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Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM) (EXIST-2)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00790400
First received: November 10, 2008
Last updated: January 3, 2017
Last verified: January 2017
Results First Received: May 23, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions: Tuberous Sclerosis Complex (TSC)
Lymphangioleiomyomatosis (LAM)
Interventions: Drug: Everolimus (RAD001)
Drug: Everolimus Placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
A multicenter trial conducted at 24 sites in 11 countries. As the primary analysis of the core phase of the study favored everolimus over placebo, an open-label extension phase started: patients randomized in placebo were offered to switch on everolimus and those still receiving everolimus at the end of the core phase could continue the treatment.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
The trial had a 2:1 randomization in favor of the everolimus arm. 118 patients were randomized to the core phase of the study. 112 patients received everolimus during core and/or extension phase.

Reporting Groups
  Description
Everolimus Study drug was given by continuous oral daily dosing of two 5 mg tablets.
Placebo Placebo was given by continuous oral daily dosing of two 5 mg tablets.

Participant Flow for 2 periods

Period 1:   Double-blind Period (Core Phase)
    Everolimus   Placebo
STARTED   79   39 
COMPLETED   72 [1]   26 [2] 
NOT COMPLETED   7   13 
Protocol Violation                1                0 
Progressive disease                0                9 
Adverse Event                2                4 
Abnormal lab value (s)                1                0 
Withdrawal by Subject                1                0 
Administrative problems                1                0 
Death                1                0 
[1] Completed = Completed the Core phase & moved to Extension phase
[2] Completed = 1st received Placebo in the Core phase, switched to Everolimus in Extension phase

Period 2:   Everolimus Period (Core or Extension)
    Everolimus   Placebo
STARTED   112 [1]   0 [2] 
COMPLETED   83 [3]   0 
NOT COMPLETED   29   0 
Adverse Event                9                0 
Abnormal lab value (s)                1                0 
Withdrawal by Subject                7                0 
Lost to Follow-up                1                0 
Administrative problems                2                0 
Death                1                0 
Disease progression                5                0 
Protocol Violation                1                0 
New treatment                2                0 
[1] 112 pts had Everolimus during core and/or extension (6 from placebo did not switch to Eve. in ext.)
[2] Placebo randomized patients who switched to Everolimus are reported in "Everolimus" arm.
[3] Treatment duration completed as per protocol



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Everolimus Study drug was given by continuous oral daily dosing of two 5 mg tablets.
Placebo Placebo was given by continuous oral daily dosing of two 5 mg tablets.
Total Total of all reporting groups

Baseline Measures
   Everolimus   Placebo   Total 
Overall Participants Analyzed 
[Units: Participants]
 79   39   118 
Age 
[Units: Years]
Mean (Standard Deviation)
 32.5  (10.37)   31.0  (9.64)   32.0  (10.12) 
Age, Customized 
[Units: Participants]
     
<30 years   35   20   55 
≥ 30 years   44   19   63 
Gender 
[Units: Participants]
Count of Participants
     
Female      52  65.8%      26  66.7%      78  66.1% 
Male      27  34.2%      13  33.3%      40  33.9% 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Angiomyolipoma Response Rate as Per Central Radiology Review   [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to 5.7 years ]

2.  Secondary:   Time to Angiomyolipoma Progression as Per Central Radiology Review   [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to about 5.7 years ]
  Hide Outcome Measure 2

Measure Type Secondary
Measure Title Time to Angiomyolipoma Progression as Per Central Radiology Review
Measure Description

Time to angiomyolipoma progression (TTAP) is defined as time from date of randomization to date of first documented angiomyolipoma progression. Angiomyolipoma progression was defined as one or more of the following: Increase from nadir of ≥ 25% in angiomyolipoma volume to value greater than baseline; the appearance of a new angiomyolipoma ≥ 1.0 cm in longest diameter; an increase from nadir of 20% or more in the volume of either kidney to a value greater than baseline; angiomyolipoma-related bleeding grade ≥ 2.

For the everolimus (core/extension periods) treatment group, the time to angiomyolipoma progression is defined starting from the start of everolimus. The baseline means the latest value on or before starting everolimus.

Time Frame From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to about 5.7 years  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set (FAS) is defined according to the Intention-to-Treat principle and consists of all randomized patients.

