RAD001 Plus Best Supportive Care (BSC) Versus BSC Plus Placebo in Patients With Metastatic Carcinoma of the Kidney Which Has Progressed After Treatment With Sorafenib and/or Sunitinib (RECORD-1)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00410124
First received: December 11, 2006
Last updated: December 7, 2012
Last verified: December 2012
Results First Received: October 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
Condition: Metastatic Renal Cell Carcinoma
Interventions: Drug: 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
Core period was terminated due to early achievements of efficacy targets and patients who were receiving study drug and patients receiving placebo in double blind phase had option to continue into the extension phase to receive open label RAD001.

Reporting Groups
  Description
RAD001 +BSC The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
Placebo + BSC / RAD001 Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care. With the documented disease progression at data cutoff of 28Feb2008, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.

Participant Flow for 2 periods

Period 1:   Core Phase Double Blind (15 Months)
    RAD001 +BSC     Placebo + BSC / RAD001  
STARTED     277 [1]   139  
Ongoing     13     4  
Completed Double Blind Treatment     62     2  
COMPLETED     75 [2]   6 [3]
NOT COMPLETED     202     133  
Adverse Event                 36                 2  
Abnormal Laboratory Value                 1                 0  
Protocol Violation                 2                 1  
Withdrawal by Subject                 13                 2  
Lost to Follow-up                 4                 0  
Administrative Problems                 2                 0  
Death                 7                 4  
Disease Progression                 137                 124  
[1] Started indicates randomized (FAS) and treated
[2] Patients ongoing/completed double blind phase had option entering extension phase continuing RAD001.
[3] All patients ongoing/completed/not completed in core had option to enter extension taking RAD001.

Period 2:   Extension Phase - Open Label (45 Months)
    RAD001 +BSC     Placebo + BSC / RAD001  
STARTED     67     111 [1]
COMPLETED     0     0  
NOT COMPLETED     67     111  
Adverse Event                 7                 19  
Abnormal Laboratory Values                 0                 1  
Abnormal Test Procedures                 0                 1  
Withdrawal by Subject                 1                 1  
Death                 2                 10  
Disease Progression                 56                 78  
Patient no longer required study drug                 1                 0  
Final Primary Analysis                 0                 1  
[1] Patients on placebo in core received RAD001 in extension phase.



  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
RAD001 +BSC The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
Placebo + BSC Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care. With the documented disease progression, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
Total Total of all reporting groups

Baseline Measures
    RAD001 +BSC     Placebo + BSC     Total  
Number of Participants  
[units: participants]
  277     139     416  
Age, Customized  
[units: participants]
     
<65 years     165     98     263  
>=65 years     112     41     153  
Gender  
[units: participants]
     
Female     61     33     94  
Male     216     106     322  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Progressive Free Survival (PFS) in Patients Who Receive RAD001 Plus Best Supportive Care(BSC) Versus Patients Who Receive Matching Placebo Plus BSC   [ Time Frame: Time from randomization to dates of disease progression, death from any cause or last tumor assessment reported between date of first patient randomized until 28Feb2008 cut of date. ]

2.  Secondary:   Overall Survival (OS) Assessed by the Monthly Overall Survival Assessments   [ Time Frame: Assessed every month up to 2 years after the last patient was randomized into the study from the date of randomization to the time of death. (Data cutoff was 15Nov2009) ]

3.  Secondary:   Best Overall Response Rate in Patients Who Receive RAD001 Plus BSC Versus Matching Placebo Plus BSC   [ Time Frame: Time from randomization to dates of disease progression, death from any cause or last tumor assessment reported, between date of first patient randomized until 28Feb2008 cutoff date ]

4.  Secondary:   Duration of Response in Patients Who Receive RAD001 Plus BSC Versus Placebo Plus BSC   [ Time Frame: Time from randomization to dates of disease progression, death from any cause or last tumor assessment reported, between date of first patient randomized until 28Feb2008 cutoff date ]

5.  Secondary:   Analysis of Time to Definitive Deterioration of the Global Health Status/QoL Scale(QL) Scores of the EORTC QLQ-30 Questionnaire by at Least 10 Percent Using Kaplan Meier Method, by Treatment.   [ Time Frame: Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date ]

