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Efficacy and Safety of Everolimus (RAD001) in Patients of All Ages With Subependymal Giant Cell Astrocytoma Associated With Tuberous Sclerosis Complex (TSC)(EXIST-1) (EXIST-1)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00789828
First received: November 12, 2008
Last updated: January 4, 2016
Last verified: January 2016
Results First Received: March 1, 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
Subependymal Giant Cell Astrocytoma
Interventions: Drug: Everolimus
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
The study was conducted at 24 centers in 10 countries.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
A total of 117 participants were enrolled and randomized into the core period. Only 111 participants completing the core period, continued in the open-label extension period of the study.

Reporting Groups
  Description
Everolimus Participants received oral dose of everolimus 4.5 milligram/square meter (mg/m^2) daily as an initial starting dose to attain the whole blood trough concentrations in range of 5-15 nanogram/millilitre (ng/mL). Dose adjustments were permitted based on safety and whole blood trough concentrations.
Placebo Participants received oral dose of placebo matching to everolimus daily.

Participant Flow for 2 periods

Period 1:   Core Period (48 Weeks)
    Everolimus   Placebo
STARTED   78   39 
COMPLETED   78   33 
NOT COMPLETED   0   6 
Administrative problems                0                1 
Withdrawal by Subject                0                4 
Lost to Follow-up                0                1 

Period 2:   Open-label Extension Period (4 Years)
    Everolimus   Placebo
STARTED   111 [1]   0 [2] 
COMPLETED   82   0 
NOT COMPLETED   29   0 
Adverse Event                10                0 
Withdrawal by Subject                6                0 
Lost to Follow-up                3                0 
Administrative problems                7                0 
Death                1                0 
Disease progression                1                0 
New treatment for indication under study                1                0 
[1] Of 117 participants only 111 completed the core period and continued in the extension period
[2] No participant received placebo.



  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 (Core Period) Participants received oral dose of everolimus 4.5 mg/m^2 daily as an initial starting dose to attain the whole blood trough concentrations in range of 5-15 ng/mL. Dose adjustments were permitted based on safety and whole blood trough concentrations.
Placebo (Core Period) Participants received oral dose of placebo matching to everolimus daily.
Total Total of all reporting groups

Baseline Measures
   Everolimus (Core Period)   Placebo (Core Period)   Total 
Overall Participants Analyzed 
[Units: Participants]
 78   39   117 
Age 
[Units: Years]
Mean (Standard Deviation)
 10.1  (5.9)   10.3  (7.3)   10.2  (6.4) 
Age, Customized 
[Units: Participants]
     
<3 years   13   7   20 
3-18 years   55   26   81 
≥18 years   10   6   16 
Gender 
[Units: Participants]
     
Female   29   21   50 
Male   49   18   67 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Percentage of Participants With Best Overall Subependymal Giant Cell Astrocytomas (SEGA) Response   [ Time Frame: End of core period (Week 48), and end of extension period (up to 4 years) ]

2.  Secondary:   Change From Baseline in Frequency of Total Seizure Events Per 24 Hours at Week 24 in Both Core and Extension Period   [ Time Frame: Baseline (Core period) to Week 24 (Core period), Baseline (Extension period, Week 24 post-core baseline) to Week 24 (Extension period, Week 48 post-core baseline) ]
  Hide Outcome Measure 2

Measure Type Secondary
Measure Title Change From Baseline in Frequency of Total Seizure Events Per 24 Hours at Week 24 in Both Core and Extension Period
Measure Description Seizure frequency per 24 hours was defined as the number of seizures in the electroencephalography (EEG) divided by the number of hours in the EEG, multiplied by 24. Seizure frequency was evaluated using a 24-hour video-EEG. Seizure frequency was listed as missing if the actual EEG recording duration was < 18 hours.
Time Frame Baseline (Core period) to Week 24 (Core period), Baseline (Extension period, Week 24 post-core baseline) to Week 24 (Extension period, Week 48 post-core baseline)  
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 analysis was performed in the FAS population. Missing values were imputed using last observation carried forward approach for core period while raw count for extension period.

