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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 26, 2016
Last verified: January 2016
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
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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
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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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
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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]
     
Female   52   26   78 
Male   27   13   40 


  Outcome Measures
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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). ]

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). ]
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Measure Type Secondary
Measure Title Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)
Measure Description Skin lesion response rate in the double-blind period was determined only among patients with at least one skin lesion at baseline, and is the percentage of this group of patients with a best overall skin lesion response on the Physician’s Global Assessment of Clinical Condition (PGA) of either 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 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 
Participants Analyzed 
[Units: Participants]
 77   37 
Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline) 
[Units: Percentage of participants]
Number (95% Confidence Interval)
 26 
 (16.6 to 37.2) 
 0 
 (0.0 to 9.5) 

No statistical analysis provided for Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)



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:   09/2016   Safety Issue:   No


  Serious Adverse Events


  Other Adverse Events
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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 (98.73%)   36/39 (92.31%) 
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
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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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