Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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 is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00790400
First received: November 10, 2008
Last updated: January 14, 2014
Last verified: January 2014
Results First Received: May 23, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions: Tuberous Sclerosis Complex (TSC)
Lymphangioleiomyomatosis (LAM)
Interventions: Drug: Everolimus (RAD001)
Drug: 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
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Participant Flow:   Overall Study
    Everolimus     Placebo  
STARTED     79     39  
COMPLETED     7 [1]   13  
NOT COMPLETED     72     26  
Ongoing in Double-blind                 72                 26  
[1] Completed means discontinued the double-blind treatment period



  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  
Number of Participants  
[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]
     
Female     52     26     78  
Male     27     13     40  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Angiomyolipoma Response Rate as Per Central Radiology Review (Double-blind Period)   [ 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 analysis cut-off date (30-June-2011). ]

2.  Secondary:   Time to Angiomyolipoma Progression as Per Central Radiology Review (Double-blind Period)   [ 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 analysis cut-off date (30-June-2011). ]
  Hide Outcome Measure 2

Measure Type Secondary
Measure Title Time to Angiomyolipoma Progression as Per Central Radiology Review (Double-blind Period)
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
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 analysis cut-off date (30-June-2011).  
Safety Issue No  

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. Patients were to be analyzed according to the treatment that they were assigned at randomization.

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.

Measured Values
    Everolimus     Placebo  
Number of Participants Analyzed  
[units: participants]
  79     39  
Time to Angiomyolipoma Progression as Per Central Radiology Review (Double-blind Period)  
[units: months]
Median ( 95% Confidence Interval )
  NA  
  ( NA to NA ) [1]
  11.37  
  ( 11.07 to NA ) [2]
[1] The median time to Angiomyolipoma Progression could not be estimated because <50% of patients had an Angiomyolipoma Progression during the time period.
[2] The upper limit was not estimable in the study as it is longer than the estimated time period till data cut-off date (30-June-2011)

No statistical analysis provided for Time to Angiomyolipoma Progression as Per Central Radiology Review (Double-blind Period)



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 analysis cut-off date (30-June-2011). ]

4.  Secondary:   Percentage of Participants With Renal Impairment   [ 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 analysis cut-off date (30-June-2011). ]

5.  Secondary:   Change From Baseline in Plasma Angiogenic Molecules   [ Time Frame: Baseline, 12 Months ]
Results not yet reported.   Anticipated Reporting Date:   12/2014   Safety Issue:   No


