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RADIANT-2: Everolimus and Octreotide in Patients With Advanced Carcinoid Tumor

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT00412061
Collaborator
(none)
429
Enrollment
70
Locations
2
Arms
78
Duration (Months)
6.1
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate whether everolimus 10 mg / day added to treatment with depot octreotide prolongs progression free survival compared to treatment with octreotide alone in patients with advanced carcinoid tumor.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
429 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-blind Placebo-controlled, Multicenter Phase III Study in Patients With Advanced Carcinoid Tumor Receiving Octreotide Depot and Everolimus 10 mg/Day or Octreotide Depot and Placebo
Study Start Date :
Dec 1, 2006
Actual Primary Completion Date :
Apr 1, 2010
Actual Study Completion Date :
Jun 1, 2013

Arms and Interventions

Arm Intervention/Treatment
Experimental: Octreotide+ Everolimus

Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.

Drug: Octreotide
Octreotide 30 mg intramuscularly (i.m.) every 28 days.
Other Names:
  • Sandostatin LAR® Depot

    • Drug: Everolimus
    A 10-mg oral daily dosing regimen (two 5-mg tablets) of everolimus.
    Other Names:
  • RAD001

    		•
    Placebo Comparator: Octreotide+ Placebo

    Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.

    Drug: Octreotide
    Octreotide 30 mg intramuscularly (i.m.) every 28 days.
    Other Names:
  • Sandostatin LAR® Depot

    • Drug: Placebo
    A 10-mg oral daily dosing regimen (two 5-mg tablets) of matching placebo.

    Outcome Measures

    Primary Outcome Measures

    1. Progression Free Survival (PFS) as Per Adjudicated Central Radiology Review [Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010]

      Progression free survival (PFS) is defined as the time from randomization to the date of first documented disease progression or death from any cause. The primary analysis of PFS was based on the independent central adjudicated assessment using Kaplan-Meier method.

    Secondary Outcome Measures

    1. Best Overall Response Rate as Per Adjudicated Central Radiology Review Based on Response Evaluation Criteria in Solid Tumors (RECIST) [Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010]

      The best overall response rate is defined as the percentage of patients having achieved confirmed Complete Response + Partial Response. Complete Response (CR) = at least two determinations of CR at least 4 weeks apart before progression. • Partial response (PR) = at least two determinations of PR or better at least 4 weeks apart before progression.

    2. Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline 5-hydroxyindoleacetic Acid (5-HIAA) Level [If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010]

      5-HIAA levels in urine are frequently elevated in patients with advanced carcinoid tumors. Baseline levels of 5-HIAA in urine were defined as 'High' if they exceeded the median value, and 'Low' if they were lower than or equal to the median.

    3. Overall Survival Using Kaplan-Meier Methodology [Months 12, 24, 36, 48]

      Overall survival was defined as the time from the date of randomization to the date of death from any cause. If a patient was not known to have died, survival was censored at the date of last contact. Kaplan-Meier methodology was used to estimate the median overall survival for each treatment group.

    4. Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase) [From first day of treatment up to 28 days after last day of treatment in double blind]

      AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.

    5. Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase) [From first day of treatment up to 28 days after last day of treatment in double blind]

      AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.

    6. Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline Chromogranin A (CgA) [If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010]

      Serum CgA levels in urine are frequently elevated in patients with advanced carcinoid tumors. Baseline levels of serum CgA were characterized relative to the upper limited of normal (ULN). CgA levels exceeding 2 x ULN were considered to be 'Elevated'; otherwise considered as "Non-elevated".

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion criteria:

    • Advanced (unresectable or metastatic) carcinoid tumor

    • Confirmed low-grade or intermediate-grade neuroendocrine carcinoma

    • Documented progression of disease within 12 months prior to randomization.

    • Measurable disease determined by triphasic computer tomography (CT) scan or magnetic resonance imaging (MRI).

    Exclusion criteria:

    • Poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoma, or small cell carcinoma.

    • Hepatic artery embolization within the last 6 months or cryoablation of hepatic metastasis within 2 months of enrollment.

    • Previous treatment with mammalian target of rapamycin (mTOR) inhibitors (sirolimus, temsirolimus, everolimus)

    • Intolerance or hypersensitivity to octreotide, everolimus, or other rapamycins.

    • Severe or uncontrolled medical conditions

    • Chronic treatment with corticosteroids or other immunosuppressive agent.

    • Other primary cancer within 3 years.

