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Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD). (COMBI-AD)

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ClinicalTrials.gov Identifier: NCT01682083
Recruitment Status : Active, not recruiting
First Posted : September 10, 2012
Results First Posted : September 26, 2018
Last Update Posted : September 26, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Melanoma
Interventions Drug: Dabrafenib
Drug: Trametinib
Drug: Placebos
Enrollment 870
Recruitment Details The study was conducted in 169 centers across 25 countries. Results reported have the data cut-off as of 30 June 2017.
Pre-assignment Details Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIA (lymph node metastasis >1 mm), IIIB, or IIIC] cutaneous melanoma.
Arm/Group Title Dabrafenib and Trametinib Combination Therapy Dabrafenib and Trametinib Placebos
Hide Arm/Group Description Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months. Subjects received matching placebos orally for 12 months
Period Title: Overall Study
Started 438 432
Completed 331 [1] 277 [2]
Not Completed 107 155
Reason Not Completed
Lost to Follow-up             11             18
Withdrawal by Subject             31             40
Death             60             93
Physician Decision             5             4
[1]
Ongoing patients at the time of data cut-off. 3 patients were untreated
[2]
Ongoing patients at the time of data cut-off.
Arm/Group Title Dabrafenib and Trametinib Combination Therapy Dabrafenib and Trametinib Placebos Total
Hide Arm/Group Description Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months. Subjects received matching placebos orally for 12 months Total of all reporting groups
Overall Number of Baseline Participants 438 432 870
Hide Baseline Analysis Population Description
The Intent-to-Treat Population (ITT) consisted of all randomized patients whether or not randomized treatment was administered.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 438 participants 432 participants 870 participants
50.4  (14.17) 50.5  (13.14) 50.4  (13.66)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 438 participants 432 participants 870 participants
Female
195
  44.5%
193
  44.7%
388
  44.6%
Male
243
  55.5%
239
  55.3%
482
  55.4%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 438 participants 432 participants 870 participants
White
432
  98.6%
427
  98.8%
859
  98.7%
Asian
6
   1.4%
5
   1.2%
11
   1.3%
1.Primary Outcome
Title Relapse-free Survival (RFS)
Hide Description Recurrence-free survival was defined as the time from randomization to disease recurrence (local recurrence, distant recurrence, second primary melanoma), or death from any cause.
Time Frame Approximately 3.5 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) Population
Arm/Group Title Dabrafenib and Trametinib Combination Therapy Dabrafenib and Trametinib Placebos
Hide Arm/Group Description:
Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.
Subjects received matching placebos orally for 12 months
Overall Number of Participants Analyzed 438 432
Measure Type: Number
Unit of Measure: Participants with events
Relapsed (event) 163 247
Died 3 1
Censored, follow-up ended 43 35
Censored, follow-up ongoing 229 149
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dabrafenib and Trametinib Combination Therapy, Dabrafenib and Trametinib Placebos
Comments The null hypothesis, H0: λ = 1 or reject it in favor of the alternative hypothesis, HA: λ ≠ 1, where λ is the hazard ratio (HR) of combination therapy relative to placebo.
Type of Statistical Test Superiority
Comments Hazard ratio is obtained from the stratified Pike estimator. A hazard ratio <1 indicates a lower risk with Dabrafenib + Trametinib compared with Placebo.
Statistical Test of Hypothesis P-Value < 0.0001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio, log
Estimated Value 0.47
Confidence Interval (2-Sided) 95%
0.39 to 0.58
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Overall Survival
Hide Description Overall survival (OS) of dabrafenib and trametinib as a combination therapy versus placebo
Time Frame approximately 3.5 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population
Arm/Group Title Dabrafenib and Trametinib Combination Therapy Dabrafenib and Trametinib Placebos
Hide Arm/Group Description:
Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.
Subjects received matching placebos orally for 12 months
Overall Number of Participants Analyzed 438 432
Measure Type: Count of Participants
Unit of Measure: Participants
Died (event) 60 93
Censored, follow-up ended 47 62
Censored, follow-up ongoing 331 277
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dabrafenib and Trametinib Combination Therapy, Dabrafenib and Trametinib Placebos
Comments Hazard ratio is obtained from the stratified Pike estimator.