  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 Everolimus
Placebo Placebo

Other Adverse Events
    Everolimus     Placebo  
Total, other (not including serious) adverse events      
# participants affected / at risk     78/79     36/39  
Blood and lymphatic system disorders      
Anaemia † 1    
# participants affected / at risk     10/79 (12.66%)     1/39 (2.56%)  
Leukopenia † 1    
# participants affected / at risk     8/79 (10.13%)     3/39 (7.69%)  
Lymphopenia † 1    
# participants affected / at risk     5/79 (6.33%)     3/39 (7.69%)  
Neutropenia † 1    
# participants affected / at risk     5/79 (6.33%)     4/39 (10.26%)  
Thrombocytopenia † 1    
# participants affected / at risk     6/79 (7.59%)     0/39 (0.00%)  
Ear and labyrinth disorders      
Vertigo † 1    
# participants affected / at risk     1/79 (1.27%)     2/39 (5.13%)  
Gastrointestinal disorders      
Abdominal pain † 1    
# participants affected / at risk     9/79 (11.39%)     3/39 (7.69%)  
Abdominal pain upper † 1    
# participants affected / at risk     1/79 (1.27%)     2/39 (5.13%)  
Aphthous stomatitis † 1    
# participants affected / at risk     15/79 (18.99%)     4/39 (10.26%)  
Constipation † 1    
# participants affected / at risk     6/79 (7.59%)     1/39 (2.56%)  
Diarrhoea † 1    
# participants affected / at risk     10/79 (12.66%)     2/39 (5.13%)  
Flatulence † 1    
# participants affected / at risk     5/79 (6.33%)     0/39 (0.00%)  
Mouth ulceration † 1    
# participants affected / at risk     13/79 (16.46%)     2/39 (5.13%)  
Nausea † 1    
# participants affected / at risk     13/79 (16.46%)     5/39 (12.82%)  
Stomatitis † 1    
# participants affected / at risk     38/79 (48.10%)     3/39 (7.69%)  
Vomiting † 1    
# participants affected / at risk     12/79 (15.19%)     2/39 (5.13%)  
General disorders      
Fatigue † 1    
# participants affected / at risk     13/79 (16.46%)     7/39 (17.95%)  
Influenza like illness † 1    
# participants affected / at risk     1/79 (1.27%)     4/39 (10.26%)  
Oedema peripheral † 1    
# participants affected / at risk     7/79 (8.86%)     3/39 (7.69%)  
Pyrexia † 1    
# participants affected / at risk     6/79 (7.59%)     3/39 (7.69%)  
Infections and infestations      
Bronchitis † 1    
# participants affected / at risk     4/79 (5.06%)     5/39 (12.82%)  
Cellulitis † 1    
# participants affected / at risk     1/79 (1.27%)     3/39 (7.69%)  
Influenza † 1    
# participants affected / at risk     2/79 (2.53%)     3/39 (7.69%)  
Nasopharyngitis † 1    
# participants affected / at risk     19/79 (24.05%)     12/39 (30.77%)  
Otitis media † 1    
# participants affected / at risk     4/79 (5.06%)     0/39 (0.00%)  
Rash pustular † 1    
# participants affected / at risk     5/79 (6.33%)     0/39 (0.00%)  
Rhinitis † 1    
# participants affected / at risk     6/79 (7.59%)     5/39 (12.82%)  
Sinusitis † 1    
# participants affected / at risk     4/79 (5.06%)     1/39 (2.56%)  
Upper respiratory tract infection † 1    
# participants affected / at risk     8/79 (10.13%)     2/39 (5.13%)  
Urinary tract infection † 1    
# participants affected / at risk     12/79 (15.19%)     6/39 (15.38%)  
Injury, poisoning and procedural complications      
Procedural pain † 1    
# participants affected / at risk     1/79 (1.27%)     2/39 (5.13%)  
Investigations      
Activated partial thromboplastin time prolonged † 1    
# participants affected / at risk     1/79 (1.27%)     2/39 (5.13%)  
Alanine aminotransferase increased † 1    
# participants affected / at risk     3/79 (3.80%)     2/39 (5.13%)  
Blood alkaline phosphatase increased † 1    
# participants affected / at risk     6/79 (7.59%)     0/39 (0.00%)  
Blood creatine phosphokinase increased † 1    
# participants affected / at risk     3/79 (3.80%)     2/39 (5.13%)  
Blood creatinine increased † 1    
# participants affected / at risk     1/79 (1.27%)     3/39 (7.69%)  
Blood lactate dehydrogenase increased † 1    