    Other protocol-defined inclusion/exclusion criteria applied

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Arizona / Arizona Cancer Center Deptof Uof A/Arizona Cancer(2) Tucson Arizona United States 85719
    2 Highlands Oncology Group The Center for Chest Care Fayetteville Arkansas United States 72703
    3 Hematology Oncology Services of Arkansas Little Rock Arkansas United States 72205
    4 Pacific Cancer Medical Center, Inc. Anaheim California United States 92801
    5 Cedars Sinai Medical Center SC-2 Los Angeles California United States 90048
    6 University of California at Los Angeles UCLA New SC Address Los Angeles California United States 90095
    7 University of Colorado Dept. of Univ. of Colorado Aurora Colorado United States 80045
    8 Rocky Mountain Cancer Centers Dept of Rocky Mountain (2) Denver Colorado United States 80218
    9 Eastern Connecticut Hematology & Oncology Associates Dept. of ECHO Norwich Connecticut United States 06360
    10 Cancer Centers of Connecticut Southington Location Southington Connecticut United States 06489
    11 Hematology Oncology PC Dept.of Hematology Oncology(2) Stamford Connecticut United States 06902
    12 Ocala Oncology Center Dept. of Ocala Oncology Center Ocala Florida United States 34471
    13 Cancer Care and Hematology Specialists of Chicagoland Niles Niles Illinois United States 60714
    14 Indiana University Dept.of IndianaUniv.CancerCtr Indianapolis Indiana United States 46202
    15 Central Indiana Cancer Centers CICC - South Indianapolis Indiana United States 46227
    16 University of Iowa Medical Center Internal Medicine Iowa City Iowa United States 52242
    17 University of Kansas Cancer Center Deptof Uof Kansas CancerCenter Kansas City Kansas United States 66160
    18 Kansas City Cancer Center KCCC Business Office Overland Park Kansas United States 66210
    19 Norton Cancer Institute Clinical Research Program Louisville Kentucky United States 40202
    20 LSU HEALTH SCIENCES CENTER/ LSU SCHOOL OF MEDICINE Deptof LSU Health Sciences (2) New Orleans Louisiana United States 70112
    21 Mayo Clinic - Rochester Division of Hematology Rochester Minnesota United States 55905
    22 Washington University School Of Medicine-Siteman Cancer Ctr Division of Oncology St. Louis Missouri United States 63110
    23 The Center for Cancer Care and Research St. Louis Missouri United States 63141
    24 Dartmouth Hitchcock Medical Center Medical Oncology Lebanon New Hampshire United States 03756
    25 New York Oncology Hematology, P.C. Dept. of New York Oncology. PC Albany New York United States 12206
    26 New York University Medical Center NYU Medical Center (2) New York New York United States 10016
    27 Duke University Medical Center Dept. of Duke Cancer Center Durham North Carolina United States 27710
    28 Fox Chase Cancer Center Philadelphia Pennsylvania United States 19111-2497
    29 Cancer Centers of the Carolinas CC of C -Eastside Greenville South Carolina United States 29615
    30 Texas Oncology, P.A. Central Austin Cancer Center Austin Texas United States 78731
    31 South Texas Institute of Cancer S. Tex Inst.- Corpus Christi Corpus Christi Texas United States 78405
    32 Sammons Cancer Center - Texas Oncology Sammons Cancer Center (SC) Dallas Texas United States 75246
    33 Texas Oncology, P.A. Forth Worth -- 12th Avenue Fort Worth Texas United States 76104
    34 University of Texas/MD Anderson Cancer Center Gastrointestinal Med. Oncology Houston Texas United States 77030
    35 Tyler Cancer Center Tyler Texas United States 75702
    36 Virginia Oncology Associates VOA - Lake Wright Norfolk Virginia United States 23502
    37 Northwest Cancer Specialists Compass Oncology -BKM Vancouver Washington United States 98684
    38 University of Wisconsin / Paul P. Carbone Comp Cancer Center GI Oncology Research Center Madison Wisconsin United States 53792
    39 Novartis Investigative Site Kogarah New South Wales Australia 2217
    40 Novartis Investigative Site Herston Queensland Australia 4029
    41 Novartis Investigative Site South Brisbane Queensland Australia 4101
    42 Novartis Investigative Site Bruxelles Belgium 1070
    43 Novartis Investigative Site London Ontario Canada N6A 4L6
    44 Novartis Investigative Site Toronto Ontario Canada M5G 2M9
    45 Novartis Investigative Site Montreal Quebec Canada H1T 2M4
    46 Novartis Investigative Site Montreal Quebec Canada H2X 1P1
    47 Novartis Investigative Site Praha 2 Czech Republic 128 08
    48 Novartis Investigative Site Pribram Czech Republic 261 95
    49 Novartis Investigative Site Helsinki Finland FIN-00290
    50 Novartis Investigative Site Clichy Cédex France 92118
    51 Novartis Investigative Site Lille Cedex France 59020
    52 Novartis Investigative Site Montpellier France 34298
    53 Novartis Investigative Site Paris Cedex 15 France 75908
    54 Novartis Investigative Site Strasbourg France 67098
    55 Novartis Investigative Site Toulouse Cedex 9 France 31059
    56 Novartis Investigative Site Villejuif Cedex France 94805
    57 Novartis Investigative Site Berlin Germany 13353
    58 Novartis Investigative Site Hamburg Germany 20246
    59 Novartis Investigative Site Athens Greece GR 11527
    60 Novartis Investigative Site Bologna BO Italy 40138
    61 Novartis Investigative Site Milano MI Italy 20100
    62 Novartis Investigative Site Milano MI Italy 20141
    63 Novartis Investigative Site Perugia PG Italy 06132
    64 Novartis Investigative Site Pisa PI Italy 56126
    65 Novartis Investigative Site Groningen Netherlands 9713 GZ
    66 Novartis Investigative Site Rotterdam Netherlands 3015 CE
    67 Novartis Investigative Site Bratislava Slovak Republic Slovakia 813 69
    68 Novartis Investigative Site Madrid Spain 28041
    69 Novartis Investigative Site Uppsala Sweden SE-751 85
    70 Novartis Investigative Site Basingstoke United Kingdom RG24 9NA

