RADIANT-3: Efficacy and Safety of Everolimus (RAD001) Compared to Placebo in Patients With Advanced Neuroendocrine Tumors
Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT00510068
Collaborator
(none)
410
82
2
80
5
0.1
Study Details
Study Description
Brief Summary
The purpose of this study was to evaluate progression free survival in those participants assigned everolimus 10 mg/day plus Best Supportive Care versus those assigned to placebo plus Best Supportive Care in Advanced Neuroendocrine Tumors of pancreatic origin.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
410 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized Double-blind Phase III Study of RAD001 10 mg/d Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Pancreatic Neuroendocrine Tumor (NET)
Study Start Date
:
Jul 1, 2007
Actual Primary Completion Date
:
Feb 1, 2010
Actual Study Completion Date
:
Mar 1, 2014
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Everolimus 10 mg/day Participants received 10 mg per day of Everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). |
Drug: Everolimus
A 10-mg dose of everolimus was given by continuous oral daily dosing of two 5-mg tablets.
Other Names:
|
| Placebo Comparator: Placebo Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
Drug: Everolimus Placebo
a 10-mg dose of matching placebo to Everolimus was given by continuous oral daily dosing of two 5-mg tablets.
|
Outcome Measures
Primary Outcome Measures
- Time to Progression Free Survival (PFS) Based as Per Investigator Using Kaplan-Meier Methodology [Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010]
Progression of disease is defined as the time from study start to the date of first documented progression of disease or death due to any cause. Progression of disease is defined by RECIST criteria: Progression = 20% increase in the sum of the longest diameter of all target lesions, from the smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions.
Secondary Outcome Measures
- Percentage of Participants With Objective Response Rate ( CR {Complete Response} OR PR {Partial Response}) [Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010]
Objective Response defined by RECIST criteria: Partial response (PR) must have ≥ 30% decrease in the sum of the longest diameter of all target lesions, from the baseline sum. Complete response (CR) must have disappearance of all target and non-target lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments within 4 weeks . Progression = 20% increase in the sum of the longest diameter of all target lesions, from the smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions
- Overall Survival [Baseline, to death- no time limit]
Overall survival (OS) was defined as the time from date of randomization to the date of death due to any cause. Analyses were performed using all deaths in the FAS population regardless of whether they were observed during the double-blind treatment period, the open-label treatment period, the post-treatment evaluations, or the survival follow-up period.
- Progression Free Survival According to Ki-67 Levels Categorized as: Less Than or Equal to 2%, > 2% to Less Than or Equal to 5% and > 5% [Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010]
The level of Ki 67 expression for evaluable tumor samples were analyzed towards progression free survival (PFS) as per local investigator assessment. The Ki-67 protein is a cellular marker for proliferation. It is strictly associated with cell proliferation. During interphase, the Ki-67 antigen can be exclusively detected within the cell nucleus, whereas in mitosis most of the protein is relocated to the surface of the chromosomes. Baseline Ki 67 levels were categorized as: less than or equal to 2%, > 2% to less than or equal to 5% and > 5%.
- Progression Free Survival According to Chromogramin A Tumor Marker (CgA) Baseline Level and According to CgA Early Response [Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010]
Baseline levels of serum CgA SE were characterized towards progression free survival (PFS) as per local investigator assessment, relative to the upper limited of normal (ULN). CgA levels exceeding 2 x ULN were considered to be 'Elevated' otherwise considered as "Non-elevated". An 'early response' (applicable to only those patients with elevated levels at baseline) was defined as a decrease of greater than or equal to 30% from baseline to Cycle 2 Day 1 or normalization by Cycle 2 Day 1. CgA is widely expressed in well-differentiated pancreatic NET. CgA is present in the secretory granules of neuroendocrine cells. Pancreatic NET patients often present with elevated circulating levels of CgA in their blood. Baseline levels of these biomarkers are considered as prognostic factors.
- Progression Free Survival According to Neuron Specific Enolase Tumor Marker (NSE) Baseline Level and According to NSE Early Response [Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010]
Baseline levels of serum NSE were characterized towards PFS as per local investigator assessment, relative to the upper limited of normal (ULN). NSE levels exceeding ULN were considered to be 'Elevated' otherwise considered as "Non-elevated". An 'early response' (applicable to only those patients with elevated levels at baseline) was defined as a decrease of greater than or equal to 30% from baseline to Cycle 2 Day 1 or normalization by Cycle 2 Day 1. NSE is widely expressed in well-differentiated pancreatic NET. NSE is usually expressed in the cytoplasm. Pancreatic NET patients often present with elevated circulating levels of NSE in their blood. Baseline levels of these biomarkers are considered as prognostic factors.
- Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) [on or after the start of double-blind study medication until no later than 28 days after double-blind study medication discontinuation]
Adverse events 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. Serious adverse events 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.
- Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) (Open-label Period) [on or after the start of open-label study medication until no later than 28 days after open-label study medication discontinuation]
Adverse events 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. Serious adverse events 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.
- Evaluation of Pharmacokinetics (PK) Parameter: AUC0-t Last [Day 1 of every cycle (28 days/cycle) throughout the study]
The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. This PK parameter is area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-t last).