Reporting Groups
  Description
Everolimus (Core Period) Participants received oral dose of everolimus 4.5 mg/m^2 daily as an initial starting dose to attain the whole blood trough concentrations in range of 5-15 ng/mL. Dose adjustments were permitted based on safety and whole blood trough concentrations.
Placebo (Core Period) Participants received oral dose of placebo matching to everolimus daily.
Everolimus (Extension Period) Participants received oral dose of everolimus 4.5 mg/m^2 daily as an initial starting dose to attain blood trough concentrations in range of 5-15 ng/mL.

Measured Values
   Everolimus (Core Period)   Placebo (Core Period)   Everolimus (Extension Period) 
Participants Analyzed 
[Units: Participants]
 78   39   34 
Change From Baseline in Frequency of Total Seizure Events Per 24 Hours at Week 24 in Both Core and Extension Period 
[Units: Seizure frequency]
Mean (Standard Deviation)
 -1.24  (6.12)   -0.24  (5.7)   -6.07  (9.719) 

No statistical analysis provided for Change From Baseline in Frequency of Total Seizure Events Per 24 Hours at Week 24 in Both Core and Extension Period



3.  Secondary:   Time to SEGA Progression   [ Time Frame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years) ]

4.  Secondary:   Time to SEGA Response   [ Time Frame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years) ]

5.  Secondary:   Duration of SEGA Response   [ Time Frame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years) ]

6.  Secondary:   Time to SEGA Worsening   [ Time Frame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years) ]

7.  Secondary:   Percentage of Participants With Skin Lesions Assessed Using Physician's Global Assessement Overall Score   [ Time Frame: End of core period (Week 48), and end of extension period (up to 4 years) ]

8.  Secondary:   Duration of Skin Lesion Response in Everolimus Treated Participants   [ Time Frame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years) ]

9.  Secondary:   Everolimus Blood Concentration (C2h) at 2 Hours Post Dose   [ Time Frame: 2 hours post dose on Week 6, Week 24, Week 48, Week 96, Week 144, and Week 240 ]

10.  Secondary:   Everolimus Trough Concentrations (Cmin) at 24 Hours After Last Dose   [ Time Frame: 24 hours post dose on Week 6, Week 24, Week 48, Week 72, Week 96, Week 144, and Week 240 ]

11.  Secondary:   Percentage of Participants With Renal Impairment During Core Period   [ Time Frame: Day 1 up to 28 days after end of treatment (Core period) ]


  Serious Adverse Events
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Time Frame Serious Adverse Events were monitored from date of First Participant First Visit (FPFV) until Last Participant Last Visit (LPLV), 48 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) until LPLV, up to 4 years.
Additional Description For safety, the reporting arms have been created on the basis of actual exposure to study treatment

Reporting Groups
  Description
Everolimus Treated (Core and Extension Period) Participants who received everolimus treatment in core period and continued to receive evrolimus treatment in extension period.
Placebo (Core) Then Everolimus Treated (Extension Period) Participants who received placebo in core period and then received evrolimus treatment in extension period.
Placebo Treated (Core Period) Participants who received placebo in core period.