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT00412061
    Other Study ID Numbers:
    • CRAD001C2325
    • 2006-004507-18
    First Posted:
    Dec 15, 2006
    Last Update Posted:
    Nov 21, 2014
    Last Verified:
    Nov 1, 2014
    Keywords provided by Novartis Pharmaceuticals
    Cancer
    Carcinoid
    Tumor
    Neuroendocrine
    Carcinoma
    Everolimus
    Octreotide
    Additional relevant MeSH terms:
    Carcinoid Tumor
    Malignant Carcinoid Syndrome
    Serotonin Syndrome
    Everolimus
    Octreotide

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Total 429 patients were randomized to double blind phase of treatment. 170 patients moved to the Open Label Phase.
    Arm/Group Title Octreotide+ Everolimus Octreotide+ Placebo Followed by Open Label Arm
    Arm/Group Description Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1. Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1. Open Label - Patients who had progressive disease in this arm, can move to the open label Everolimus + depot octreotide by choice.
    Period Title: Double Blind Phase
    STARTED 216 213
    Safety Set 215 211
    COMPLETED 0 0
    NOT COMPLETED 216 213
    Period Title: Double Blind Phase
    STARTED 0 170
    COMPLETED 0 0
    NOT COMPLETED 0 170

    Baseline Characteristics

    Arm/Group Title Octreotide+ Everolimus Octreotide+ Placebo Total
    Arm/Group Description Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1. Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1. Total of all reporting groups
    Overall Participants 216 213 429
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    60.1
    (10.72)
    59.4
    (11.13)
    59.8
    (10.92)
    Sex: Female, Male (Count of Participants)
    Female
    119
    55.1%
    89
    41.8%
    208
    48.5%
    Male
    97
    44.9%
    124
    58.2%
    221
    51.5%

    Outcome Measures

    1. Primary Outcome
    Title Progression Free Survival (PFS) as Per Adjudicated Central Radiology Review
    Description Progression free survival (PFS) is defined as the time from randomization to the date of first documented disease progression or death from any cause. The primary analysis of PFS was based on the independent central adjudicated assessment using Kaplan-Meier method.
    Time Frame Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010

    Outcome Measure Data

    Analysis Population Description
    The Full Analysis Set (FAS) consisted of all randomized patients.
    Arm/Group Title Octreotide+ Everolimus Octreotide+ Placebo
    Arm/Group Description Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1. Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.
    Measure Participants 216 213
    Median (95% Confidence Interval) [Months]
    16.43
    11.33
    2. Secondary Outcome
    Title Best Overall Response Rate as Per Adjudicated Central Radiology Review Based on Response Evaluation Criteria in Solid Tumors (RECIST)
    Description The best overall response rate is defined as the percentage of patients having achieved confirmed Complete Response + Partial Response. Complete Response (CR) = at least two determinations of CR at least 4 weeks apart before progression. • Partial response (PR) = at least two determinations of PR or better at least 4 weeks apart before progression.
    Time Frame Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010

    Outcome Measure Data

    Analysis Population Description
    The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients.
    Arm/Group Title Octreotide+ Everolimus Octreotide+ Placebo
    Arm/Group Description Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1. Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.
    Measure Participants 216 213
    Number (95% Confidence Interval) [Percentage of patients]
    2.3
    1.9
    3. Secondary Outcome
    Title Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline 5-hydroxyindoleacetic Acid (5-HIAA) Level
    Description 5-HIAA levels in urine are frequently elevated in patients with advanced carcinoid tumors. Baseline levels of 5-HIAA in urine were defined as 'High' if they exceeded the median value, and 'Low' if they were lower than or equal to the median.
    Time Frame If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010

    Outcome Measure Data

    Analysis Population Description
    The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients. This analysis includes PFS patients with non missing baseline 5-HIAA data.
    Arm/Group Title Octreotide+ Everolimus Octreotide+ Placebo
    Arm/Group Description Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1. Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.
    Measure Participants 187 191
    5-HIAA <=median (n=93,96)
    21.75
    13.90
    5-HIAA > median (n=94,95)
    13.83
    8.41
    4. Secondary Outcome
    Title Overall Survival Using Kaplan-Meier Methodology
    Description Overall survival was defined as the time from the date of randomization to the date of death from any cause. If a patient was not known to have died, survival was censored at the date of last contact. Kaplan-Meier methodology was used to estimate the median overall survival for each treatment group.
    Time Frame Months 12, 24, 36, 48

    Outcome Measure Data

    Analysis Population Description
    The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients.
    Arm/Group Title Octreotide+ Everolimus Octreotide+ Placebo Followed by Open Label Arm
    Arm/Group Description Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1. Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1. Open Label - Patients who had progressive disease in this arm, can move to the open label Everolimus + depot octreotide by choice.
    Measure Participants 216 213
    12 Months
    80.5
    37.3%
    81.8
    38.4%
    24 Months
    57.0
    26.4%
    63.6
    29.9%
    36 Months
    42.9
    19.9%
    48.5
    22.8%
    48 Months
    38.0
    17.6%
    41.6
    19.5%
    5. Secondary Outcome
    Title Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase)
    Description AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.
    Time Frame From first day of treatment up to 28 days after last day of treatment in double blind

    Outcome Measure Data

    Analysis Population Description
    The Safety Set consists of all patients who received at least one dose of study drug and who had at least one valid post-baseline safety assessment.
    Arm/Group Title Octreotide+ Everolimus Octreotide+ Placebo
    Arm/Group Description Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1. Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.
    Measure Participants 215 211
    Clinically notable AE
    208
    146
    Grade 3-4 Adverse Events
    162
    109
    On treatment death
    19
    11
    Serious adverse events
    126
    74
    6. Secondary Outcome
    Title Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase)
    Description AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.
    Time Frame From first day of treatment up to 28 days after last day of treatment in double blind