- Evaluation of Pharmacokinetics (PK) Parameters: Cmax, Cmin [Day 1 of every cycle (28 days/cycle) throughout the study]
The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. The PK parameter: maximum (peak) drug concentration (Cmax) and minimum (trough) drug concentration (Cmin).
- Evaluation of Pharmacokinetics (PK) Parameter: CL/F [Day 1 of every cycle (28 days/cycle) throughout the study]
The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. The PK parameter clearance of distribution expressed as a function of bioavailability (CL/F).
- Evaluation of Pharmacokinetics (PK) Parameter: Tmax -Time to Maximum (Peak) Drug Concentration [Day 1 of every cycle (28 days/cycle) throughout the study]
The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. Values for tmax where summarized in median (range).
- Analysis of Time to Definitive Deterioration of WHO Performance Status Using Kaplan-Meier [3 months, 6 months]
Time to definitive worsening is defined as a definitive increase in performance status from a baseline of 0 or 1 to WHO >= 2, or from a baseline value of 2 to WHO >= 3. If no earlier deterioration, patients were censored at the end of follow-up or at the start of further antineoplastic therapy. Rates of patients with no deterioration at 3 and 6 months were computed using Kaplan-meier method. Grade 0: Able to carry out all activity without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory & able to do light work; Grade 2: Ambulatory & capable of all self-care but unable to carry out any work. Up & about more than 50% of waking hours; Grade 3: Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; Grade 4: Completely disabled & cannot carry on any self-care; totally confined to bed or chair.
- Plasma Angiogenesis Marker: Basic Fibroblast Growth Factor (bFGF) [Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1]
This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.
- Plasma Angiogenesis Marker: Placental Growth Factor (PLGF) [Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1]
This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.
- Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 1 (sVEGFR1) [Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1]
This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.
- Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR2) [Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1]
This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.
- Plasma Angiogenesis Marker: Vascular Endothelial Growth Factor (VEGF) [Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1]
This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion criteria:
-
Patients must have advanced (unresectable or metastatic) biopsy-proven pancreatic NET
-
Measurable disease by radiologic assessment
-
Adequate blood work
-
Performance Status 0-2 : Ability to be out of bed most of the time
-
Adult male or female patients ≥ 18 years of age
-
Women of childbearing potential must have a negative serum pregnancy test
-
Written informed consent from patients must be obtained in accordance to local guidelines
Exclusion criteria:
-
Patients with severe kind of (poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma) cancer are not eligible
-
Other chemotherapy, immunotherapy or radiotherapy within 4 weeks prior to starting this trial
-
Hepatic artery procedure called embolization within the last 6 months (1 month if there are other sites of measurable disease), or cryoablation/ radiofrequency ablation of hepatic metastasis within 2 months of enrollment
-
Prior therapy with the same kind of medication (mTOR inhibitors: sirolimus, temsirolimus, everolimus).
-
Uncontrolled diabetes mellitus Patients who have any severe and/or uncontrolled medical conditions such as:
-
Patients receiving chronic treatment with corticosteroids or another immunosuppressive agent
-
Patients with a known history of HIV seropositivity
-
No other prior or concurrent cancer at the time enrolling to this trial
Other protocol defined inclusion/ exclusion criteria applied
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of South Alabama / Mitchell Cancer Institute Deptof Mitchell Cancer Inst(2) | Mobile | Alabama | United States | 36688 |
| 2 | Pacific Cancer Medical Center, Inc. | Anaheim | California | United States | 92801 |
| 3 | Cedars Sinai Medical Center SC-2 | Los Angeles | California | United States | 90048 |
| 4 | University of California at Los Angeles UCLA (3) | Los Angeles | California | United States | 90095 |
| 5 | University of California San Francisco Dept. of UCSF Comp. Cancer | San Francisco | California | United States | 94143-0128 |
| 6 | Kaiser Permanente Northwest Franklin Medical Offices | Denver | Colorado | United States | |
| 7 | H. Lee Moffitt Cancer Center & Research Institute Malignant Hematology Clinic | Tampa | Florida | United States | 33612 |
| 8 | Indiana University Health Goshen Center for Cancer Dept. of Indiana Univ. Cancer | Indianapolis | Indiana | United States | 46202 |
| 9 | University of Iowa Medical Center Dept. of Iowa Medical Center | Iowa City | Iowa | United States | 52242 |
| 10 | University of Louisville / James Graham Brown Cancer Center SC | Louisville | Kentucky | United States | 40202 |
| 11 | LSU HEALTH SCIENCES CENTER/ LSU SCHOOL OF MEDICINE Dept. of Neuroendocrine Clinic | New Orleans | Louisiana | United States | 70115 |
| 12 | Boston Medical Center BMC | Boston | Massachusetts | United States | 02118 |
| 13 | Wayne State University/Karmanos Cancer Institute Dept.of KarmanosCancerInst (4) | Detroit | Michigan | United States | 48201 |
| 14 | Mayo Clinic - Rochester | Rochester | Minnesota | United States | 55905 |
| 15 | Littleton Regional Hospital Dept. of Hematology/Oncology | Littleton | New Hampshire | United States | 03561 |