Type of Statistical Test Superiority
Comments A hazard ratio <1 indicates a lower risk with dabrafenib + trametinib compared with Placebo.
Statistical Test of Hypothesis P-Value 0.006
Comments [Not Specified]
Method Log Rank
Comments the two-sided threshold for significance at this first interim analysis was p=0.000019
Method of Estimation Estimation Parameter Hazard Ratio, log
Estimated Value 0.57
Confidence Interval (2-Sided) 95%
0.42 to 0.79
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Distant Metastasis-free Survival
Hide Description Distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus placebo. In the DMFS analysis, the first occurrence of distant metastasis or death (if it occurred before documented recurrence) was counted as an event.
Time Frame approximately 3.5 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population
Arm/Group Title Dabrafenib and Trametinib Combination Therapy Dabrafenib and Trametinib Placebos
Hide Arm/Group Description:
Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.
Subjects received matching placebos orally for 12 months
Overall Number of Participants Analyzed 438 432
Measure Type: Number
Unit of Measure: Participants with events
Number of Subjects - Relapsed 106 150
Number of Subjects - died 4 2
Number of Subjects - censored, follow-up ended 99 131
Number of Subjects - follow-up ongoing 229 149
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dabrafenib and Trametinib Combination Therapy, Dabrafenib and Trametinib Placebos
Comments Hazard ratio is estimated using Pike estimator.
Type of Statistical Test Superiority
Comments A hazard ratio <1 indicates a lower risk with Dabrafenib + Trametinib compared with Placebo.
Method of Estimation Estimation Parameter Hazard Ratio, log
Estimated Value 0.51
Confidence Interval (2-Sided) 95%
0.40 to 0.65
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Freedom From Relapse
Hide Description Freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus placebo. In the FFR analysis, local or distant recurrence or a new primary melanoma were counted as events, and patients who died of causes other than melanoma or treatment-related toxicity were censored.
Time Frame approximately 3.5 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population
Arm/Group Title Dabrafenib and Trametinib Combination Therapy Dabrafenib and Trametinib Placebos
Hide Arm/Group Description:
Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.
Subjects received matching placebos orally for 12 months
Overall Number of Participants Analyzed 438 432
Measure Type: Number
Unit of Measure: Participants with events
Number of Subjects - relapsed 163 247
Number of Subjects - died 2 0
Number of Subjects - censored, follow-up ended 44 36
Number of Subjects - censored, follow-up ongoing 229 149
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dabrafenib and Trametinib Combination Therapy, Dabrafenib and Trametinib Placebos
Comments Hazard ratio is estimated using Pike estimator.
Type of Statistical Test Superiority
Comments A hazard ratio <1 indicates a lower risk with Dabrafenib + Trametinib compared with Placebo.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.47
Confidence Interval (2-Sided) 95%
0.39 to 0.57
Estimation Comments [Not Specified]
Time Frame Adverse events (AEs) were collected from the time the first dose of study treatment is administered until 30 days after discontinuation of study treatment. Serious AEs (SAEs) were reported over the same time period as AEs except SAEs assessed as related to study participation, study treatment or concomitant medication were recorded from the time a subject consents to participate in the study up to and including any follow-up contact.
Adverse Event Reporting Description All cause mortality provided for the treatment period only.
