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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:
ClinicalTrials.gov Identifier:
NCT00790400
First Posted: November 13, 2008
Last Update Posted: February 17, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
Results First Submitted: May 23, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (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


  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 ]

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
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Additional Description No text entered.

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

Serious Adverse Events
    Everolimus Randomized (Core & Ext)   Placebo Randomized/Crossed Over to Everolimus   Placebo Randomized/Never Crossed-over
Total, Serious Adverse Events       
# participants affected / at risk   28/79 (35.44%)   17/33 (51.52%)   3/6 (50.00%) 
Blood and lymphatic system disorders       
Bone marrow oedema † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Cardiac disorders       
Cardiac failure congestive † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Cardiovascular insufficiency † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Ear and labyrinth disorders       
Vertigo positional † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Eye disorders       
Visual acuity reduced † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Gastrointestinal disorders       
Abdominal adhesions † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Abdominal compartment syndrome † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Abdominal hernia † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Colitis † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Constipation † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Diarrhoea † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Diarrhoea haemorrhagic † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Gastric ulcer † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Ileal perforation † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Intestinal perforation † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Salivary gland calculus † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Volvulus † 1       
# participants affected / at risk   0/79 (0.00%)   0/33 (0.00%)   1/6 (16.67%) 
Vomiting † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
General disorders       
Adverse drug reaction † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Fatigue † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Hepatobiliary disorders       
Bile duct stenosis † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Immune system disorders       
Hypersensitivity † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Infections and infestations       
Abscess † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Appendicitis † 1       
# participants affected / at risk   2/79 (2.53%)   0/33 (0.00%)   0/6 (0.00%) 
Bronchitis † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Bronchopneumonia † 1       
# participants affected / at risk   1/79 (1.27%)   1/33 (3.03%)   0/6 (0.00%) 
Campylobacter gastroenteritis † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Erysipelas † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Gastroenteritis † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Gastrointestinal infection † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Incision site infection † 1       
# participants affected / at risk   0/79 (0.00%)   0/33 (0.00%)   1/6 (16.67%) 
Peritonitis † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Pneumonia † 1       
# participants affected / at risk   1/79 (1.27%)   3/33 (9.09%)   0/6 (0.00%) 
Pyelonephritis † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Sepsis † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Tonsillitis † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Urinary tract infection † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Viral infection † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Injury, poisoning and procedural complications       
Fall † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Toxicity to various agents † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Investigations       
Blood creatinine increased † 1       
# participants affected / at risk   2/79 (2.53%)   0/33 (0.00%)   0/6 (0.00%) 
Metabolism and nutrition disorders       
Decreased appetite † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Gout † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Musculoskeletal and connective tissue disorders       
Back pain † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Chondropathy † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Joint effusion † 1       
# participants affected / at risk   2/79 (2.53%)   0/33 (0.00%)   0/6 (0.00%) 
Rhabdomyolysis † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Spinal osteoarthritis † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Angiomyolipoma † 1       
# participants affected / at risk   0/79 (0.00%)   0/33 (0.00%)   1/6 (16.67%) 
Nasal sinus cancer † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Pancreatic carcinoma † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Nervous system disorders       
Complex regional pain syndrome † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Convulsion † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Diplegia † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Epilepsy † 1       
# participants affected / at risk   3/79 (3.80%)   3/33 (9.09%)   0/6 (0.00%) 
Generalised tonic-clonic seizure † 1       
# participants affected / at risk   2/79 (2.53%)   1/33 (3.03%)   0/6 (0.00%) 
Hydrocephalus † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Syncope † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Transient ischaemic attack † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Psychiatric disorders       
Affective disorder † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Aggression † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Alcohol abuse † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Anxiety † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Hallucination † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   1/6 (16.67%) 
Psychiatric decompensation † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Psychogenic seizure † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Psychotic disorder † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Renal and urinary disorders       
Renal failure acute † 1       
# participants affected / at risk   1/79 (1.27%)   1/33 (3.03%)   0/6 (0.00%) 
Renal failure chronic † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Renal haemorrhage † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Renal impairment † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Reproductive system and breast disorders       
Breast hypoplasia † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Endometrial hyperplasia † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Ovarian cyst † 1       
# participants affected / at risk   1/79 (1.27%)   1/33 (3.03%)   0/6 (0.00%) 
Ovarian cyst ruptured † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Bronchospasm † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Haemoptysis † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Pleuritic pain † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Pneumothorax † 1       
# participants affected / at risk   2/79 (2.53%)   1/33 (3.03%)   0/6 (0.00%) 
Skin and subcutaneous tissue disorders       
Angioedema † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Vascular disorders       
Aortic aneurysm † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Haemodynamic instability † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Hypertension † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Hypertensive crisis † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Thrombosis † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA V18.1




  Other Adverse Events


  Limitations and Caveats
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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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