Reporting Groups
  Description
Everolimus Randomized (Core Period) Study drug was given by continuous oral daily dosing of two 5 mg tablets.
Placebo Randomized (Core Period) Placebo was given by continuous oral daily dosing of two 5 mg tablets.
Everolimus (Core and/or Extension Period) Patients initially randomized in everolimus and patients initially randomized in placebo but who crossed-over to everolimus during extension.

Measured Values
   Everolimus Randomized (Core Period)   Placebo Randomized (Core Period)   Everolimus (Core and/or Extension Period) 
Participants Analyzed 
[Units: Participants]
 79   39   112 
Time to Angiomyolipoma Progression as Per Central Radiology Review 
[Units: Months]
Median (95% Confidence Interval)
 NA [1]   11.37 [2] 
 (11.07 to N/A) 
 NA [3] 
[1] Median not reached since too few number of patients with progressions (n=3).
[2] Upper limit not estimable due to few number of patients at this time point.
[3] Median not reached since too few number of patients with progressions (n=16)

No statistical analysis provided for Time to Angiomyolipoma Progression as Per Central Radiology Review



3.  Secondary:   Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)   [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to 5.7 years ]

4.  Secondary:   Percentage of Participants With Renal Impairment   [ Time Frame: Day 1 up to 28 days after end of treatment ]

5.  Secondary:   Change From Baseline in Plasma Angiogenic Molecules - Vascular Endothelial Growth Factor (VEGF) Marker   [ Time Frame: 4 weeks, 12 weeks, 24 weeks, 36 weeks 48 weeks, 60 weeks, 72 weeks ]

6.  Secondary:   Everolimus Trough Concentrations (Cmin)   [ Time Frame: Prior to dosing at weeks 2, 4, 12, 24, 48 ]

7.  Secondary:   Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose   [ Time Frame: 2 hours post-dose administration at Weeks 2, 4, 12, 24, 48 ]

8.  Secondary:   Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response   [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to 5.7 years ]

9.  Secondary:   Duration of Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response   [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to about 5.7 years ]

10.  Secondary:   Duration of Skin Lesion Response - Only Everolimus Patients With Best Overall Skin Lesion Response of Complete Clinical Response (CCR) or Partial Response (PR)   [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to about 5.7 years ]


  Serious Adverse Events


  Other Adverse Events
  Hide Other Adverse Events

Time Frame No text entered.
Additional Description No text entered.

Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
Everolimus Randomized (Core & Ext) Patients who were randomized and treated with Everolimus during the Core and Extension phase
Placebo Randomized/Crossed Over to Everolimus Patients who were randomized to placebo in the Core phase and who crossed-over to Everolimus in the Extension phase
Placebo Randomized/Never Crossed-over Patients randomized to placebo who never crossed-over to Everolimus

