); SAE: From time of informed consent up to 4 weeks after last study dose (approximately 2 years)
Adverse Event Reporting Description	Safety set population included all participants who were randomized and received at least 1 dose of study drug.
Arm/Group Title	Panobinostat
Arm/Group Description	Participants received panobinostat 40 mg, capsules, orally, with or without food, three times a week on Monday, Wednesday, and Friday for up to 6 treatment cycles (each cycle of 28-days) with dose adjustments possible.
All Cause Mortality
	Panobinostat
	Affected / at Risk (%)	# Events
Total	1/35 (2.9%)
Serious Adverse Events
	Panobinostat
	Affected / at Risk (%)	# Events
Total	19/35 (54.3%)
Blood and lymphatic system disorders
Anaemia	1/35 (2.9%)
Leukopenia	1/35 (2.9%)
Neutropenia	1/35 (2.9%)
Splenic infarction	1/35 (2.9%)
Thrombocytopenia	7/35 (20%)
Cardiac disorders
Cardio-respiratory arrest	1/35 (2.9%)
Gastrointestinal disorders
Ascites	1/35 (2.9%)
Diarrhoea	1/35 (2.9%)
Diverticulum intestinal haemorrhagic	1/35 (2.9%)
Gastritis haemorrhagic	1/35 (2.9%)
Gastrointestinal haemorrhage	1/35 (2.9%)
Nausea	1/35 (2.9%)
Vomiting	1/35 (2.9%)
General disorders
Asthenia	1/35 (2.9%)
Pyrexia	2/35 (5.7%)
Infections and infestations
Clostridium difficile colitis	1/35 (2.9%)
Lobar pneumonia	1/35 (2.9%)
Pneumonia	2/35 (5.7%)
Sepsis	1/35 (2.9%)
Urosepsis	1/35 (2.9%)
Investigations
Haemoglobin decreased	1/35 (2.9%)
Metabolism and nutrition disorders
Hypercalcaemia	1/35 (2.9%)
Hypovolaemia	1/35 (2.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/35 (2.9%)
Bone pain	1/35 (2.9%)
Psychiatric disorders
Confusional state	1/35 (2.9%)
Delirium	1/35 (2.9%)
Renal and urinary disorders
Renal failure acute	1/35 (2.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/35 (5.7%)
Hypoxia	1/35 (2.9%)
Interstitial lung disease	1/35 (2.9%)
Vascular disorders
Arterial haemorrhage	1/35 (2.9%)
Hypotension	1/35 (2.9%)
Orthostatic hypotension	1/35 (2.9%)
Other (Not Including Serious) Adverse Events
	Panobinostat
	Affected / at Risk (%)	# Events
Total	35/35 (100%)
Blood and lymphatic system disorders
Anaemia	10/35 (28.6%)
Leukopenia	4/35 (11.4%)
Lymphopenia	1/35 (2.9%)
Neutropenia	6/35 (17.1%)
Thrombocytopenia	18/35 (51.4%)
Cardiac disorders
Acute myocardial infarction	1/35 (2.9%)
Arrhythmia	2/35 (5.7%)
Atrial fibrillation	1/35 (2.9%)
Palpitations	1/35 (2.9%)
Tachycardia	2/35 (5.7%)
Endocrine disorders
Cushingoid	1/35 (2.9%)
Hypothyroidism	2/35 (5.7%)
Eye disorders
Eye haemorrhage	1/35 (2.9%)
Lacrimation increased	1/35 (2.9%)
Gastrointestinal disorders
Abdominal discomfort	1/35 (2.9%)
Abdominal distension	6/35 (17.1%)
Abdominal pain	7/35 (20%)
Abdominal pain lower	1/35 (2.9%)
Abdominal pain upper	1/35 (2.9%)
Ascites	2/35 (5.7%)
Constipation	8/35 (22.9%)
Diarrhoea	27/35 (77.1%)
Dry mouth	7/35 (20%)
Dyspepsia	3/35 (8.6%)
Dysphagia	1/35 (2.9%)
Faecal incontinence	1/35 (2.9%)
Faeces discoloured	1/35 (2.9%)
Flatulence	1/35 (2.9%)
Gastrointestinal haemorrhage	1/35 (2.9%)
Gastrointestinal pain	1/35 (2.9%)
Haemorrhoids	1/35 (2.9%)
Large intestinal haemorrhage	1/35 (2.9%)
Mallory-Weiss syndrome	1/35 (2.9%)
Melaena	2/35 (5.7%)
Mouth haemorrhage	1/35 (2.9%)
Nausea	19/35 (54.3%)
Oesophageal haemorrhage	1/35 (2.9%)
Rectal haemorrhage	1/35 (2.9%)
Retching	1/35 (2.9%)
Stomatitis	1/35 (2.9%)
Toothache	1/35 (2.9%)
Vomiting	13/35 (37.1%)
General disorders
Adverse drug reaction	1/35 (2.9%)
Asthenia	4/35 (11.4%)
Chills	4/35 (11.4%)