 
Arm/Group Title Dabrafenib + Trametinib Combination Therapy Dabrafenib and Trametinib Placebos
Hide Arm/Group Description Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months. Subjects received matching placebos orally for 12 months
All-Cause Mortality
Dabrafenib + Trametinib Combination Therapy Dabrafenib and Trametinib Placebos
Affected / at Risk (%) Affected / at Risk (%)
Total   4/435 (0.92%)   1/432 (0.23%) 
Show Serious Adverse Events Hide Serious Adverse Events
Dabrafenib + Trametinib Combination Therapy Dabrafenib and Trametinib Placebos
Affected / at Risk (%) Affected / at Risk (%)
Total   155/435 (35.63%)   44/432 (10.19%) 
Blood and lymphatic system disorders     
Febrile neutropenia  1  2/435 (0.46%)  0/432 (0.00%) 
Haemorrhagic anaemia  1  1/435 (0.23%)  0/432 (0.00%) 
Neutropenia  1  1/435 (0.23%)  0/432 (0.00%) 
Pancytopenia  1  1/435 (0.23%)  0/432 (0.00%) 
Cardiac disorders     
Atrial fibrillation  1  1/435 (0.23%)  0/432 (0.00%) 
Atrioventricular block second degree  1  1/435 (0.23%)  0/432 (0.00%) 
Cardiac ventricular thrombosis  1  0/435 (0.00%)  1/432 (0.23%) 
Tachycardia  1  0/435 (0.00%)  1/432 (0.23%) 
Endocrine disorders     
Inappropriate antidiuretic hormone secretion  1  0/435 (0.00%)  1/432 (0.23%) 
Eye disorders     
Chorioretinopathy  1  5/435 (1.15%)  0/432 (0.00%) 
Iritis  1  1/435 (0.23%)  0/432 (0.00%) 
Macular oedema  1  1/435 (0.23%)  0/432 (0.00%) 
Retinal detachment  1  2/435 (0.46%)  0/432 (0.00%) 
Uveitis  1  2/435 (0.46%)  0/432 (0.00%) 
Visual acuity reduced  1  1/435 (0.23%)  0/432 (0.00%) 
Gastrointestinal disorders     
Abdominal pain  1  1/435 (0.23%)  0/432 (0.00%) 
Abdominal pain upper  1  0/435 (0.00%)  1/432 (0.23%) 
Diarrhoea  1  1/435 (0.23%)  0/432 (0.00%) 
Gastrooesophageal reflux disease  1  1/435 (0.23%)  0/432 (0.00%) 
Inguinal hernia  1  1/435 (0.23%)  0/432 (0.00%) 
Pancreatic toxicity  1  1/435 (0.23%)  0/432 (0.00%) 
Pancreatitis  1  1/435 (0.23%)  0/432 (0.00%) 
Proctalgia  1  0/435 (0.00%)  1/432 (0.23%) 
Retroperitoneal haematoma  1  1/435 (0.23%)  0/432 (0.00%) 
Vomiting  1  4/435 (0.92%)  0/432 (0.00%) 
General disorders     
Asthenia  1  1/435 (0.23%)  0/432 (0.00%) 
Chills  1  13/435 (2.99%)  0/432 (0.00%) 
Fatigue  1  2/435 (0.46%)  0/432 (0.00%) 
Influenza like illness  1  3/435 (0.69%)  0/432 (0.00%) 
Pyrexia  1  67/435 (15.40%)  4/432 (0.93%) 
Systemic inflammatory response syndrome  1  1/435 (0.23%)  0/432 (0.00%) 
Hepatobiliary disorders     
Drug-induced liver injury  1  1/435 (0.23%)  0/432 (0.00%) 
Hepatic haemorrhage  1  0/435 (0.00%)  1/432 (0.23%) 
Hepatotoxicity  1  1/435 (0.23%)  0/432 (0.00%) 
Hyperbilirubinaemia  1  1/435 (0.23%)  0/432 (0.00%) 
Infections and infestations     
Abscess jaw  1  1/435 (0.23%)  0/432 (0.00%) 
Cellulitis  1  5/435 (1.15%)  1/432 (0.23%) 
Cholecystitis infective  1  1/435 (0.23%)  0/432 (0.00%) 
Epstein-Barr virus infection  1  1/435 (0.23%)  0/432 (0.00%) 
Erysipelas  1  8/435 (1.84%)  1/432 (0.23%) 