Other Adverse Events
    Everolimus Randomized (Core & Ext)   Placebo Randomized/Crossed Over to Everolimus   Placebo Randomized/Never Crossed-over
Total, Other (not including serious) Adverse Events       
# participants affected / at risk   79/79 (100.00%)   33/33 (100.00%)   5/6 (83.33%) 
Blood and lymphatic system disorders       
Anaemia † 1       
# participants affected / at risk   9/79 (11.39%)   6/33 (18.18%)   0/6 (0.00%) 
Leukopenia † 1       
# participants affected / at risk   9/79 (11.39%)   7/33 (21.21%)   0/6 (0.00%) 
Lymphopenia † 1       
# participants affected / at risk   5/79 (6.33%)   5/33 (15.15%)   0/6 (0.00%) 
Neutropenia † 1       
# participants affected / at risk   7/79 (8.86%)   4/33 (12.12%)   0/6 (0.00%) 
Thrombocytopenia † 1       
# participants affected / at risk   6/79 (7.59%)   3/33 (9.09%)   0/6 (0.00%) 
Cardiac disorders       
Palpitations † 1       
# participants affected / at risk   0/79 (0.00%)   2/33 (6.06%)   0/6 (0.00%) 
Tachycardia † 1       
# participants affected / at risk   2/79 (2.53%)   2/33 (6.06%)   0/6 (0.00%) 
Congenital, familial and genetic disorders       
Hamartoma † 1       
# participants affected / at risk   1/79 (1.27%)   3/33 (9.09%)   0/6 (0.00%) 
Ear and labyrinth disorders       
Vertigo † 1       
# participants affected / at risk   3/79 (3.80%)   4/33 (12.12%)   0/6 (0.00%) 
Gastrointestinal disorders       
Abdominal pain † 1       
# participants affected / at risk   13/79 (16.46%)   5/33 (15.15%)   2/6 (33.33%) 
Abdominal pain upper † 1       
# participants affected / at risk   7/79 (8.86%)   4/33 (12.12%)   1/6 (16.67%) 
Aphthous stomatitis † 1       
# participants affected / at risk   19/79 (24.05%)   12/33 (36.36%)   1/6 (16.67%) 
Constipation † 1       
# participants affected / at risk   8/79 (10.13%)   6/33 (18.18%)   1/6 (16.67%) 
Dental caries † 1       
# participants affected / at risk   1/79 (1.27%)   2/33 (6.06%)   0/6 (0.00%) 
Diarrhoea † 1       
# participants affected / at risk   17/79 (21.52%)   11/33 (33.33%)   1/6 (16.67%) 
Dyspepsia † 1       
# participants affected / at risk   4/79 (5.06%)   0/33 (0.00%)   0/6 (0.00%) 
Flatulence † 1       
# participants affected / at risk   5/79 (6.33%)   3/33 (9.09%)   0/6 (0.00%) 
Gastrooesophageal reflux disease † 1       
# participants affected / at risk   4/79 (5.06%)   0/33 (0.00%)   0/6 (0.00%) 
Mouth ulceration † 1       
# participants affected / at risk   15/79 (18.99%)   4/33 (12.12%)   1/6 (16.67%) 
Nausea † 1       
# participants affected / at risk   18/79 (22.78%)   7/33 (21.21%)   2/6 (33.33%) 
Stomatitis † 1       
# participants affected / at risk   41/79 (51.90%)   10/33 (30.30%)   0/6 (0.00%) 
Toothache † 1       
# participants affected / at risk   5/79 (6.33%)   3/33 (9.09%)   0/6 (0.00%) 
Vomiting † 1       
# participants affected / at risk   18/79 (22.78%)   5/33 (15.15%)   0/6 (0.00%) 
General disorders       
Asthenia † 1       
# participants affected / at risk   2/79 (2.53%)   2/33 (6.06%)   0/6 (0.00%) 
Fatigue † 1       
# participants affected / at risk   17/79 (21.52%)   13/33 (39.39%)   1/6 (16.67%) 
Influenza like illness † 1       
# participants affected / at risk   2/79 (2.53%)   5/33 (15.15%)   1/6 (16.67%) 
Malaise † 1       
# participants affected / at risk   0/79 (0.00%)   2/33 (6.06%)   0/6 (0.00%) 
Oedema peripheral † 1       
# participants affected / at risk   16/79 (20.25%)   10/33 (30.30%)   0/6 (0.00%) 
Pyrexia † 1       
# participants affected / at risk   11/79 (13.92%)   6/33 (18.18%)   1/6 (16.67%) 
Immune system disorders       
Hypersensitivity † 1       