| 16 | Columbia University Medical Center- New York Presbyterian Dept. of Columbia Med. Center | New York | New York | United States | 10032 |
| 17 | Levine Cancer Institute | Charlotte | North Carolina | United States | 28203 |
| 18 | Ohio State Comprehensive Cancer Center/James Cancer Hospital Dept. of OHSU Medical Center | Columbus | Ohio | United States | 43210 |
| 19 | Oregon Health & Science University Dept. of OHSU (3) | Portland | Oregon | United States | 97239 |
| 20 | St. Luke's Hospital and Health Network St. Luke's Cancer Network | Bethlehem | Pennsylvania | United States | |
| 21 | Fox Chase Cancer Center | Philadelphia | Pennsylvania | United States | 19111-2497 |
| 22 | University of Pittsburgh Medical Center Hillman Cancer Center | Pittsburgh | Pennsylvania | United States | 15213 |
| 23 | The Center for Cancer and Blood Disorders | Fort Worth | Texas | United States | 76104 |
| 24 | University of Texas/MD Anderson Cancer Center Dept of MD Anderson CancerCent | Houston | Texas | United States | 77030-4009 |
| 25 | Novartis Investigative Site | Bruxelles | Belgium | 1070 | |
| 26 | Novartis Investigative Site | Bruxelles | Belgium | 1200 | |
| 27 | Novartis Investigative Site | Leuven | Belgium | 3000 | |
| 28 | Novartis Investigative Site | Fortaleza | CE | Brazil | 60430-370 |
| 29 | Novartis Investigative Site | Calgary | Alberta | Canada | T2N 4N2 |
| 30 | Novartis Investigative Site | Edmonton | Alberta | Canada | T6G 1Z2 |
| 31 | Novartis Investigative Site | London | Ontario | Canada | N6A 4L6 |
| 32 | Novartis Investigative Site | Montreal | Quebec | Canada | H1T 2M4 |
| 33 | Novartis Investigative Site | Montreal | Quebec | Canada | H3A 1A1 |
| 34 | Novartis Investigative Site | Besancon Cedex | France | 25030 | |
| 35 | Novartis Investigative Site | Clichy | France | 92110 | |
| 36 | Novartis Investigative Site | Dijon | France | 21079 | |
| 37 | Novartis Investigative Site | Lille Cedex | France | 59020 | |
| 38 | Novartis Investigative Site | Lyon | France | 69437 | |
| 39 | Novartis Investigative Site | Marseille cedex 05 | France | 13385 | |
| 40 | Novartis Investigative Site | Montpellier Cedex 5 | France | 34298 | |
| 41 | Novartis Investigative Site | Paris Cedex 13 | France | 75651 | |
| 42 | Novartis Investigative Site | Paris | France | 75015 | |
| 43 | Novartis Investigative Site | Reims | France | 51092 | |
| 44 | Novartis Investigative Site | Strasbourg | France | 67098 | |
| 45 | Novartis Investigative Site | Toulouse Cedex 4 | France | 31054 | |
| 46 | Novartis Investigative Site | Villejuif Cedex | France | 94805 | |
| 47 | Novartis Investigative Site | Bad Berka | Germany | 99438 | |
| 48 | Novartis Investigative Site | Berlin | Germany | 13353 | |
| 49 | Novartis Investigative Site | Mainz | Germany | 55131 | |
| 50 | Novartis Investigative Site | Marburg | Germany | 35033 | |
| 51 | Novartis Investigative Site | München | Germany | 81377 | |
| 52 | Novartis Investigative Site | Athens | GR | Greece | 115 27 |
| 53 | Novartis Investigative Site | Athens | Greece | GR-115 22 | |
| 54 | Novartis Investigative Site | Bologna | BO | Italy | 40138 |
| 55 | Novartis Investigative Site | Milano | MI | Italy | 20132 |
| 56 | Novartis Investigative Site | Milano | MI | Italy | 20141 |
| 57 | Novartis Investigative Site | Milano | MI | Italy | 20162 |
| 58 | Novartis Investigative Site | Modena | MO | Italy | 41100 |
| 59 | Novartis Investigative Site | Pisa | PI | Italy | 56124 |
| 60 | Novartis Investigative Site | Kashiwa | Chiba | Japan | |
| 61 | Novartis Investigative Site | Fukuoka-city | Fukuoka | Japan | 812-8582 |
| 62 | Novartis Investigative Site | Chuo-ku | Tokyo | Japan | |
| 63 | Novartis Investigative Site | Seoul | Korea | Korea, Republic of | 110 744 |
| 64 | Novartis Investigative Site | Seoul | Korea | Korea, Republic of | 120-752 |
| 65 | Novartis Investigative Site | Seoul | Korea | Korea, Republic of | 135-710 |
| 66 | Novartis Investigative Site | Seoul | Korea, Republic of | 738-736 | |
| 67 | Novartis Investigative Site | Groningen | Netherlands | 9713 GZ | |
| 68 | Novartis Investigative Site | Martin | Slovak Republic | Slovakia | 036 59 |
| 69 | Novartis Investigative Site | Barcelona | Catalunya | Spain | 08035 |
| 70 | Novartis Investigative Site | Hospitalet de LLobregat | Cataluña | Spain | 08907 |
| 71 | Novartis Investigative Site | Uppsala | Sweden | SE-751 85 | |
| 72 | Novartis Investigative Site | Zurich | Switzerland | 8091 | |
| 73 | Novartis Investigative Site | Taipei | Taiwan, ROC | Taiwan | 112 |
| 74 | Novartis Investigative Site | Kaohsiung | Taiwan | 807 | |
| 75 | Novartis Investigative Site | Lin-Ko | Taiwan | 33305 | |
| 76 | Novartis Investigative Site | Taipei | Taiwan | 10002 | |
| 77 | Novartis Investigative Site | Bangkok | Thailand | 10400 | |
| 78 | Novartis Investigative Site | Songkla | Thailand | 90110 | |
| 79 | Novartis Investigative Site | Withington | Greater Manchester | United Kingdom | M20 4BX |
| 80 | Novartis Investigative Site | Glasgow | United Kingdom | G12 0YN | |
| 81 | Novartis Investigative Site | London | United Kingdom | EC1A 7BE | |
| 82 | Novartis Investigative Site | London | United Kingdom | SE5 9RS |
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:
NCT00510068
Other Study ID Numbers:
- CRAD001C2324
- 2006-006819-75
First Posted:
Aug 1, 2007
Last Update Posted:
Jul 1, 2015
Last Verified:
Jun 1, 2015
Keywords provided by Novartis Pharmaceuticals
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Everolimus 10 mg/Day | Placebo |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
| Period Title: Double-blind Period | ||
| STARTED | 207 | 203 |
| Safety Population | 204 | 203 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 207 | 203 |
| Period Title: Double-blind Period | ||
| STARTED | 225 | 0 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 225 | 0 |
Baseline Characteristics