Febrile infection  1  1/435 (0.23%)  0/432 (0.00%) 
Gastroenteritis  1  1/435 (0.23%)  0/432 (0.00%) 
Groin abscess  1  1/435 (0.23%)  0/432 (0.00%) 
Groin infection  1  1/435 (0.23%)  0/432 (0.00%) 
Herpes zoster  1  0/435 (0.00%)  1/432 (0.23%) 
Influenza  1  2/435 (0.46%)  0/432 (0.00%) 
Lower respiratory tract infection  1  3/435 (0.69%)  0/432 (0.00%) 
Parvovirus infection  1  1/435 (0.23%)  0/432 (0.00%) 
Pharyngitis  1  1/435 (0.23%)  0/432 (0.00%) 
Pneumonia  1  3/435 (0.69%)  0/432 (0.00%) 
Post procedural infection  1  0/435 (0.00%)  1/432 (0.23%) 
Rash pustular  1  1/435 (0.23%)  0/432 (0.00%) 
Retinitis  1  1/435 (0.23%)  0/432 (0.00%) 
Salpingitis  1  1/435 (0.23%)  0/432 (0.00%) 
Sepsis  1  4/435 (0.92%)  0/432 (0.00%) 
Soft tissue infection  1  0/435 (0.00%)  1/432 (0.23%) 
Subcutaneous abscess  1  0/435 (0.00%)  1/432 (0.23%) 
Upper respiratory tract infection  1  1/435 (0.23%)  0/432 (0.00%) 
Urinary tract infection  1  0/435 (0.00%)  1/432 (0.23%) 
Urosepsis  1  1/435 (0.23%)  0/432 (0.00%) 
Vulval abscess  1  1/435 (0.23%)  0/432 (0.00%) 
Wound infection  1  0/435 (0.00%)  1/432 (0.23%) 
Injury, poisoning and procedural complications     
Limb injury  1  0/435 (0.00%)  1/432 (0.23%) 
Post procedural haemorrhage  1  0/435 (0.00%)  1/432 (0.23%) 
Seroma  1  1/435 (0.23%)  1/432 (0.23%) 
Upper limb fracture  1  0/435 (0.00%)  1/432 (0.23%) 
Investigations     
Alanine aminotransferase increased  1  3/435 (0.69%)  0/432 (0.00%) 
Aspartate aminotransferase increased  1  2/435 (0.46%)  0/432 (0.00%) 
Blood creatine phosphokinase increased  1  1/435 (0.23%)  0/432 (0.00%) 
Ejection fraction decreased  1  13/435 (2.99%)  5/432 (1.16%) 
Right ventricular systolic pressure increased  1  0/435 (0.00%)  1/432 (0.23%) 
Transaminases increased  1  1/435 (0.23%)  0/432 (0.00%) 
Troponin increased  1  1/435 (0.23%)  0/432 (0.00%) 
Metabolism and nutrition disorders     
Decreased appetite  1  1/435 (0.23%)  0/432 (0.00%) 
Dehydration  1  4/435 (0.92%)  0/432 (0.00%) 
Diabetes mellitus inadequate control  1  0/435 (0.00%)  1/432 (0.23%) 
Hyperglycaemia  1  2/435 (0.46%)  0/432 (0.00%) 
Hyponatraemia  1  1/435 (0.23%)  0/432 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  1/435 (0.23%)  0/432 (0.00%) 
Intervertebral disc protrusion  1  1/435 (0.23%)  0/432 (0.00%) 
Myopathy  1  1/435 (0.23%)  0/432 (0.00%) 
Pain in extremity  1  1/435 (0.23%)  0/432 (0.00%) 
Rhabdomyolysis  1  2/435 (0.46%)  0/432 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Acanthoma  1  0/435 (0.00%)  1/432 (0.23%) 
B-cell lymphoma  1  1/435 (0.23%)  0/432 (0.00%) 
Basal cell carcinoma  1  0/435 (0.00%)  1/432 (0.23%) 
Bladder transitional cell carcinoma  1  0/435 (0.00%)  1/432 (0.23%) 
Bowen's disease  1  2/435 (0.46%)  2/432 (0.46%) 
Colon adenoma  1  1/435 (0.23%)  0/432 (0.00%) 
Endometrial adenocarcinoma  1  2/435 (0.46%)  0/432 (0.00%) 
Focal nodular hyperplasia  1  1/435 (0.23%)  0/432 (0.00%) 
Keratoacanthoma  1  1/435 (0.23%)  1/432 (0.23%) 