6.  Secondary:   Time to Definitive Deterioration of the FKS-DRS Risk Score by at Least 2 Score Units Using Kaplan-Meier Method, by Treatment.   [ Time Frame: Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date ]

7.  Secondary:   Time to Definitive Deterioration of the Physical Functioning Scale (PF)Score of the EORTC QLQ-C30 Questionnaire by at Least 10 Percent Using Kaplan_Meier Method, by Treatment.   [ Time Frame: Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date ]

8.  Secondary:   Pharmacokinetics of RAD001:Peak Concentration in a Dosing Interval (C-max); Pre-dose Concentration at 24-h Time Point in Dosing Interval (C-min) and Average Concentration in a Dosing Interval =(C-avg)   [ Time Frame: At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day1, Cycle 1 Day 15 and at pre-dose from Cycle 2(day1) and all subsequent treatment cycles up until data cut-off 28 Feb 2008. ]

9.  Secondary:   Pharmacokinetics of RAD001: Time at Which C-Max Occurs (t-Max)   [ Time Frame: At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose of From Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008. ]

10.  Secondary:   Pharmacokinetics of RAD001: Area Under Curve (AUC) in a Dosing Interval From Time-zero to Time of the Last Quantifiable Concentration. (AUC 0-tlast)   [ Time Frame: At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008. ]

11.  Secondary:   Pharmacokinetics of RAD001: Time of the Last Quantifiable Concentration in a Dosing Interval - (Tlast)   [ Time Frame: At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008. ]

12.  Secondary:   Pharmacokinetics of RAD001: Apparent Systemic Clearance From Blood Following Extravascular Administration (CL/F)   [ Time Frame: At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008. ]

13.  Secondary:   Pharmacokinetics of RAD001: Normalized to Body Surface Area (CL/F)   [ Time Frame: At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008. ]


  Serious Adverse Events


  Other Adverse Events
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Time Frame No text entered.
Additional Description The Safety population consists of all patients who received at least one dose of study drug and who had at least one valid post-baseline safety assessment. Patients were analyzed according to the treatment actually received.

Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
Randomized to RAD001+ BSC ( Blinded + Open Label) The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
Randomized to Placebo + BSC (Open Label) With the documented disease progression at data cutoff of 28Feb2008, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
Randomized to Placebo + BSC (Double Blind Only) Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care.