| Arm/Group Title | Everolimus 10 mg/Day | Placebo | Total |
|---|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). | Total of all reporting groups |
| Overall Participants | 207 | 203 | 410 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
57.1
(12.2)
|
56.2
(11.4)
|
56.6
(11.8)
|
| Age, Customized (Number) [Number] | |||
| <65 years |
146
70.5%
|
153
75.4%
|
299
72.9%
|
| >=65 years |
61
29.5%
|
50
24.6%
|
111
27.1%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
97
46.9%
|
86
42.4%
|
183
44.6%
|
| Male |
110
53.1%
|
117
57.6%
|
227
55.4%
|
| Race/Ethnicity, Customized (Number) [Number] | |||
| Caucasian |
156
75.4%
|
166
81.8%
|
322
78.5%
|
| Asian |
40
19.3%
|
34
16.7%
|
74
18%
|
| Black |
9
4.3%
|
2
1%
|
11
2.7%
|
| Other |
2
1%
|
1
0.5%
|
3
0.7%
|
Outcome Measures
| Title | Time to Progression Free Survival (PFS) Based as Per Investigator Using Kaplan-Meier Methodology |
|---|---|
| Description | Progression of disease is defined as the time from study start to the date of first documented progression of disease or death due to any cause. Progression of disease is defined by RECIST criteria: Progression = 20% increase in the sum of the longest diameter of all target lesions, from the smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions. |
| 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, 17 August 2007, until cut-off date 28 February 2010 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consists of all patients who were randomized. |
| Arm/Group Title | Everolimus 10 mg/Day | Placebo |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 207 | 203 |
| Median (95% Confidence Interval) [Months] |
11.04
|
4.60
|
| Title | Percentage of Participants With Objective Response Rate ( CR {Complete Response} OR PR {Partial Response}) |
|---|---|
| Description | Objective Response defined by RECIST criteria: Partial response (PR) must have ≥ 30% decrease in the sum of the longest diameter of all target lesions, from the baseline sum. Complete response (CR) must have disappearance of all target and non-target lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments within 4 weeks . Progression = 20% increase in the sum of the longest diameter of all target lesions, from the smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions |
| 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, 17 August 2007, until cut-off date 28 February 2010 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consists of all patients who were randomized. |
| Arm/Group Title | Everolimus 10 mg/Day | Placebo |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 207 | 203 |
| Number (95% Confidence Interval) [Percentage of participants] |
4.8
2.3%
|
2.0
1%
|
| Title | Overall Survival |
|---|---|
| Description | Overall survival (OS) was defined as the time from date of randomization to the date of death due to any cause. Analyses were performed using all deaths in the FAS population regardless of whether they were observed during the double-blind treatment period, the open-label treatment period, the post-treatment evaluations, or the survival follow-up period. |
| Time Frame | Baseline, to death- no time limit |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) included all randomized patients. |
| Arm/Group Title | Everolimus 10 mg/Day | Placebo |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 207 | 203 |
| Median (95% Confidence Interval) [Months] |
44.02
|
37.68
|
| Title | Progression Free Survival According to Ki-67 Levels Categorized as: Less Than or Equal to 2%, > 2% to Less Than or Equal to 5% and > 5% |
|---|---|
| Description | The level of Ki 67 expression for evaluable tumor samples were analyzed towards progression free survival (PFS) as per local investigator assessment. The Ki-67 protein is a cellular marker for proliferation. It is strictly associated with cell proliferation. During interphase, the Ki-67 antigen can be exclusively detected within the cell nucleus, whereas in mitosis most of the protein is relocated to the surface of the chromosomes. Baseline Ki 67 levels were categorized as: less than or equal to 2%, > 2% to less than or equal to 5% and > 5%. |
| 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, 17 August 2007, until cut-off date 28 February 2010 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consisted of all patients who were randomized. |
| Arm/Group Title | Everolimus 10 mg/Day | Placebo |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 207 | 203 |
| Ki67 <=2% (n: 7, 17) |
12.52
|
3.68
|
| 2% <Ki67 <=5% (n: 24, 13) |
10.94
|
8.48
|
| Ki67 >5% (n: 20, 22) |
7.69
|
3.15
|
| Title | Progression Free Survival According to Chromogramin A Tumor Marker (CgA) Baseline Level and According to CgA Early Response |
|---|---|
| Description | Baseline levels of serum CgA SE were characterized towards progression free survival (PFS) as per local investigator assessment, relative to the upper limited of normal (ULN). CgA levels exceeding 2 x ULN were considered to be 'Elevated' otherwise considered as "Non-elevated". An 'early response' (applicable to only those patients with elevated levels at baseline) was defined as a decrease of greater than or equal to 30% from baseline to Cycle 2 Day 1 or normalization by Cycle 2 Day 1. CgA is widely expressed in well-differentiated pancreatic NET. CgA is present in the secretory granules of neuroendocrine cells. Pancreatic NET patients often present with elevated circulating levels of CgA in their blood. Baseline levels of these biomarkers are considered as prognostic factors. |
| 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, 17 August 2007, until cut-off date 28 February 2010 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consisted of all patients who were randomized. |
| Arm/Group Title | Everolimus 10 mg/Day | Placebo |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 207 | 203 |