# participants affected / at risk   1/79 (1.27%)   2/33 (6.06%)   0/6 (0.00%) 
Seasonal allergy † 1       
# participants affected / at risk   3/79 (3.80%)   2/33 (6.06%)   0/6 (0.00%) 
Infections and infestations       
Bronchitis † 1       
# participants affected / at risk   9/79 (11.39%)   9/33 (27.27%)   1/6 (16.67%) 
Cellulitis † 1       
# participants affected / at risk   2/79 (2.53%)   4/33 (12.12%)   0/6 (0.00%) 
Conjunctivitis † 1       
# participants affected / at risk   4/79 (5.06%)   2/33 (6.06%)   0/6 (0.00%) 
Ear infection † 1       
# participants affected / at risk   5/79 (6.33%)   1/33 (3.03%)   0/6 (0.00%) 
Folliculitis † 1       
# participants affected / at risk   4/79 (5.06%)   1/33 (3.03%)   0/6 (0.00%) 
Furuncle † 1       
# participants affected / at risk   4/79 (5.06%)   2/33 (6.06%)   0/6 (0.00%) 
Gastroenteritis † 1       
# participants affected / at risk   9/79 (11.39%)   4/33 (12.12%)   0/6 (0.00%) 
Gastroenteritis viral † 1       
# participants affected / at risk   4/79 (5.06%)   0/33 (0.00%)   0/6 (0.00%) 
Gastrointestinal infection † 1       
# participants affected / at risk   1/79 (1.27%)   2/33 (6.06%)   0/6 (0.00%) 
Gingivitis † 1       
# participants affected / at risk   2/79 (2.53%)   3/33 (9.09%)   0/6 (0.00%) 
Influenza † 1       
# participants affected / at risk   8/79 (10.13%)   3/33 (9.09%)   1/6 (16.67%) 
Nasopharyngitis † 1       
# participants affected / at risk   36/79 (45.57%)   19/33 (57.58%)   1/6 (16.67%) 
Oral candidiasis † 1       
# participants affected / at risk   1/79 (1.27%)   2/33 (6.06%)   0/6 (0.00%) 
Oral herpes † 1       
# participants affected / at risk   5/79 (6.33%)   1/33 (3.03%)   0/6 (0.00%) 
Otitis externa † 1       
# participants affected / at risk   0/79 (0.00%)   3/33 (9.09%)   0/6 (0.00%) 
Otitis media † 1       
# participants affected / at risk   6/79 (7.59%)   2/33 (6.06%)   0/6 (0.00%) 
Periodontitis † 1       
# participants affected / at risk   6/79 (7.59%)   0/33 (0.00%)   0/6 (0.00%) 
Pharyngitis † 1       
# participants affected / at risk   5/79 (6.33%)   1/33 (3.03%)   0/6 (0.00%) 
Pharyngitis streptococcal † 1       
# participants affected / at risk   5/79 (6.33%)   0/33 (0.00%)   0/6 (0.00%) 
Pneumonia † 1       
# participants affected / at risk   6/79 (7.59%)   2/33 (6.06%)   0/6 (0.00%) 
Rash pustular † 1       
# participants affected / at risk   7/79 (8.86%)   3/33 (9.09%)   0/6 (0.00%) 
Respiratory tract infection † 1       
# participants affected / at risk   5/79 (6.33%)   2/33 (6.06%)   0/6 (0.00%) 
Respiratory tract infection viral † 1       
# participants affected / at risk   5/79 (6.33%)   0/33 (0.00%)   0/6 (0.00%) 
Rhinitis † 1       
# participants affected / at risk   7/79 (8.86%)   6/33 (18.18%)   1/6 (16.67%) 
Sinusitis † 1       
# participants affected / at risk   11/79 (13.92%)   4/33 (12.12%)   1/6 (16.67%) 
Tonsillitis † 1       
# participants affected / at risk   1/79 (1.27%)   6/33 (18.18%)   0/6 (0.00%) 
Tooth abscess † 1       
# participants affected / at risk   7/79 (8.86%)   2/33 (6.06%)   0/6 (0.00%) 
Tooth infection † 1       
# participants affected / at risk   4/79 (5.06%)   3/33 (9.09%)   0/6 (0.00%) 
Upper respiratory tract infection † 1       
# participants affected / at risk   15/79 (18.99%)   4/33 (12.12%)   0/6 (0.00%) 
Urinary tract infection † 1       
# participants affected / at risk   25/79 (31.65%)   12/33 (36.36%)   1/6 (16.67%) 
Injury, poisoning and procedural complications       
Contusion † 1       
# participants affected / at risk   0/79 (0.00%)   3/33 (9.09%)   0/6 (0.00%) 
Fall † 1       