    Outcome Measure Data

    Analysis Population Description
    The Safety Set consists of all patients who received at least one dose of study drug and who had at least one valid post-baseline safety assessment.
    Arm/Group Title Everolimus Open Label Arm
    Arm/Group Description Patients who had progressive disease in this arm, can move to the open label Everolimus + depot octreotide by choice.
    Measure Participants 170
    Clinically notable AE
    154
    Grade 3-4 Adverse Events
    115
    On treatment death
    22
    Serious adverse events
    93
    7. Secondary Outcome
    Title Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline Chromogranin A (CgA)
    Description Serum CgA levels in urine are frequently elevated in patients with advanced carcinoid tumors. Baseline levels of serum CgA were characterized relative to the upper limited of normal (ULN). CgA levels exceeding 2 x ULN were considered to be 'Elevated'; otherwise considered as "Non-elevated".
    Time Frame If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010

    Outcome Measure Data

    Analysis Population Description
    The Full Analysis Set (FAS; Intent-to-treat Population) consists of all randomized patients. This analysis includes PFS patients with non missing baseline CgA data.
    Arm/Group Title Octreotide+ Everolimus Octreotide+ Placebo
    Arm/Group Description Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1. Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.
    Measure Participants 212 208
    CgA<=2x ULN (n=60,78)
    31.31
    20.07
    CgA>2x ULN (n=152,130)
    13.93
    8.41