Other Adverse Events
    Randomized to RAD001+ BSC ( Blinded + Open Label)     Randomized to Placebo + BSC (Open Label)     Randomized to Placebo + BSC (Double Blind Only)  
Total, other (not including serious) adverse events        
# participants affected / at risk     261/274     106/111     23/26  
Blood and lymphatic system disorders        
Anaemia † 1      
# participants affected / at risk     108/274 (39.42%)     42/111 (37.84%)     4/26 (15.38%)  
Lymphopenia † 1      
# participants affected / at risk     29/274 (10.58%)     7/111 (6.31%)     0/26 (0.00%)  
Thrombocytopenia † 1      
# participants affected / at risk     19/274 (6.93%)     8/111 (7.21%)     0/26 (0.00%)  
Ear and labyrinth disorders        
Ear pain † 1      
# participants affected / at risk     3/274 (1.09%)     6/111 (5.41%)     0/26 (0.00%)  
Gastrointestinal disorders        
Abdominal pain † 1      
# participants affected / at risk     31/274 (11.31%)     10/111 (9.01%)     1/26 (3.85%)  
Abdominal pain upper † 1      
# participants affected / at risk     20/274 (7.30%)     6/111 (5.41%)     1/26 (3.85%)  
Aphthous stomatitis † 1      
# participants affected / at risk     26/274 (9.49%)     13/111 (11.71%)     0/26 (0.00%)  
Constipation † 1      
# participants affected / at risk     60/274 (21.90%)     25/111 (22.52%)     5/26 (19.23%)  
Diarrhoea † 1      
# participants affected / at risk     90/274 (32.85%)     28/111 (25.23%)     2/26 (7.69%)  
Dry mouth † 1      
# participants affected / at risk     22/274 (8.03%)     5/111 (4.50%)     4/26 (15.38%)  
Haemorrhoids † 1      
# participants affected / at risk     17/274 (6.20%)     1/111 (0.90%)     0/26 (0.00%)  
Nausea † 1      
# participants affected / at risk     78/274 (28.47%)     27/111 (24.32%)     5/26 (19.23%)  
Stomatitis † 1      
# participants affected / at risk     106/274 (38.69%)     33/111 (29.73%)     3/26 (11.54%)  
Vomiting † 1      
# participants affected / at risk     63/274 (22.99%)     19/111 (17.12%)     3/26 (11.54%)  
General disorders        
Asthenia † 1      
# participants affected / at risk     96/274 (35.04%)     31/111 (27.93%)     9/26 (34.62%)  
Fatigue † 1      
# participants affected / at risk     86/274 (31.39%)     40/111 (36.04%)     8/26 (30.77%)  
General physical health deterioration † 1      
# participants affected / at risk     6/274 (2.19%)     3/111 (2.70%)     2/26 (7.69%)  
Mucosal inflammation † 1      
# participants affected / at risk     53/274 (19.34%)     26/111 (23.42%)     0/26 (0.00%)  
Non-cardiac chest pain † 1      
# participants affected / at risk     12/274 (4.38%)     8/111 (7.21%)     0/26 (0.00%)  
Oedema peripheral † 1      
# participants affected / at risk     79/274 (28.83%)     25/111 (22.52%)     5/26 (19.23%)  
Pyrexia † 1      
# participants affected / at risk     55/274 (20.07%)     24/111 (21.62%)     1/26 (3.85%)  
Infections and infestations        
Bronchitis † 1      
# participants affected / at risk     17/274 (6.20%)     6/111 (5.41%)     1/26 (3.85%)  
Nasopharyngitis † 1      
# participants affected / at risk     20/274 (7.30%)     8/111 (7.21%)     1/26 (3.85%)  
Urinary tract infection † 1      
# participants affected / at risk     14/274 (5.11%)     5/111 (4.50%)     0/26 (0.00%)  
Investigations        
Blood alkaline phosphatase increased † 1      
# participants affected / at risk     11/274 (4.01%)     6/111 (5.41%)     0/26 (0.00%)  
Blood creatinine increased † 1      
# participants affected / at risk     29/274 (10.58%)     3/111 (2.70%)     0/26 (0.00%)  
Gamma-glutamyltransferase increased † 1      
# participants affected / at risk     20/274 (7.30%)     7/111 (6.31%)     0/26 (0.00%)  
Weight decreased † 1      
# participants affected / at risk     27/274 (9.85%)     19/111 (17.12%)     2/26 (7.69%)  
Metabolism and nutrition disorders        
Decreased appetite † 1      
# participants affected / at risk     82/274 (29.93%)     24/111 (21.62%)     6/26 (23.08%)  
Dehydration † 1      
# participants affected / at risk     9/274 (3.28%)     5/111 (4.50%)     2/26 (7.69%)  
Hypercalcaemia † 1      
# participants affected / at risk     10/274 (3.65%)     4/111 (3.60%)     3/26 (11.54%)  
Hypercholesterolaemia † 1      