# participants affected / at risk   2/79 (2.53%)   2/33 (6.06%)   0/6 (0.00%) 
Incision site pain † 1       
# participants affected / at risk   0/79 (0.00%)   0/33 (0.00%)   1/6 (16.67%) 
Laceration † 1       
# participants affected / at risk   3/79 (3.80%)   2/33 (6.06%)   0/6 (0.00%) 
Procedural pain † 1       
# participants affected / at risk   2/79 (2.53%)   2/33 (6.06%)   1/6 (16.67%) 
Investigations       
Activated partial thromboplastin time prolonged † 1       
# participants affected / at risk   10/79 (12.66%)   5/33 (15.15%)   0/6 (0.00%) 
Alanine aminotransferase increased † 1       
# participants affected / at risk   9/79 (11.39%)   5/33 (15.15%)   0/6 (0.00%) 
Aspartate aminotransferase increased † 1       
# participants affected / at risk   10/79 (12.66%)   2/33 (6.06%)   0/6 (0.00%) 
Blood alkaline phosphatase increased † 1       
# participants affected / at risk   11/79 (13.92%)   5/33 (15.15%)   0/6 (0.00%) 
Blood cholesterol increased † 1       
# participants affected / at risk   11/79 (13.92%)   3/33 (9.09%)   0/6 (0.00%) 
Blood creatine phosphokinase increased † 1       
# participants affected / at risk   3/79 (3.80%)   5/33 (15.15%)   0/6 (0.00%) 
Blood creatinine increased † 1       
# participants affected / at risk   4/79 (5.06%)   4/33 (12.12%)   0/6 (0.00%) 
Blood fibrinogen increased † 1       
# participants affected / at risk   4/79 (5.06%)   5/33 (15.15%)   0/6 (0.00%) 
Blood lactate dehydrogenase increased † 1       
# participants affected / at risk   9/79 (11.39%)   4/33 (12.12%)   0/6 (0.00%) 
Blood phosphorus decreased † 1       
# participants affected / at risk   6/79 (7.59%)   1/33 (3.03%)   0/6 (0.00%) 
Blood triglycerides increased † 1       
# participants affected / at risk   10/79 (12.66%)   4/33 (12.12%)   0/6 (0.00%) 
C-reactive protein increased † 1       
# participants affected / at risk   3/79 (3.80%)   2/33 (6.06%)   0/6 (0.00%) 
Carbon monoxide diffusing capacity decreased † 1       
# participants affected / at risk   7/79 (8.86%)   1/33 (3.03%)   0/6 (0.00%) 
Gamma-glutamyltransferase increased † 1       
# participants affected / at risk   5/79 (6.33%)   1/33 (3.03%)   0/6 (0.00%) 
Haemoglobin decreased † 1       
# participants affected / at risk   11/79 (13.92%)   3/33 (9.09%)   0/6 (0.00%) 
International normalised ratio increased † 1       
# participants affected / at risk   4/79 (5.06%)   3/33 (9.09%)   0/6 (0.00%) 
Low density lipoprotein increased † 1       
# participants affected / at risk   1/79 (1.27%)   2/33 (6.06%)   0/6 (0.00%) 
Weight decreased † 1       
# participants affected / at risk   7/79 (8.86%)   4/33 (12.12%)   0/6 (0.00%) 
Weight increased † 1       
# participants affected / at risk   4/79 (5.06%)   0/33 (0.00%)   0/6 (0.00%) 
White blood cell count decreased † 1       
# participants affected / at risk   1/79 (1.27%)   2/33 (6.06%)   0/6 (0.00%) 
Metabolism and nutrition disorders       
Decreased appetite † 1       
# participants affected / at risk   8/79 (10.13%)   6/33 (18.18%)   0/6 (0.00%) 
Hypercholesterolaemia † 1       
# participants affected / at risk   29/79 (36.71%)   11/33 (33.33%)   0/6 (0.00%) 
Hyperglycaemia † 1       
# participants affected / at risk   3/79 (3.80%)   4/33 (12.12%)   0/6 (0.00%) 
Hyperlipidaemia † 1       
# participants affected / at risk   10/79 (12.66%)   5/33 (15.15%)   0/6 (0.00%) 
Hypertriglyceridaemia † 1       
# participants affected / at risk   8/79 (10.13%)   4/33 (12.12%)   0/6 (0.00%) 
Hypokalaemia † 1       
# participants affected / at risk   2/79 (2.53%)   5/33 (15.15%)   0/6 (0.00%) 
Hypophosphataemia † 1       