    Adverse Events

    Time Frame
    Adverse Event Reporting Description Double blind period, Safety Set consists all patients received at least one dose of study drug and who had at least one valid post-baseline safety assessment. The Open-label Set consists all patients received at least one dose of open-label everolimus and who had at least one valid safety assessment after initiation of open-label treatment
    Arm/Group Title Everolimus + Octreotide Placebo + Octreotide Everolimus Open Label
    Arm/Group Description Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1. Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1. Open Label - Patients who had progressive disease in this arm, can move to the open label Everolimus + depot octreotide by choice.
    All Cause Mortality
    Everolimus + Octreotide Placebo + Octreotide Everolimus Open Label
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Everolimus + Octreotide Placebo + Octreotide Everolimus Open Label
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 126/215 (58.6%) 74/211 (35.1%) 93/170 (54.7%)
    Blood and lymphatic system disorders
    Anaemia 4/215 (1.9%) 2/211 (0.9%) 4/170 (2.4%)
    Disseminated intravascular coagulation 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Febrile neutropenia 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Haemorrhagic anaemia 0/215 (0%) 1/211 (0.5%) 2/170 (1.2%)
    Leukopenia 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Pancytopenia 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Thrombocytopenia 3/215 (1.4%) 0/211 (0%) 1/170 (0.6%)
    Cardiac disorders
    Acute myocardial infarction 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Angina pectoris 2/215 (0.9%) 3/211 (1.4%) 1/170 (0.6%)
    Aortic valve incompetence 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Arrhythmia 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Atrial fibrillation 0/215 (0%) 1/211 (0.5%) 1/170 (0.6%)
    Atrial flutter 0/215 (0%) 1/211 (0.5%) 1/170 (0.6%)
    Carcinoid heart disease 2/215 (0.9%) 2/211 (0.9%) 2/170 (1.2%)
    Cardiac arrest 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Cardiac failure 2/215 (0.9%) 0/211 (0%) 0/170 (0%)
    Cardiac failure congestive 2/215 (0.9%) 2/211 (0.9%) 0/170 (0%)
    Cardiac valve disease 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Cardio-respiratory arrest 1/215 (0.5%) 1/211 (0.5%) 0/170 (0%)
    Cardiopulmonary failure 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Coronary artery disease 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Coronary artery occlusion 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Dilatation ventricular 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Left ventricular dysfunction 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Mitral valve stenosis 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Myocardial infarction 1/215 (0.5%) 2/211 (0.9%) 1/170 (0.6%)
    Myocardial ischaemia 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Palpitations 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Pericardial effusion 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Pulmonary valve incompetence 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Pulmonary valve stenosis 1/215 (0.5%) 0/211 (0%) 1/170 (0.6%)
    Right ventricular failure 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Stress cardiomyopathy 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Tachycardia paroxysmal 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Tricuspid valve disease 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Tricuspid valve incompetence 1/215 (0.5%) 2/211 (0.9%) 0/170 (0%)
    Tricuspid valve prolapse 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Tricuspid valve stenosis 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Congenital, familial and genetic disorders
    Atrial septal defect 2/215 (0.9%) 0/211 (0%) 0/170 (0%)
    Ear and labyrinth disorders
    Vertigo 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Endocrine disorders
    Adrenocortical insufficiency acute 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Carcinoid crisis 1/215 (0.5%) 0/211 (0%) 1/170 (0.6%)
    Carcinoid syndrome 2/215 (0.9%) 1/211 (0.5%) 2/170 (1.2%)
    Eye disorders
    Diplopia 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Gastrointestinal disorders
    Abdominal adhesions 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Abdominal distension 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Abdominal hernia 1/215 (0.5%) 1/211 (0.5%) 1/170 (0.6%)
    Abdominal pain 15/215 (7%) 11/211 (5.2%) 11/170 (6.5%)
    Abdominal pain lower 2/215 (0.9%) 0/211 (0%) 0/170 (0%)
    Abdominal pain upper 1/215 (0.5%) 2/211 (0.9%) 1/170 (0.6%)
    Ascites 0/215 (0%) 5/211 (2.4%) 0/170 (0%)
    Colitis 2/215 (0.9%) 0/211 (0%) 1/170 (0.6%)
    Constipation 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Diarrhoea 9/215 (4.2%) 5/211 (2.4%) 7/170 (4.1%)
    Duodenal obstruction 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Duodenal stenosis 0/215 (0%) 1/211 (0.5%) 2/170 (1.2%)
    Enteritis 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Faeces discoloured 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Food poisoning 0/215 (0%) 2/211 (0.9%) 0/170 (0%)
    Gastric haemorrhage 0/215 (0%) 1/211 (0.5%) 1/170 (0.6%)
    Gastric ulcer 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Gastritis erosive 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Gastrointestinal angiodysplasia 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Gastrointestinal fistula 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Gastrointestinal haemorrhage 1/215 (0.5%) 1/211 (0.5%) 2/170 (1.2%)
    Gastrooesophageal reflux disease 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Haematemesis 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Haematochezia 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Haemorrhoids 1/215 (0.5%) 1/211 (0.5%) 0/170 (0%)
    Ileus 5/215 (2.3%) 1/211 (0.5%) 0/170 (0%)
    Inguinal hernia, obstructive 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Intestinal angina 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Intestinal obstruction 2/215 (0.9%) 5/211 (2.4%) 3/170 (1.8%)
    Intestinal perforation 0/215 (0%) 0/211 (0%) 2/170 (1.2%)