Lentigo maligna  1  0/435 (0.00%)  1/432 (0.23%) 
Malignant melanoma  1  1/435 (0.23%)  3/432 (0.69%) 
Malignant melanoma in situ  1  0/435 (0.00%)  1/432 (0.23%) 
Prostate cancer  1  1/435 (0.23%)  0/432 (0.00%) 
Renal cancer  1  0/435 (0.00%)  1/432 (0.23%) 
Salivary gland adenoma  1  0/435 (0.00%)  1/432 (0.23%) 
Squamous cell carcinoma  1  3/435 (0.69%)  3/432 (0.69%) 
Squamous cell carcinoma of skin  1  1/435 (0.23%)  1/432 (0.23%) 
Nervous system disorders     
Amyotrophic lateral sclerosis  1  0/435 (0.00%)  1/432 (0.23%) 
Carpal tunnel syndrome  1  0/435 (0.00%)  1/432 (0.23%) 
Demyelinating polyneuropathy  1  1/435 (0.23%)  0/432 (0.00%) 
Dizziness  1  2/435 (0.46%)  0/432 (0.00%) 
Facial paralysis  1  1/435 (0.23%)  0/432 (0.00%) 
Headache  1  4/435 (0.92%)  0/432 (0.00%) 
Loss of consciousness  1  1/435 (0.23%)  0/432 (0.00%) 
Meningoradiculitis  1  1/435 (0.23%)  0/432 (0.00%) 
Migraine  1  1/435 (0.23%)  1/432 (0.23%) 
Paraesthesia  1  1/435 (0.23%)  0/432 (0.00%) 
Peripheral sensorimotor neuropathy  1  1/435 (0.23%)  0/432 (0.00%) 
Presyncope  1  2/435 (0.46%)  0/432 (0.00%) 
Seizure  1  1/435 (0.23%)  0/432 (0.00%) 
Psychiatric disorders     
Mental status changes  1  1/435 (0.23%)  0/432 (0.00%) 
Obsessive-compulsive disorder  1  0/435 (0.00%)  1/432 (0.23%) 
Renal and urinary disorders     
Acute kidney injury  1  2/435 (0.46%)  0/432 (0.00%) 
Calculus urinary  1  1/435 (0.23%)  0/432 (0.00%) 
Nephrotic syndrome  1  1/435 (0.23%)  0/432 (0.00%) 
Renal colic  1  1/435 (0.23%)  0/432 (0.00%) 
Reproductive system and breast disorders     
Ovarian disorder  1  1/435 (0.23%)  0/432 (0.00%) 
Priapism  1  1/435 (0.23%)  0/432 (0.00%) 
Testicular mass  1  0/435 (0.00%)  1/432 (0.23%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  1/435 (0.23%)  0/432 (0.00%) 
Lung disorder  1  1/435 (0.23%)  0/432 (0.00%) 
Pleural effusion  1  1/435 (0.23%)  0/432 (0.00%) 
Pulmonary embolism  1  3/435 (0.69%)  1/432 (0.23%) 
Pulmonary hypertension  1  1/435 (0.23%)  0/432 (0.00%) 
Skin and subcutaneous tissue disorders     
Erythema nodosum  1  1/435 (0.23%)  0/432 (0.00%) 
Panniculitis  1  1/435 (0.23%)  0/432 (0.00%) 
Rash generalised  1  1/435 (0.23%)  0/432 (0.00%) 
Vascular disorders     
Embolism  1  0/435 (0.00%)  1/432 (0.23%) 
Hypotension  1  6/435 (1.38%)  0/432 (0.00%) 
Lymphoedema  1  0/435 (0.00%)  1/432 (0.23%) 
Vascular occlusion  1  1/435 (0.23%)  0/432 (0.00%) 
1
Term from vocabulary, MedDRA (19.1)
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Dabrafenib + Trametinib Combination Therapy Dabrafenib and Trametinib Placebos
Affected / at Risk (%) Affected / at Risk (%)
Total   414/435 (95.17%)   340/432 (78.70%) 
Blood and lymphatic system disorders     
Neutropenia  1  34/435 (7.82%)  4/432 (0.93%) 
Eye disorders     
Dry eye  1  22/435 (5.06%)  13/432 (3.01%) 
Vision blurred  1  27/435 (6.21%)  16/432 (3.70%) 
Gastrointestinal disorders     
Abdominal pain  1  34/435 (7.82%)  23/432 (5.32%) 