Serious Adverse Events
    Everolimus Treated (Core and Extension Period)   Placebo (Core) Then Everolimus Treated (Extension Period)   Placebo Treated (Core Period)
Total, serious adverse events       
# participants affected / at risk   33/78 (42.31%)   17/33 (51.52%)   3/6 (50.00%) 
Blood and lymphatic system disorders       
Anaemia † 1       
# participants affected / at risk   0/78 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Lymphadenopathy † 1       
# participants affected / at risk   0/78 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Gastrointestinal disorders       
Abdominal pain † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Dysphagia † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Gastrooesophageal reflux disease † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Large intestinal ulcer † 1       
# participants affected / at risk   0/78 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Mouth ulceration † 1       
# participants affected / at risk   0/78 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Small intestinal obstruction † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Umbilical hernia † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Vomiting † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
General disorders       
Pyrexia † 1       
# participants affected / at risk   3/78 (3.85%)   2/33 (6.06%)   1/6 (16.67%) 
Immune system disorders       
Hypersensitivity † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Infections and infestations       
Acinetobacter bacteraemia † 1       
# participants affected / at risk   0/78 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Adenovirus infection † 1       
# participants affected / at risk   2/78 (2.56%)   0/33 (0.00%)   0/6 (0.00%) 
Bronchitis † 1       
# participants affected / at risk   3/78 (3.85%)   1/33 (3.03%)   0/6 (0.00%) 
Bronchopneumonia † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Cellulitis † 1       
# participants affected / at risk   2/78 (2.56%)   1/33 (3.03%)   0/6 (0.00%) 
Croup infectious † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Ear infection bacterial † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Epstein-Barr virus infection † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Febrile infection † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Gastroenteritis † 1       
# participants affected / at risk   4/78 (5.13%)   0/33 (0.00%)   0/6 (0.00%) 
Gastroenteritis viral † 1       
# participants affected / at risk   3/78 (3.85%)   0/33 (0.00%)   0/6 (0.00%) 
Gastrointestinal infection † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Herpes zoster † 1       
# participants affected / at risk   0/78 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Infected bites † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Influenza † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Laryngitis † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Mastoiditis † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Meningitis viral † 1       
# participants affected / at risk   0/78 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Nasopharyngitis † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Otitis media † 1       
# participants affected / at risk   2/78 (2.56%)   0/33 (0.00%)   0/6 (0.00%) 
Parainfluenzae virus infection † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Pertussis † 1       
# participants affected / at risk   0/78 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Pneumonia † 1       
# participants affected / at risk   11/78 (14.10%)   5/33 (15.15%)   1/6 (16.67%) 
Respiratory tract infection viral † 1       
# participants affected / at risk   1/78 (1.28%)   1/33 (3.03%)   0/6 (0.00%) 
Sinusitis † 1       
# participants affected / at risk   0/78 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Tonsillitis † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Tooth abscess † 1       
# participants affected / at risk   0/78 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Upper respiratory tract infection † 1       
# participants affected / at risk   2/78 (2.56%)   1/33 (3.03%)   0/6 (0.00%) 
Urinary tract infection † 1       
# participants affected / at risk   1/78 (1.28%)   2/33 (6.06%)   0/6 (0.00%) 
Injury, poisoning and procedural complications       
Accidental overdose † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Foreign body aspiration † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Procedural pain † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Investigations       
Blood alkaline phosphatase increased † 1       
# participants affected / at risk   0/78 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Metabolism and nutrition disorders       
Dehydration † 1       
# participants affected / at risk   3/78 (3.85%)   1/33 (3.03%)   0/6 (0.00%) 
Hyponatraemia † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Musculoskeletal and connective tissue disorders       
Patellofemoral pain syndrome † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Temporomandibular joint syndrome † 1       
# participants affected / at risk   0/78 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Tendon disorder † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Nervous system disorders       
Ataxia † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Complex partial seizures † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Convulsion † 1       
# participants affected / at risk   4/78 (5.13%)   1/33 (3.03%)   2/6 (33.33%) 
Drooling † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Epilepsy † 1       
# participants affected / at risk   2/78 (2.56%)   0/33 (0.00%)   0/6 (0.00%) 
Febrile convulsion † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Grand mal convulsion † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Headache † 1       
# participants affected / at risk   0/78 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Partial seizures † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Status epilepticus † 1       
# participants affected / at risk   2/78 (2.56%)   1/33 (3.03%)   0/6 (0.00%) 
Psychiatric disorders       
Affective disorder † 1       
# participants affected / at risk   1/78 (1.28%)   1/33 (3.03%)   0/6 (0.00%) 
Agitation † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Renal and urinary disorders       
Focal segmental glomerulosclerosis † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Asphyxia † 1       
# participants affected / at risk   0/78 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Pneumonia aspiration † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Pneumothorax † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Pulmonary pneumatocele † 1       
# participants affected / at risk   0/78 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Tonsillar hypertrophy † 1       
# participants affected / at risk   1/78 (1.28%)   0/33 (0.00%)   0/6 (0.00%) 
Vascular disorders       
Raynaud's phenomenon † 1       
# participants affected / at risk   0/78 (0.00%)   0/33 (0.00%)   1/6 (16.67%) 
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA V17.0




  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
No text entered.


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