    Lip oedema 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Lower gastrointestinal haemorrhage 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Melaena 0/215 (0%) 1/211 (0.5%) 1/170 (0.6%)
    Nausea 4/215 (1.9%) 4/211 (1.9%) 2/170 (1.2%)
    Oesophageal spasm 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Pancreatitis acute 1/215 (0.5%) 0/211 (0%) 1/170 (0.6%)
    Pneumatosis intestinalis 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Rectal haemorrhage 3/215 (1.4%) 0/211 (0%) 1/170 (0.6%)
    Retroperitoneal haematoma 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Small intestinal haemorrhage 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Small intestinal obstruction 8/215 (3.7%) 3/211 (1.4%) 4/170 (2.4%)
    Small intestinal stenosis 2/215 (0.9%) 0/211 (0%) 0/170 (0%)
    Stomatitis 1/215 (0.5%) 0/211 (0%) 1/170 (0.6%)
    Subileus 3/215 (1.4%) 2/211 (0.9%) 0/170 (0%)
    Upper gastrointestinal haemorrhage 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Vomiting 7/215 (3.3%) 6/211 (2.8%) 5/170 (2.9%)
    General disorders
    Asthenia 2/215 (0.9%) 3/211 (1.4%) 1/170 (0.6%)
    Brain death 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Chest pain 1/215 (0.5%) 1/211 (0.5%) 1/170 (0.6%)
    Chills 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Face oedema 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Fatigue 2/215 (0.9%) 1/211 (0.5%) 0/170 (0%)
    General physical health deterioration 6/215 (2.8%) 3/211 (1.4%) 5/170 (2.9%)
    Generalised oedema 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Hypothermia 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Malaise 2/215 (0.9%) 1/211 (0.5%) 0/170 (0%)
    Non-cardiac chest pain 3/215 (1.4%) 0/211 (0%) 0/170 (0%)
    Oedema peripheral 3/215 (1.4%) 4/211 (1.9%) 3/170 (1.8%)
    Pain 1/215 (0.5%) 2/211 (0.9%) 0/170 (0%)
    Performance status decreased 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Pyrexia 8/215 (3.7%) 3/211 (1.4%) 3/170 (1.8%)
    Spinal pain 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Sudden death 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Hepatobiliary disorders
    Bile duct obstruction 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Cholangitis 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Cholangitis acute 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Cholecystitis 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Cholecystitis acute 2/215 (0.9%) 0/211 (0%) 1/170 (0.6%)
    Cholelithiasis 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Cholestasis 1/215 (0.5%) 0/211 (0%) 1/170 (0.6%)
    Hepatic failure 2/215 (0.9%) 1/211 (0.5%) 0/170 (0%)
    Hepatic function abnormal 1/215 (0.5%) 1/211 (0.5%) 0/170 (0%)
    Hepatocellular injury 1/215 (0.5%) 0/211 (0%) 1/170 (0.6%)
    Hepatotoxicity 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Hyperbilirubinaemia 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Jaundice 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Immune system disorders
    Drug hypersensitivity 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Infections and infestations
    Abdominal wall abscess 0/215 (0%) 1/211 (0.5%) 1/170 (0.6%)
    Abscess intestinal 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Arthritis infective 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Aspergillosis 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Bacteraemia 1/215 (0.5%) 1/211 (0.5%) 0/170 (0%)
    Bronchiolitis 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Bronchopneumonia 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Cellulitis 3/215 (1.4%) 0/211 (0%) 0/170 (0%)
    Cholecystitis infective 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Clostridium difficile colitis 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Diverticulitis 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Erysipelas 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Escherichia sepsis 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Gastroenteritis 2/215 (0.9%) 1/211 (0.5%) 2/170 (1.2%)
    Gastroenteritis viral 0/215 (0%) 1/211 (0.5%) 1/170 (0.6%)
    Herpes zoster 1/215 (0.5%) 0/211 (0%) 1/170 (0.6%)
    Infected skin ulcer 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Infection 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Influenza 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Localised infection 0/215 (0%) 0/211 (0%) 2/170 (1.2%)
    Lung infection 1/215 (0.5%) 0/211 (0%) 2/170 (1.2%)
    Osteomyelitis 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Peritonitis 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Pneumonia 9/215 (4.2%) 1/211 (0.5%) 5/170 (2.9%)
    Pneumonia viral 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Sepsis 2/215 (0.9%) 1/211 (0.5%) 4/170 (2.4%)
    Sinusitis 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Staphylococcal infection 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Urinary tract infection 2/215 (0.9%) 2/211 (0.9%) 0/170 (0%)
    Urinary tract infection bacterial 0/215 (0%) 2/211 (0.9%) 0/170 (0%)
    Urosepsis 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Injury, poisoning and procedural complications
    Bone fissure 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Femoral neck fracture 1/215 (0.5%) 1/211 (0.5%) 0/170 (0%)
    Fractured sacrum 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Heat exhaustion 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Hip fracture 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Humerus fracture 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Joint injury 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Post procedural complication 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Post procedural haemorrhage 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Pulmonary contusion 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Rib fracture 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Scapula fracture 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Seroma 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Toxicity to various agents 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Traumatic intracranial haemorrhage 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Investigations
    Alanine aminotransferase increased 1/215 (0.5%) 0/211 (0%) 1/170 (0.6%)
    Aspartate aminotransferase increased 2/215 (0.9%) 0/211 (0%) 1/170 (0.6%)