Abdominal pain upper  1  30/435 (6.90%)  27/432 (6.25%) 
Constipation  1  51/435 (11.72%)  27/432 (6.25%) 
Diarrhoea  1  143/435 (32.87%)  65/432 (15.05%) 
Dry mouth  1  41/435 (9.43%)  15/432 (3.47%) 
Dyspepsia  1  24/435 (5.52%)  26/432 (6.02%) 
Nausea  1  172/435 (39.54%)  88/432 (20.37%) 
Vomiting  1  120/435 (27.59%)  43/432 (9.95%) 
General disorders     
Asthenia  1  58/435 (13.33%)  42/432 (9.72%) 
Chills  1  158/435 (36.32%)  19/432 (4.40%) 
Fatigue  1  204/435 (46.90%)  122/432 (28.24%) 
Influenza like illness  1  66/435 (15.17%)  29/432 (6.71%) 
Oedema peripheral  1  58/435 (13.33%)  19/432 (4.40%) 
Pyrexia  1  248/435 (57.01%)  44/432 (10.19%) 
Infections and infestations     
Folliculitis  1  24/435 (5.52%)  9/432 (2.08%) 
Nasopharyngitis  1  41/435 (9.43%)  48/432 (11.11%) 
Urinary tract infection  1  26/435 (5.98%)  8/432 (1.85%) 
Investigations     
Alanine aminotransferase increased  1  64/435 (14.71%)  6/432 (1.39%) 
Aspartate aminotransferase increased  1  61/435 (14.02%)  7/432 (1.62%) 
Blood alkaline phosphatase increased  1  31/435 (7.13%)  1/432 (0.23%) 
Blood lactate dehydrogenase increased  1  22/435 (5.06%)  1/432 (0.23%) 
Metabolism and nutrition disorders     
Decreased appetite  1  47/435 (10.80%)  25/432 (5.79%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  119/435 (27.36%)  61/432 (14.12%) 
Back pain  1  38/435 (8.74%)  34/432 (7.87%) 
Muscle spasms  1  39/435 (8.97%)  13/432 (3.01%) 
Myalgia  1  70/435 (16.09%)  40/432 (9.26%) 
Pain in extremity  1  60/435 (13.79%)  38/432 (8.80%) 
Nervous system disorders     
Dizziness  1  34/435 (7.82%)  33/432 (7.64%) 
Dysgeusia  1  29/435 (6.67%)  12/432 (2.78%) 
Headache  1  169/435 (38.85%)  102/432 (23.61%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  73/435 (16.78%)  33/432 (7.64%) 
Dyspnoea  1  30/435 (6.90%)  17/432 (3.94%) 
Epistaxis  1  41/435 (9.43%)  2/432 (0.46%) 
Oropharyngeal pain  1  39/435 (8.97%)  15/432 (3.47%) 
Skin and subcutaneous tissue disorders     
Alopecia  1  24/435 (5.52%)  18/432 (4.17%) 
Dermatitis acneiform  1  54/435 (12.41%)  10/432 (2.31%) 
Dry skin  1  55/435 (12.64%)  32/432 (7.41%) 
Erythema  1  48/435 (11.03%)  14/432 (3.24%) 
Hyperhidrosis  1  30/435 (6.90%)  7/432 (1.62%) 
Night sweats  1  23/435 (5.29%)  11/432 (2.55%) 
Palmar-plantar erythrodysaesthesia syndrome  1  24/435 (5.52%)  6/432 (1.39%) 
Pruritus  1  40/435 (9.20%)  29/432 (6.71%) 
Rash  1  106/435 (24.37%)  47/432 (10.88%) 
Rash maculo-papular  1  31/435 (7.13%)  11/432 (2.55%) 
Vascular disorders     
Hypertension  1  49/435 (11.26%)  35/432 (8.10%) 
Lymphoedema  1  34/435 (7.82%)  24/432 (5.56%) 
1
Term from vocabulary, MedDRA (19.1)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01682083     History of Changes
Other Study ID Numbers: 115532
First Submitted: September 6, 2012
First Posted: September 10, 2012
Results First Submitted: May 29, 2018
Results First Posted: September 26, 2018
Last Update Posted: September 26, 2018