| CgA Levels at baseline: CgA <= 2x ULN (n:121, 97) |
11.17
|
4.90
|
| CgA levels at baseline: CgA > 2x ULN (n:84, 103) |
8.54
|
4.34
|
| Early CgA response: Response (n: 48, 22) |
8.54
|
5.70
|
| Early CgA response: Non-Response (n:40, 82) |
11.14
|
3.19
|
| Title | Progression Free Survival According to Neuron Specific Enolase Tumor Marker (NSE) Baseline Level and According to NSE Early Response |
|---|---|
| Description | Baseline levels of serum NSE were characterized towards PFS as per local investigator assessment, relative to the upper limited of normal (ULN). NSE levels exceeding ULN were considered to be 'Elevated' otherwise considered as "Non-elevated". An 'early response' (applicable to only those patients with elevated levels at baseline) was defined as a decrease of greater than or equal to 30% from baseline to Cycle 2 Day 1 or normalization by Cycle 2 Day 1. NSE is widely expressed in well-differentiated pancreatic NET. NSE is usually expressed in the cytoplasm. Pancreatic NET patients often present with elevated circulating levels of NSE in their blood. Baseline levels of these biomarkers are considered as prognostic factors. |
| 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, 17 August 2007, until cut-off date 28 February 2010 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consisted of all patients who were randomized. |
| Arm/Group Title | Everolimus 10 mg/Day | Placebo |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 207 | 203 |
| NSE Levels at baseline: <= ULN (n: 155, 138) |
13.86
|
5.36
|
| NSE levels at baseline: > ULN (n: 48, 56) |
8.11
|
2.83
|
| Early NSE response: Response (n: 24, 16) |
8.11
|
3.06
|
| Early NSE response: Non-Response (n:16, 27) |
3.79
|
2.58
|
| Title | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) |
|---|---|
| Description | Adverse events 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. Serious adverse events 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 | on or after the start of double-blind study medication until no later than 28 days after double-blind study medication discontinuation |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Safety Set consists of all patients who received any study drug and had at least one post-baseline safety assessment. |
| Arm/Group Title | Everolimus 10 mg/Day | Placebo |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 204 | 203 |
| Adverse events (AEs) |
203
98.1%
|
198
97.5%
|
| Death |
111
53.6%
|
23
11.3%
|
| Serious Adverse Events |
84
40.6%
|
52
25.6%
|
| Title | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) (Open-label Period) |
|---|---|
| Description | Adverse events 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. Serious adverse events 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 | on or after the start of open-label study medication until no later than 28 days after open-label study medication discontinuation |
Outcome Measure Data
| Analysis Population Description |
|---|
| The open-label set was used to summarize the safety analyses performed on data collected in the open-label period of the study: the open-label set included only patients who received at least one dose of open-label everolimus 10 mg and had at least one safety assessment during the open-label period of the study. |
| Arm/Group Title | Everolimus 10 mg/Day | Placebo |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 225 | 0 |
| Adverse events (AEs) |
221
106.8%
|
|
| Death |
122
58.9%
|
|
| Serious Adverse Events |
108
52.2%
|
| Title | Evaluation of Pharmacokinetics (PK) Parameter: AUC0-t Last |
|---|---|
| Description | The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. This PK parameter is area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-t last). |
| Time Frame | Day 1 of every cycle (28 days/cycle) throughout the study |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Safety Set consisted of all patients who received any study drug and had at least one postbaseline safety assessment. |
| Arm/Group Title | Everolimus 10 mg/Day | Everolimus 5 mg/Day |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received 5 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 7 | 1 |
| Mean (Standard Deviation) [ng.h/mL] |
594
(313)
|
481
(NA)
|
| Title | Evaluation of Pharmacokinetics (PK) Parameters: Cmax, Cmin |
|---|---|
| Description | The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. The PK parameter: maximum (peak) drug concentration (Cmax) and minimum (trough) drug concentration (Cmin). |
| Time Frame | Day 1 of every cycle (28 days/cycle) throughout the study |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Safety Set consisted of all patients who received any study drug and had at least one postbaseline safety assessment. |
| Arm/Group Title | Everolimus 10 mg/Day | Everolimus 5 mg/Day |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received 5 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 7 | 1 |
| Cmax |
62.4
(18.5)
|
27.4
(NA)
|
| Cmin |
9.80
(4.95)
|
12.2
(NA)
|
| Title | Evaluation of Pharmacokinetics (PK) Parameter: CL/F |
|---|---|
| Description | The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. The PK parameter clearance of distribution expressed as a function of bioavailability (CL/F). |
| Time Frame | Day 1 of every cycle (28 days/cycle) throughout the study |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Safety Set consisted of all patients who received any study drug and had at least one postbaseline safety assessment. |
| Arm/Group Title | Everolimus 10 mg/Day | Everolimus 5 mg/Day |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received 5 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 7 | 1 |
| Mean (Standard Deviation) [L/h] |
20.2
(7.7)
|
10.7
(NA)
|