    Blood alkaline phosphatase increased 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Blood creatinine increased 2/215 (0.9%) 0/211 (0%) 4/170 (2.4%)
    Blood urea increased 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Cardiac murmur 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Coagulation time shortened 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Heart rate increased 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Lipase increased 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Weight decreased 1/215 (0.5%) 1/211 (0.5%) 0/170 (0%)
    Metabolism and nutrition disorders
    Cachexia 2/215 (0.9%) 0/211 (0%) 0/170 (0%)
    Decreased appetite 0/215 (0%) 1/211 (0.5%) 2/170 (1.2%)
    Dehydration 7/215 (3.3%) 1/211 (0.5%) 3/170 (1.8%)
    Failure to thrive 0/215 (0%) 1/211 (0.5%) 1/170 (0.6%)
    Hypercalcaemia 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Hyperglycaemia 2/215 (0.9%) 0/211 (0%) 3/170 (1.8%)
    Hypocalcaemia 2/215 (0.9%) 0/211 (0%) 1/170 (0.6%)
    Hypoglycaemia 2/215 (0.9%) 1/211 (0.5%) 0/170 (0%)
    Hypokalaemia 4/215 (1.9%) 0/211 (0%) 1/170 (0.6%)
    Hypomagnesaemia 2/215 (0.9%) 0/211 (0%) 0/170 (0%)
    Hypophosphataemia 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Malnutrition 1/215 (0.5%) 2/211 (0.9%) 0/170 (0%)
    Metabolic acidosis 2/215 (0.9%) 0/211 (0%) 1/170 (0.6%)
    Type 2 diabetes mellitus 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Arthritis 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Back pain 0/215 (0%) 4/211 (1.9%) 1/170 (0.6%)
    Bone pain 2/215 (0.9%) 0/211 (0%) 0/170 (0%)
    Flank pain 2/215 (0.9%) 1/211 (0.5%) 0/170 (0%)
    Muscle spasms 1/215 (0.5%) 0/211 (0%) 1/170 (0.6%)
    Musculoskeletal chest pain 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Neck pain 0/215 (0%) 1/211 (0.5%) 1/170 (0.6%)
    Osteoarthritis 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Osteoporosis 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Pain in extremity 2/215 (0.9%) 0/211 (0%) 0/170 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell type acute leukaemia 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Brain neoplasm malignant 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Cancer pain 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Glioblastoma 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Lung infiltration malignant 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Malignant pleural effusion 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Metastatic pain 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Pancreatic carcinoma 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Tumour compression 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Nervous system disorders
    Cerebral ischaemia 0/215 (0%) 1/211 (0.5%) 1/170 (0.6%)
    Cerebrovascular accident 1/215 (0.5%) 0/211 (0%) 1/170 (0.6%)
    Convulsion 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Depressed level of consciousness 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Dizziness postural 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Encephalopathy 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Facial paresis 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Grand mal convulsion 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Headache 0/215 (0%) 2/211 (0.9%) 0/170 (0%)
    Hypoaesthesia 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Intracranial haematoma 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Lethargy 1/215 (0.5%) 1/211 (0.5%) 0/170 (0%)
    Mental impairment 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Metabolic encephalopathy 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Radicular syndrome 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Radiculopathy 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Sciatica 1/215 (0.5%) 1/211 (0.5%) 0/170 (0%)
    Subarachnoid haemorrhage 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Syncope 2/215 (0.9%) 1/211 (0.5%) 2/170 (1.2%)
    Psychiatric disorders
    Confusional state 1/215 (0.5%) 1/211 (0.5%) 1/170 (0.6%)
    Depression 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Hallucination 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Mental status changes 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Renal and urinary disorders
    Bladder tamponade 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Calculus ureteric 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Calculus urinary 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Eosinophilic cystitis 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Haematuria 0/215 (0%) 1/211 (0.5%) 1/170 (0.6%)
    Hydronephrosis 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Nephrolithiasis 1/215 (0.5%) 1/211 (0.5%) 2/170 (1.2%)
    Renal failure 4/215 (1.9%) 0/211 (0%) 3/170 (1.8%)
    Renal failure acute 3/215 (1.4%) 1/211 (0.5%) 1/170 (0.6%)
    Renal failure chronic 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Renal impairment 1/215 (0.5%) 0/211 (0%) 1/170 (0.6%)
    Renal infarct 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Ureteric obstruction 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Urinary bladder haemorrhage 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Urinary retention 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Reproductive system and breast disorders
    Testicular swelling 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Atelectasis 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Cough 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Dyspnoea 8/215 (3.7%) 2/211 (0.9%) 1/170 (0.6%)
    Granulomatous pneumonitis 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Haemoptysis 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Hypoxia 3/215 (1.4%) 1/211 (0.5%) 0/170 (0%)
    Interstitial lung disease 3/215 (1.4%) 0/211 (0%) 1/170 (0.6%)
    Laryngeal oedema 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Lung infiltration 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Organising pneumonia 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Pleural effusion 3/215 (1.4%) 0/211 (0%) 2/170 (1.2%)
    Pneumonitis 2/215 (0.9%) 0/211 (0%) 2/170 (1.2%)
    Pneumothorax 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Pulmonary embolism 6/215 (2.8%) 1/211 (0.5%) 3/170 (1.8%)
    Pulmonary hypertension 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Respiratory arrest 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Respiratory distress 0/215 (0%) 0/211 (0%) 1/170 (0.6%)