# participants affected / at risk   15/79 (18.99%)   4/33 (12.12%)   0/6 (0.00%) 
Iron deficiency † 1       
# participants affected / at risk   7/79 (8.86%)   1/33 (3.03%)   0/6 (0.00%) 
Musculoskeletal and connective tissue disorders       
Arthralgia † 1       
# participants affected / at risk   13/79 (16.46%)   3/33 (9.09%)   0/6 (0.00%) 
Back pain † 1       
# participants affected / at risk   12/79 (15.19%)   14/33 (42.42%)   0/6 (0.00%) 
Flank pain † 1       
# participants affected / at risk   5/79 (6.33%)   5/33 (15.15%)   1/6 (16.67%) 
Muscle spasms † 1       
# participants affected / at risk   2/79 (2.53%)   2/33 (6.06%)   1/6 (16.67%) 
Musculoskeletal chest pain † 1       
# participants affected / at risk   1/79 (1.27%)   4/33 (12.12%)   0/6 (0.00%) 
Musculoskeletal pain † 1       
# participants affected / at risk   2/79 (2.53%)   2/33 (6.06%)   0/6 (0.00%) 
Myalgia † 1       
# participants affected / at risk   7/79 (8.86%)   5/33 (15.15%)   1/6 (16.67%) 
Neck pain † 1       
# participants affected / at risk   1/79 (1.27%)   2/33 (6.06%)   0/6 (0.00%) 
Pain in extremity † 1       
# participants affected / at risk   5/79 (6.33%)   7/33 (21.21%)   0/6 (0.00%) 
Nervous system disorders       
Convulsion † 1       
# participants affected / at risk   8/79 (10.13%)   4/33 (12.12%)   0/6 (0.00%) 
Dizziness † 1       
# participants affected / at risk   9/79 (11.39%)   4/33 (12.12%)   1/6 (16.67%) 
Epilepsy † 1       
# participants affected / at risk   3/79 (3.80%)   2/33 (6.06%)   0/6 (0.00%) 
Headache † 1       
# participants affected / at risk   26/79 (32.91%)   15/33 (45.45%)   0/6 (0.00%) 
Lethargy † 1       
# participants affected / at risk   1/79 (1.27%)   2/33 (6.06%)   0/6 (0.00%) 
Migraine † 1       
# participants affected / at risk   9/79 (11.39%)   1/33 (3.03%)   0/6 (0.00%) 
Peripheral sensory neuropathy † 1       
# participants affected / at risk   0/79 (0.00%)   3/33 (9.09%)   0/6 (0.00%) 
Petit mal epilepsy † 1       
# participants affected / at risk   4/79 (5.06%)   2/33 (6.06%)   0/6 (0.00%) 
Psychiatric disorders       
Affective disorder † 1       
# participants affected / at risk   0/79 (0.00%)   2/33 (6.06%)   0/6 (0.00%) 
Aggression † 1       
# participants affected / at risk   1/79 (1.27%)   3/33 (9.09%)   0/6 (0.00%) 
Anxiety † 1       
# participants affected / at risk   4/79 (5.06%)   1/33 (3.03%)   0/6 (0.00%) 
Depression † 1       
# participants affected / at risk   8/79 (10.13%)   4/33 (12.12%)   0/6 (0.00%) 
Insomnia † 1       
# participants affected / at risk   6/79 (7.59%)   1/33 (3.03%)   0/6 (0.00%) 
Mood swings † 1       
# participants affected / at risk   3/79 (3.80%)   2/33 (6.06%)   0/6 (0.00%) 
Sleep disorder † 1       
# participants affected / at risk   2/79 (2.53%)   3/33 (9.09%)   0/6 (0.00%) 
Renal and urinary disorders       
Haematuria † 1       
# participants affected / at risk   2/79 (2.53%)   3/33 (9.09%)   1/6 (16.67%) 
Leukocyturia † 1       
# participants affected / at risk   0/79 (0.00%)   2/33 (6.06%)   0/6 (0.00%) 
Proteinuria † 1       
# participants affected / at risk   11/79 (13.92%)   10/33 (30.30%)   0/6 (0.00%) 
Renal pain † 1       
# participants affected / at risk   0/79 (0.00%)   2/33 (6.06%)   0/6 (0.00%) 
Reproductive system and breast disorders       
Amenorrhoea † 1       
# participants affected / at risk   16/79 (20.25%)   6/33 (18.18%)   0/6 (0.00%) 
Dysmenorrhoea † 1       
# participants affected / at risk   3/79 (3.80%)   1/33 (3.03%)   1/6 (16.67%) 
Menorrhagia † 1       
# participants affected / at risk   11/79 (13.92%)   2/33 (6.06%)   0/6 (0.00%) 
Menstruation irregular † 1       
