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
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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
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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.
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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.
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
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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). ]

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
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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
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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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  More Information
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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:

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00790400     History of Changes
Other Study ID Numbers: CRAD001M2302, 2008-002113-48
Study First Received: November 10, 2008
Results First Received: May 23, 2012
Last Updated: January 14, 2014
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
France: Ministry of Health
Germany: Federal Institute for Drugs and Medical Devices
Italy: Ministry of Health
Japan: Ministry of Health, Labour and Welfare, Pharmaceutical amd Medical Safety Bureau
Netherlands: Medical Ethics Review Committee (METC)
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Russia: Federal Service on Surveillance in Healthcare and Social Development of Russian Federation
Spain: Ministerio de Sanidad y Politica Social
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Japan: Ministry of Health, Labour and Welfare, Pharmaceutical and Medical Safety Bureau