    Respiratory failure 1/215 (0.5%) 1/211 (0.5%) 0/170 (0%)
    Tachypnoea 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Skin and subcutaneous tissue disorders
    Angioedema 1/215 (0.5%) 0/211 (0%) 1/170 (0.6%)
    Palmar-plantar erythrodysaesthesia syndrome 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Vascular disorders
    Aortic dissection 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Deep vein thrombosis 1/215 (0.5%) 1/211 (0.5%) 2/170 (1.2%)
    Flushing 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Haematoma 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Hypertension 1/215 (0.5%) 1/211 (0.5%) 1/170 (0.6%)
    Hypotension 0/215 (0%) 1/211 (0.5%) 0/170 (0%)
    Jugular vein thrombosis 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Orthostatic hypotension 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Phlebitis 1/215 (0.5%) 0/211 (0%) 0/170 (0%)
    Other (Not Including Serious) Adverse Events
    Everolimus + Octreotide Placebo + Octreotide Everolimus Open Label
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 214/215 (99.5%) 194/211 (91.9%) 162/170 (95.3%)
    Blood and lymphatic system disorders
    Anaemia 58/215 (27%) 21/211 (10%) 34/170 (20%)
    Leukopenia 16/215 (7.4%) 2/211 (0.9%) 2/170 (1.2%)
    Neutropenia 18/215 (8.4%) 3/211 (1.4%) 13/170 (7.6%)
    Thrombocytopenia 34/215 (15.8%) 1/211 (0.5%) 15/170 (8.8%)
    Gastrointestinal disorders
    Abdominal distension 12/215 (5.6%) 12/211 (5.7%) 10/170 (5.9%)
    Abdominal pain 65/215 (30.2%) 68/211 (32.2%) 43/170 (25.3%)
    Abdominal pain upper 22/215 (10.2%) 26/211 (12.3%) 16/170 (9.4%)
    Aphthous stomatitis 28/215 (13%) 3/211 (1.4%) 15/170 (8.8%)
    Ascites 17/215 (7.9%) 9/211 (4.3%) 8/170 (4.7%)
    Constipation 31/215 (14.4%) 22/211 (10.4%) 17/170 (10%)
    Diarrhoea 114/215 (53%) 77/211 (36.5%) 77/170 (45.3%)
    Dry mouth 22/215 (10.2%) 6/211 (2.8%) 7/170 (4.1%)
    Dysphagia 15/215 (7%) 5/211 (2.4%) 4/170 (2.4%)
    Flatulence 27/215 (12.6%) 28/211 (13.3%) 12/170 (7.1%)
    Haemorrhoids 17/215 (7.9%) 9/211 (4.3%) 9/170 (5.3%)
    Mouth ulceration 17/215 (7.9%) 5/211 (2.4%) 11/170 (6.5%)
    Nausea 92/215 (42.8%) 63/211 (29.9%) 60/170 (35.3%)
    Stomatitis 109/215 (50.7%) 25/211 (11.8%) 63/170 (37.1%)
    Vomiting 69/215 (32.1%) 40/211 (19%) 30/170 (17.6%)
    General disorders
    Asthenia 51/215 (23.7%) 30/211 (14.2%) 30/170 (17.6%)
    Chills 15/215 (7%) 10/211 (4.7%) 5/170 (2.9%)
    Fatigue 103/215 (47.9%) 91/211 (43.1%) 63/170 (37.1%)
    Oedema peripheral 92/215 (42.8%) 47/211 (22.3%) 62/170 (36.5%)
    Pyrexia 42/215 (19.5%) 21/211 (10%) 32/170 (18.8%)
    Infections and infestations
    Bronchitis 11/215 (5.1%) 7/211 (3.3%) 8/170 (4.7%)
    Nasopharyngitis 19/215 (8.8%) 26/211 (12.3%) 19/170 (11.2%)
    Sinusitis 12/215 (5.6%) 9/211 (4.3%) 17/170 (10%)
    Upper respiratory tract infection 27/215 (12.6%) 12/211 (5.7%) 11/170 (6.5%)
    Urinary tract infection 27/215 (12.6%) 16/211 (7.6%) 19/170 (11.2%)
    Investigations
    Alanine aminotransferase increased 9/215 (4.2%) 6/211 (2.8%) 10/170 (5.9%)
    Aspartate aminotransferase increased 11/215 (5.1%) 8/211 (3.8%) 8/170 (4.7%)
    Blood creatinine increased 15/215 (7%) 5/211 (2.4%) 8/170 (4.7%)
    Weight decreased 59/215 (27.4%) 31/211 (14.7%) 33/170 (19.4%)
    Metabolism and nutrition disorders
    Decreased appetite 64/215 (29.8%) 36/211 (17.1%) 33/170 (19.4%)
    Dehydration 17/215 (7.9%) 12/211 (5.7%) 9/170 (5.3%)
    Hypercholesterolaemia 17/215 (7.9%) 6/211 (2.8%) 7/170 (4.1%)
    Hyperglycaemia 42/215 (19.5%) 9/211 (4.3%) 24/170 (14.1%)
    Hyperlipidaemia 15/215 (7%) 3/211 (1.4%) 4/170 (2.4%)
    Hypocalcaemia 17/215 (7.9%) 4/211 (1.9%) 11/170 (6.5%)
    Hypokalaemia 50/215 (23.3%) 8/211 (3.8%) 27/170 (15.9%)
    Hypomagnesaemia 15/215 (7%) 5/211 (2.4%) 6/170 (3.5%)
    Hypophosphataemia 11/215 (5.1%) 6/211 (2.8%) 8/170 (4.7%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 38/215 (17.7%) 28/211 (13.3%) 19/170 (11.2%)
    Back pain 33/215 (15.3%) 41/211 (19.4%) 18/170 (10.6%)
    Muscle spasms 17/215 (7.9%) 13/211 (6.2%) 10/170 (5.9%)
    Musculoskeletal chest pain 18/215 (8.4%) 7/211 (3.3%) 11/170 (6.5%)
    Musculoskeletal pain 21/215 (9.8%) 21/211 (10%) 8/170 (4.7%)
    Myalgia 16/215 (7.4%) 14/211 (6.6%) 8/170 (4.7%)
    Pain in extremity 32/215 (14.9%) 24/211 (11.4%) 19/170 (11.2%)
    Nervous system disorders
    Dizziness 29/215 (13.5%) 24/211 (11.4%) 12/170 (7.1%)
    Dysgeusia 42/215 (19.5%) 12/211 (5.7%) 30/170 (17.6%)
    Headache 65/215 (30.2%) 49/211 (23.2%) 32/170 (18.8%)
    Psychiatric disorders
    Anxiety 14/215 (6.5%) 14/211 (6.6%) 12/170 (7.1%)
    Depression 16/215 (7.4%) 11/211 (5.2%) 12/170 (7.1%)
    Insomnia 20/215 (9.3%) 15/211 (7.1%) 12/170 (7.1%)
    Renal and urinary disorders
    Dysuria 12/215 (5.6%) 5/211 (2.4%) 7/170 (4.1%)
    Pollakiuria 10/215 (4.7%) 6/211 (2.8%) 11/170 (6.5%)
    Respiratory, thoracic and mediastinal disorders
    Cough 59/215 (27.4%) 32/211 (15.2%) 38/170 (22.4%)
    Dyspnoea 59/215 (27.4%) 19/211 (9%) 27/170 (15.9%)
    Dyspnoea exertional 9/215 (4.2%) 11/211 (5.2%) 7/170 (4.1%)
    Epistaxis 33/215 (15.3%) 5/211 (2.4%) 24/170 (14.1%)
    Oropharyngeal pain 20/215 (9.3%) 6/211 (2.8%) 13/170 (7.6%)
    Pleural effusion 12/215 (5.6%) 6/211 (2.8%) 7/170 (4.1%)
    Pneumonitis 20/215 (9.3%) 2/211 (0.9%) 6/170 (3.5%)
    Skin and subcutaneous tissue disorders
    Alopecia 13/215 (6%) 4/211 (1.9%) 7/170 (4.1%)
    Dry skin 23/215 (10.7%) 5/211 (2.4%) 9/170 (5.3%)
    Erythema 17/215 (7.9%) 4/211 (1.9%) 7/170 (4.1%)
    Hyperhidrosis 9/215 (4.2%) 13/211 (6.2%) 5/170 (2.9%)
    Onychoclasis 11/215 (5.1%) 1/211 (0.5%) 10/170 (5.9%)
    Pruritus 42/215 (19.5%) 12/211 (5.7%) 18/170 (10.6%)
    Rash 88/215 (40.9%) 37/211 (17.5%) 59/170 (34.7%)
    Vascular disorders
    Flushing 20/215 (9.3%) 20/211 (9.5%) 6/170 (3.5%)
    Hypertension 24/215 (11.2%) 21/211 (10%) 16/170 (9.4%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.

    Results Point of Contact

    Name/Title Study Director
    Organization Novartis Pharmaceuticals
    Phone 862-778-8300
    Email
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT00412061
    Other Study ID Numbers:
    • CRAD001C2325
    • 2006-004507-18
    First Posted:
    Dec 15, 2006
    Last Update Posted:
    Nov 21, 2014
    Last Verified:
    Nov 1, 2014