# participants affected / at risk     60/274 (21.90%)     21/111 (18.92%)     0/26 (0.00%)  
Hyperglycaemia † 1      
# participants affected / at risk     36/274 (13.14%)     15/111 (13.51%)     2/26 (7.69%)  
Hypertriglyceridaemia † 1      
# participants affected / at risk     45/274 (16.42%)     17/111 (15.32%)     0/26 (0.00%)  
Hypophosphataemia † 1      
# participants affected / at risk     18/274 (6.57%)     4/111 (3.60%)     0/26 (0.00%)  
Musculoskeletal and connective tissue disorders        
Arthralgia † 1      
# participants affected / at risk     39/274 (14.23%)     20/111 (18.02%)     1/26 (3.85%)  
Back pain † 1      
# participants affected / at risk     39/274 (14.23%)     13/111 (11.71%)     2/26 (7.69%)  
Bone pain † 1      
# participants affected / at risk     11/274 (4.01%)     9/111 (8.11%)     1/26 (3.85%)  
Musculoskeletal chest pain † 1      
# participants affected / at risk     14/274 (5.11%)     3/111 (2.70%)     0/26 (0.00%)  
Musculoskeletal pain † 1      
# participants affected / at risk     10/274 (3.65%)     8/111 (7.21%)     1/26 (3.85%)  
Myalgia † 1      
# participants affected / at risk     7/274 (2.55%)     8/111 (7.21%)     0/26 (0.00%)  
Pain in extremity † 1      
# participants affected / at risk     34/274 (12.41%)     17/111 (15.32%)     3/26 (11.54%)  
Nervous system disorders        
Dizziness † 1      
# participants affected / at risk     19/274 (6.93%)     3/111 (2.70%)     3/26 (11.54%)  
Dysgeusia † 1      
# participants affected / at risk     32/274 (11.68%)     14/111 (12.61%)     1/26 (3.85%)  
Headache † 1      
# participants affected / at risk     53/274 (19.34%)     14/111 (12.61%)     2/26 (7.69%)  
Paraesthesia † 1      
# participants affected / at risk     12/274 (4.38%)     1/111 (0.90%)     2/26 (7.69%)  
Psychiatric disorders        
Anxiety † 1      
# participants affected / at risk     14/274 (5.11%)     3/111 (2.70%)     2/26 (7.69%)  
Insomnia † 1      
# participants affected / at risk     30/274 (10.95%)     11/111 (9.91%)     2/26 (7.69%)  
Renal and urinary disorders        
Dysuria † 1      
# participants affected / at risk     5/274 (1.82%)     6/111 (5.41%)     0/26 (0.00%)  
Haematuria † 1      
# participants affected / at risk     4/274 (1.46%)     0/111 (0.00%)     2/26 (7.69%)  
Nocturia † 1      
# participants affected / at risk     10/274 (3.65%)     8/111 (7.21%)     1/26 (3.85%)  
Respiratory, thoracic and mediastinal disorders        
Cough † 1      
# participants affected / at risk     96/274 (35.04%)     30/111 (27.03%)     4/26 (15.38%)  
Dyspnoea † 1      
# participants affected / at risk     59/274 (21.53%)     28/111 (25.23%)     3/26 (11.54%)  
Dyspnoea exertional † 1      
# participants affected / at risk     17/274 (6.20%)     8/111 (7.21%)     1/26 (3.85%)  
Epistaxis † 1      
# participants affected / at risk     51/274 (18.61%)     12/111 (10.81%)     0/26 (0.00%)  
Oropharyngeal pain † 1      
# participants affected / at risk     10/274 (3.65%)     6/111 (5.41%)     0/26 (0.00%)  
Pleural effusion † 1      
# participants affected / at risk     13/274 (4.74%)     8/111 (7.21%)     0/26 (0.00%)  
Pneumonitis † 1      
# participants affected / at risk     18/274 (6.57%)     4/111 (3.60%)     0/26 (0.00%)  
Skin and subcutaneous tissue disorders        
Dry skin † 1      
# participants affected / at risk     38/274 (13.87%)     14/111 (12.61%)     3/26 (11.54%)  
Erythema † 1      
# participants affected / at risk     15/274 (5.47%)     2/111 (1.80%)     0/26 (0.00%)  
Nail disorder † 1      
# participants affected / at risk     20/274 (7.30%)     7/111 (6.31%)     0/26 (0.00%)  
Onychoclasis † 1      
# participants affected / at risk     16/274 (5.84%)     2/111 (1.80%)     0/26 (0.00%)  
Pruritus † 1      
# participants affected / at risk     43/274 (15.69%)     12/111 (10.81%)     2/26 (7.69%)  
Rash † 1      
# participants affected / at risk     83/274 (30.29%)     29/111 (26.13%)     1/26 (3.85%)  
Vascular disorders        
Hypertension † 1      
# participants affected / at risk     14/274 (5.11%)     7/111 (6.31%)     0/26 (0.00%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA



  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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