# participants affected / at risk     9/79 (11.39%)     2/39 (5.13%)  
Blood phosphorus decreased † 1    
# participants affected / at risk     4/79 (5.06%)     0/39 (0.00%)  
Carbon monoxide diffusing capacity decreased † 1    
# participants affected / at risk     7/79 (8.86%)     0/39 (0.00%)  
Gamma-glutamyltransferase increased † 1    
# participants affected / at risk     4/79 (5.06%)     0/39 (0.00%)  
Metabolism and nutrition disorders      
Decreased appetite † 1    
# participants affected / at risk     5/79 (6.33%)     0/39 (0.00%)  
Hypercholesterolaemia † 1    
# participants affected / at risk     16/79 (20.25%)     1/39 (2.56%)  
Hyperlipidaemia † 1    
# participants affected / at risk     6/79 (7.59%)     0/39 (0.00%)  
Hypophosphataemia † 1    
# participants affected / at risk     9/79 (11.39%)     0/39 (0.00%)  
Iron deficiency † 1    
# participants affected / at risk     4/79 (5.06%)     1/39 (2.56%)  
Musculoskeletal and connective tissue disorders      
Arthralgia † 1    
# participants affected / at risk     10/79 (12.66%)     2/39 (5.13%)  
Back pain † 1    
# participants affected / at risk     5/79 (6.33%)     5/39 (12.82%)  
Flank pain † 1    
# participants affected / at risk     3/79 (3.80%)     5/39 (12.82%)  
Musculoskeletal chest pain † 1    
# participants affected / at risk     1/79 (1.27%)     2/39 (5.13%)  
Myalgia † 1    
# participants affected / at risk     5/79 (6.33%)     1/39 (2.56%)  
Pain in extremity † 1    
# participants affected / at risk     2/79 (2.53%)     3/39 (7.69%)  
Nervous system disorders      
Convulsion † 1    
# participants affected / at risk     2/79 (2.53%)     4/39 (10.26%)  
Dizziness † 1    
# participants affected / at risk     6/79 (7.59%)     3/39 (7.69%)  
Headache † 1    
# participants affected / at risk     17/79 (21.52%)     7/39 (17.95%)  
Migraine † 1    
# participants affected / at risk     4/79 (5.06%)     0/39 (0.00%)  
Psychiatric disorders      
Affective disorder † 1    
# participants affected / at risk     0/79 (0.00%)     2/39 (5.13%)  
Depression † 1    
# participants affected / at risk     4/79 (5.06%)     0/39 (0.00%)  
Renal and urinary disorders      
Haematuria † 1    
# participants affected / at risk     1/79 (1.27%)     3/39 (7.69%)  
Leukocyturia † 1    
# participants affected / at risk     0/79 (0.00%)     2/39 (5.13%)  
Proteinuria † 1    
# participants affected / at risk     3/79 (3.80%)     3/39 (7.69%)  
Reproductive system and breast disorders      
Amenorrhoea † 1    
# participants affected / at risk     7/79 (8.86%)     1/39 (2.56%)  
Menorrhagia † 1    
# participants affected / at risk     4/79 (5.06%)     0/39 (0.00%)  
Menstruation irregular † 1    
# participants affected / at risk     4/79 (5.06%)     0/39 (0.00%)  
Vaginal haemorrhage † 1    
# participants affected / at risk     4/79 (5.06%)     0/39 (0.00%)  
Respiratory, thoracic and mediastinal disorders      
Cough † 1    
# participants affected / at risk     16/79 (20.25%)     5/39 (12.82%)  
Epistaxis † 1    
# participants affected / at risk     7/79 (8.86%)     1/39 (2.56%)  
Oropharyngeal pain † 1    
# participants affected / at risk     8/79 (10.13%)     4/39 (10.26%)  
Skin and subcutaneous tissue disorders      
Acne † 1    
# participants affected / at risk     17/79 (21.52%)     2/39 (5.13%)  
Dermatitis acneiform † 1    
# participants affected / at risk     6/79 (7.59%)     0/39 (0.00%)  
Dry skin † 1    
# participants affected / at risk     7/79 (8.86%)     2/39 (5.13%)  
Eczema † 1    
# participants affected / at risk     8/79 (10.13%)     3/39 (7.69%)  
Papule † 1    
# participants affected / at risk     4/79 (5.06%)     1/39 (2.56%)  
Vascular disorders      
Haematoma † 1    
# participants affected / at risk     1/79 (1.27%)     2/39 (5.13%)  
Hypertension † 1    
# participants affected / at risk     7/79 (8.86%)     4/39 (10.26%)  
Events were collected by systematic assessment
1 Term from vocabulary, 14.0



  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