| Title | Evaluation of Pharmacokinetics (PK) Parameter: Tmax -Time to Maximum (Peak) Drug Concentration |
|---|---|
| Description | The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. Values for tmax where summarized in median (range). |
| Time Frame | Day 1 of every cycle (28 days/cycle) throughout the study |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Safety Set consisted of all patients who received any study drug and had at least one postbaseline safety assessment. |
| Arm/Group Title | Everolimus 10 mg/Day | Everolimus 5 mg/Day |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received 5 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 7 | 1 |
| Median (Full Range) [h] |
1.17
|
3.0
|
| Title | Analysis of Time to Definitive Deterioration of WHO Performance Status Using Kaplan-Meier |
|---|---|
| Description | Time to definitive worsening is defined as a definitive increase in performance status from a baseline of 0 or 1 to WHO >= 2, or from a baseline value of 2 to WHO >= 3. If no earlier deterioration, patients were censored at the end of follow-up or at the start of further antineoplastic therapy. Rates of patients with no deterioration at 3 and 6 months were computed using Kaplan-meier method. Grade 0: Able to carry out all activity without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory & able to do light work; Grade 2: Ambulatory & capable of all self-care but unable to carry out any work. Up & about more than 50% of waking hours; Grade 3: Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; Grade 4: Completely disabled & cannot carry on any self-care; totally confined to bed or chair. |
| Time Frame | 3 months, 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consists of all patients who were randomized. |
| Arm/Group Title | Everolimus 10 mg/Day | Placebo |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 207 | 203 |
| Month 3 |
94.4
45.6%
|
91.8
45.2%
|
| Month 6 |
90.6
43.8%
|
86.3
42.5%
|
| Title | Plasma Angiogenesis Marker: Basic Fibroblast Growth Factor (bFGF) |
|---|---|
| Description | This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules. |
| Time Frame | Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consists of all patients who were randomized. |
| Arm/Group Title | Everolimus 10 mg/Day | Placebo |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 207 | 203 |
| Baseline (n:198, 195) |
52.59
(101.659)
|
51.49
(78.049)
|
| Cycle 2 Day 1 (n: 185, 184) |
38.43
(51.809)
|
58.33
(72.938)
|
| Cycle 3 Day 1 (n: 185, 174) |
51.97
(89.064)
|
59.08
(72.495)
|
| Cycle 4 Day 1 (n: 171, 159) |
51.28
(82.139)
|
54.58
(75.350)
|
| Title | Plasma Angiogenesis Marker: Placental Growth Factor (PLGF) |
|---|---|
| Description | This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules. |
| Time Frame | Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consists of all patients who were randomized. |
| Arm/Group Title | Everolimus 10 mg/Day | Placebo |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 207 | 203 |
| Baseline (n:198, 195) |
45.82
(282.084)
|
32.92
(52.586)
|
| Cycle 2 Day 1 (n: 185, 184) |
25.78
(33.420)
|
35.38
(57.135)
|
| Cycle 3 Day 1 (n: 185, 174) |
26.55
(28.839)
|
33.84
(65.361)
|
| Cycle 4 Day 1 (n: 171, 159) |
25.69
(18.312)
|
35.47
(67.314)
|
| Title | Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 1 (sVEGFR1) |
|---|---|
| Description | This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules. |
| Time Frame | Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consists of all patients who were randomized. |
| Arm/Group Title | Everolimus 10 mg/Day | Placebo |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 207 | 203 |
| Baseline (n:198, 195) |
264.18
(272.190)
|
256.69
(187.866)
|
| Cycle 2 Day 1 (n: 185, 184) |
307.46
(808.316)
|
299.03
(541.933)
|
| Cycle 3 Day 1 (n: 185, 174) |
263.81
(187.329)
|
253.37
(250.841)
|
| Cycle 4 Day 1 (n: 171, 159) |
258.03
(223.980)
|
242.17
(163.561)
|
| Title | Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR2) |
|---|---|
| Description | This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules. |
| Time Frame | Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consists of all patients who were randomized. |
| Arm/Group Title | Everolimus 10 mg/Day | Placebo |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 207 | 203 |
| Baseline (n:197, 193) |
30061.30
(8607.379)
|
31299.61
(9091.460)
|
| Cycle 2 Day 1 (n: 185, 183) |
22691.18
(6793.409)
|
30223.21
(8447.992)
|
| Cycle 3 Day 1 (n: 185, 173) |
22021.23
(6393.414)
|
29264.67
(8408.405)
|
| Cycle 4 Day 1 (n: 172, 158) |
21218.17
(6249.977)
|
28308.58
(8477.049)
|
| Title | Plasma Angiogenesis Marker: Vascular Endothelial Growth Factor (VEGF) |
|---|---|
| Description | This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules. |
| Time Frame | Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consists of all patients who were randomized. |
| Arm/Group Title | Everolimus 10 mg/Day | Placebo |
|---|---|---|
| Arm/Group Description | Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). |
| Measure Participants | 207 | 203 |
| Baseline (n:198, 195) |
265.09
(283.123)
|
326.16
(323.891)
|
| Cycle 2 Day 1 (n: 185, 184) |
243.03
(183.010)
|
326.78
(377.752)
|
| Cycle 3 Day 1 (n: 185, 174) |
280.18
(268.582)
|
292.27
(286.154)
|
| Cycle 4 Day 1 (n: 171, 159) |
283.51
(326.634)
|
319.60
(325.409)
|
Adverse Events
| Time Frame | ||||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Everolimus 10mg/Day | Placebo | Open Label - Everolimus 10mg | |||
| Arm/Group Description | Afinitor DB: Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). | Afinitor OL (for data collected in the open-label period of the study): The open-label set included only patients who received at least one dose of open-label everolimus 10 mg and had at least one safety assessment during the open-label period of the study. | |||