# participants affected / at risk   11/79 (13.92%)   4/33 (12.12%)   0/6 (0.00%) 
Metrorrhagia † 1       
# participants affected / at risk   4/79 (5.06%)   3/33 (9.09%)   0/6 (0.00%) 
Ovarian cyst † 1       
# participants affected / at risk   5/79 (6.33%)   3/33 (9.09%)   0/6 (0.00%) 
Vaginal haemorrhage † 1       
# participants affected / at risk   7/79 (8.86%)   5/33 (15.15%)   0/6 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Asthma † 1       
# participants affected / at risk   2/79 (2.53%)   2/33 (6.06%)   0/6 (0.00%) 
Cough † 1       
# participants affected / at risk   21/79 (26.58%)   7/33 (21.21%)   2/6 (33.33%) 
Dyspnoea † 1       
# participants affected / at risk   3/79 (3.80%)   3/33 (9.09%)   0/6 (0.00%) 
Epistaxis † 1       
# participants affected / at risk   10/79 (12.66%)   3/33 (9.09%)   0/6 (0.00%) 
Lymphangioleiomyomatosis † 1       
# participants affected / at risk   1/79 (1.27%)   1/33 (3.03%)   1/6 (16.67%) 
Nasal congestion † 1       
# participants affected / at risk   2/79 (2.53%)   1/33 (3.03%)   1/6 (16.67%) 
Oropharyngeal pain † 1       
# participants affected / at risk   13/79 (16.46%)   6/33 (18.18%)   1/6 (16.67%) 
Pneumothorax † 1       
# participants affected / at risk   0/79 (0.00%)   2/33 (6.06%)   0/6 (0.00%) 
Productive cough † 1       
# participants affected / at risk   1/79 (1.27%)   2/33 (6.06%)   0/6 (0.00%) 
Rhinitis allergic † 1       
# participants affected / at risk   2/79 (2.53%)   3/33 (9.09%)   0/6 (0.00%) 
Rhinorrhoea † 1       
# participants affected / at risk   4/79 (5.06%)   0/33 (0.00%)   0/6 (0.00%) 
Sinus congestion † 1       
# participants affected / at risk   2/79 (2.53%)   1/33 (3.03%)   1/6 (16.67%) 
Skin and subcutaneous tissue disorders       
Acne † 1       
# participants affected / at risk   25/79 (31.65%)   11/33 (33.33%)   0/6 (0.00%) 
Alopecia † 1       
# participants affected / at risk   7/79 (8.86%)   2/33 (6.06%)   0/6 (0.00%) 
Dermatitis † 1       
# participants affected / at risk   4/79 (5.06%)   1/33 (3.03%)   0/6 (0.00%) 
Dermatitis acneiform † 1       
# participants affected / at risk   6/79 (7.59%)   1/33 (3.03%)   0/6 (0.00%) 
Dry skin † 1       
# participants affected / at risk   8/79 (10.13%)   5/33 (15.15%)   0/6 (0.00%) 
Eczema † 1       
# participants affected / at risk   11/79 (13.92%)   3/33 (9.09%)   0/6 (0.00%) 
Papule † 1       
# participants affected / at risk   4/79 (5.06%)   2/33 (6.06%)   0/6 (0.00%) 
Pigmentation disorder † 1       
# participants affected / at risk   4/79 (5.06%)   2/33 (6.06%)   0/6 (0.00%) 
Pruritus † 1       
# participants affected / at risk   8/79 (10.13%)   5/33 (15.15%)   0/6 (0.00%) 
Rash † 1       
# participants affected / at risk   5/79 (6.33%)   3/33 (9.09%)   0/6 (0.00%) 
Rash pruritic † 1       
# participants affected / at risk   1/79 (1.27%)   2/33 (6.06%)   0/6 (0.00%) 
Skin mass † 1       
# participants affected / at risk   0/79 (0.00%)   2/33 (6.06%)   0/6 (0.00%) 
Vascular disorders       
Circulatory collapse † 1       
# participants affected / at risk   2/79 (2.53%)   2/33 (6.06%)   0/6 (0.00%) 
Haematoma † 1       
# participants affected / at risk   2/79 (2.53%)   2/33 (6.06%)   0/6 (0.00%) 
Hypertension † 1       
# participants affected / at risk   22/79 (27.85%)   12/33 (36.36%)   0/6 (0.00%) 
Lymphoedema † 1       
# participants affected / at risk   4/79 (5.06%)   2/33 (6.06%)   0/6 (0.00%) 
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA V18.1



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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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