Try our beta test site
IMPORTANT: Listing of a study on this site does not reflect endorsement by the National Institutes of Health. Talk with a trusted healthcare professional before volunteering for a study. Read more...

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
  Hide Participant Flow

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
  Hide Baseline Characteristics

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
  Hide Serious Adverse Events

Time Frame No text entered.
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
  Hide Limitations and Caveats

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
No text entered.


  More Information
  Hide More Information

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 agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Novartis Pharmaceuticals
Organization: Novartis Pharmaceuticals
phone: 862-778-8300


Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00790400     History of Changes
Other Study ID Numbers: CRAD001M2302
2008-002113-48 ( EudraCT Number )
Study First Received: November 10, 2008
Results First Received: May 23, 2012
Last Updated: January 3, 2017