All Cause Mortality |
||||||
| Everolimus 10mg/Day | Placebo | Open Label - Everolimus 10mg | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Everolimus 10mg/Day | Placebo | Open Label - Everolimus 10mg | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 84/204 (41.2%) | 52/203 (25.6%) | 108/225 (48%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 7/204 (3.4%) | 3/203 (1.5%) | 3/225 (1.3%) | |||
| Febrile neutropenia | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Lymphadenopathy | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Microcytic anaemia | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Neutropenia | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Thrombocytopenia | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Cardiac disorders | ||||||
| Acute coronary syndrome | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Angina pectoris | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Atrial flutter | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Cardiac arrest | 2/204 (1%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Cardiac failure | 2/204 (1%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Cardiac failure congestive | 2/204 (1%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Cardio-respiratory arrest | 1/204 (0.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Coronary artery stenosis | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Left ventricular dysfunction | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Myocardial infarction | 1/204 (0.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Myocarditis | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Palpitations | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Pericardial effusion | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Right ventricular dysfunction | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Right ventricular failure | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Supraventricular tachycardia | 0/204 (0%) | 0/203 (0%) | 3/225 (1.3%) | |||
| Tricuspid valve incompetence | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Congenital, familial and genetic disorders | ||||||
| Branchial cyst | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Ear and labyrinth disorders | ||||||
| Deafness | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Endocrine disorders | ||||||
| Adrenal insufficiency | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Hypercalcaemia of malignancy | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Eye disorders | ||||||
| Cataract | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Macular fibrosis | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Ophthalmoplegia | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal discomfort | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Abdominal distension | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Abdominal hernia | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Abdominal hernia obstructive | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Abdominal pain | 6/204 (2.9%) | 5/203 (2.5%) | 13/225 (5.8%) | |||
| Abdominal pain upper | 2/204 (1%) | 2/203 (1%) | 3/225 (1.3%) | |||
| Abdominal rigidity | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Ascites | 3/204 (1.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Colitis | 2/204 (1%) | 0/203 (0%) | 0/225 (0%) | |||
| Colitis ischaemic | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Diarrhoea | 5/204 (2.5%) | 2/203 (1%) | 3/225 (1.3%) | |||
| Duodenal stenosis | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Dyspepsia | 0/204 (0%) | 1/203 (0.5%) | 1/225 (0.4%) | |||
| Enterocolitis | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Gastritis | 0/204 (0%) | 0/203 (0%) | 2/225 (0.9%) | |||
| Gastritis erosive | 1/204 (0.5%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Gastrointestinal haemorrhage | 1/204 (0.5%) | 2/203 (1%) | 5/225 (2.2%) | |||
| Gastrooesophageal reflux disease | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Haematemesis | 1/204 (0.5%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Ileus | 1/204 (0.5%) | 1/203 (0.5%) | 1/225 (0.4%) | |||
| Ileus paralytic | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Intestinal dilatation | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Melaena | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Nausea | 3/204 (1.5%) | 4/203 (2%) | 7/225 (3.1%) | |||
| Oesophageal haemorrhage | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Oesophageal stenosis | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Oesophageal varices haemorrhage | 1/204 (0.5%) | 1/203 (0.5%) | 1/225 (0.4%) | |||
| Pancreatitis | 1/204 (0.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Pancreatitis acute | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Peptic ulcer haemorrhage | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Rectal haemorrhage | 0/204 (0%) | 2/203 (1%) | 1/225 (0.4%) | |||
| Small intestinal haemorrhage | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Small intestinal obstruction | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Stomatitis | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Subileus | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Swollen tongue | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Tongue oedema | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Upper gastrointestinal haemorrhage | 2/204 (1%) | 1/203 (0.5%) | 1/225 (0.4%) | |||
| Vomiting | 2/204 (1%) | 4/203 (2%) | 10/225 (4.4%) | |||
| General disorders | ||||||
| Asthenia | 5/204 (2.5%) | 2/203 (1%) | 6/225 (2.7%) | |||
| Chest pain | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Chills | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Death | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Device occlusion | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Fatigue | 0/204 (0%) | 2/203 (1%) | 1/225 (0.4%) | |||