Fatigue	20/35 (57.1%)
Feeling jittery	1/35 (2.9%)
General physical health deterioration	1/35 (2.9%)
Generalised oedema	1/35 (2.9%)
Mucosal inflammation	1/35 (2.9%)
Oedema	3/35 (8.6%)
Oedema peripheral	6/35 (17.1%)
Pain	2/35 (5.7%)
Pyrexia	6/35 (17.1%)
Immune system disorders
Drug hypersensitivity	1/35 (2.9%)
Hypersensitivity	1/35 (2.9%)
Infections and infestations
Candidiasis	1/35 (2.9%)
Clostridium difficile colitis	1/35 (2.9%)
Furuncle	1/35 (2.9%)
Herpes simplex	1/35 (2.9%)
Oral candidiasis	1/35 (2.9%)
Pneumonia	1/35 (2.9%)
Staphylococcal infection	1/35 (2.9%)
Subcutaneous abscess	1/35 (2.9%)
Urinary tract infection	2/35 (5.7%)
Investigations
Blood alkaline phosphatase increased	1/35 (2.9%)
Blood bilirubin increased	1/35 (2.9%)
Blood creatinine increased	4/35 (11.4%)
Blood magnesium decreased	1/35 (2.9%)
Haemoglobin decreased	2/35 (5.7%)
International normalised ratio increased	1/35 (2.9%)
Vitamin D decreased	1/35 (2.9%)
Weight decreased	1/35 (2.9%)
Weight increased	1/35 (2.9%)
White blood cell count increased	1/35 (2.9%)
Metabolism and nutrition disorders
Decreased appetite	19/35 (54.3%)
Dehydration	3/35 (8.6%)
Diabetes mellitus	1/35 (2.9%)
Gout	1/35 (2.9%)
Hypercalcaemia	1/35 (2.9%)
Hyperglycaemia	3/35 (8.6%)
Hypermagnesaemia	1/35 (2.9%)
Hyperphosphataemia	1/35 (2.9%)
Hyperuricaemia	2/35 (5.7%)
Hypoalbuminaemia	3/35 (8.6%)
Hypocalcaemia	6/35 (17.1%)
Hypokalaemia	4/35 (11.4%)
Hypomagnesaemia	4/35 (11.4%)
Hyponatraemia	3/35 (8.6%)
Hypophosphataemia	4/35 (11.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/35 (2.9%)
Back pain	2/35 (5.7%)
Bone pain	1/35 (2.9%)
Coccydynia	1/35 (2.9%)
Facet joint syndrome	1/35 (2.9%)
Flank pain	3/35 (8.6%)
Joint swelling	1/35 (2.9%)
Muscle spasms	2/35 (5.7%)
Muscular weakness	3/35 (8.6%)
Musculoskeletal pain	1/35 (2.9%)
Myalgia	1/35 (2.9%)
Neck pain	3/35 (8.6%)
Pain in extremity	3/35 (8.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm	1/35 (2.9%)
Nervous system disorders
Cognitive disorder	1/35 (2.9%)
Dizziness	7/35 (20%)
Dysarthria	1/35 (2.9%)
Dysgeusia	7/35 (20%)
Headache	5/35 (14.3%)
Lethargy	2/35 (5.7%)
Memory impairment	1/35 (2.9%)
Peripheral sensory neuropathy	1/35 (2.9%)
Sinus headache	1/35 (2.9%)
Syncope	3/35 (8.6%)
Psychiatric disorders
Agitation	2/35 (5.7%)
Anxiety	2/35 (5.7%)
Confusional state	1/35 (2.9%)
Hallucination	1/35 (2.9%)
Insomnia	2/35 (5.7%)
Psychotic disorder	1/35 (2.9%)
Renal and urinary disorders
Haematuria	1/35 (2.9%)
Renal failure acute	1/35 (2.9%)
Ureteric obstruction	1/35 (2.9%)
Urinary incontinence	3/35 (8.6%)
Urinary retention	1/35 (2.9%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/35 (2.9%)
Cough	4/35 (11.4%)
Dyspnoea	7/35 (20%)
Epistaxis	4/35 (11.4%)
Haemoptysis	1/35 (2.9%)
Hiccups	1/35 (2.9%)
Oropharyngeal pain	2/35 (5.7%)
Pleural effusion	1/35 (2.9%)
Pleuritic pain	1/35 (2.9%)
Productive cough	2/35 (5.7%)
Pulmonary hypertension	1/35 (2.9%)
Sinus congestion	1/35 (2.9%)
Wheezing	1/35 (2.9%)
Skin and subcutaneous tissue disorders
Alopecia	1/35 (2.9%)
Dermatitis exfoliative	1/35 (2.9%)
Ecchymosis	1/35 (2.9%)
Increased tendency to bruise	2/35 (5.7%)
Night sweats	2/35 (5.7%)
Petechiae	3/35 (8.6%)
Purpura	2/35 (5.7%)
Rash macular	1/35 (2.9%)
Skin hyperpigmentation	1/35 (2.9%)
Urticaria	1/35 (2.9%)
Vascular disorders
Flushing	1/35 (2.9%)
Hypertension	1/35 (2.9%)
Hypotension	1/35 (2.9%)
Orthostatic hypotension	1/35 (2.9%)

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.