| General physical health deterioration | 1/204 (0.5%) | 1/203 (0.5%) | 3/225 (1.3%) | |||
| Generalised oedema | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Influenza like illness | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Malaise | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Multi-organ failure | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Non-cardiac chest pain | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Oedema | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Oedema peripheral | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Performance status decreased | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Pyrexia | 8/204 (3.9%) | 3/203 (1.5%) | 8/225 (3.6%) | |||
| Sudden death | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Thrombosis in device | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Hepatobiliary disorders | ||||||
| Bile duct obstruction | 0/204 (0%) | 1/203 (0.5%) | 2/225 (0.9%) | |||
| Bile duct stenosis | 0/204 (0%) | 1/203 (0.5%) | 1/225 (0.4%) | |||
| Cholangitis | 2/204 (1%) | 0/203 (0%) | 5/225 (2.2%) | |||
| Cholangitis acute | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Cholecystitis acute | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Cholecystitis chronic | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Cholelithiasis | 1/204 (0.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Cholestasis | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Hepatic failure | 1/204 (0.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Hepatic necrosis | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Hepatotoxicity | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Hyperbilirubinaemia | 1/204 (0.5%) | 1/203 (0.5%) | 1/225 (0.4%) | |||
| Jaundice | 1/204 (0.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Jaundice cholestatic | 1/204 (0.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Immune system disorders | ||||||
| Anaphylactic reaction | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Anaphylactic shock | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Drug hypersensitivity | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Infections and infestations | ||||||
| Arthritis bacterial | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Atypical pneumonia | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Bacteraemia | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Bacterial infection | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Biliary tract infection | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Campylobacter infection | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Cellulitis | 0/204 (0%) | 0/203 (0%) | 3/225 (1.3%) | |||
| Cholecystitis infective | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Clostridium difficile infection | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Cystitis | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Diverticulitis | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Enterococcal bacteraemia | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Escherichia sepsis | 2/204 (1%) | 0/203 (0%) | 0/225 (0%) | |||
| Escherichia urinary tract infection | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Gastroenteritis | 2/204 (1%) | 2/203 (1%) | 2/225 (0.9%) | |||
| Gastroenteritis viral | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Infection | 3/204 (1.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Liver abscess | 1/204 (0.5%) | 0/203 (0%) | 2/225 (0.9%) | |||
| Lobar pneumonia | 1/204 (0.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Lung infection | 0/204 (0%) | 0/203 (0%) | 2/225 (0.9%) | |||
| Perihepatic abscess | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Pilonidal cyst | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Pneumonia | 3/204 (1.5%) | 2/203 (1%) | 10/225 (4.4%) | |||
| Pneumonia mycoplasmal | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Post procedural infection | 1/204 (0.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Pulmonary tuberculosis | 1/204 (0.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Sepsis | 0/204 (0%) | 1/203 (0.5%) | 1/225 (0.4%) | |||
| Septic shock | 1/204 (0.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Sinusitis | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Staphylococcal sepsis | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Streptococcal sepsis | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Subcutaneous abscess | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Tonsillitis | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Urinary tract infection | 0/204 (0%) | 0/203 (0%) | 2/225 (0.9%) | |||
| Viral infection | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Wound infection staphylococcal | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Injury, poisoning and procedural complications | ||||||
| Femoral neck fracture | 1/204 (0.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Foot fracture | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Hip fracture | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Incisional hernia | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Intentional overdose | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Overdose | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Patella fracture | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Procedural pain | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Rib fracture | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Wound complication | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Wound secretion | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Investigations | ||||||
| Alanine aminotransferase increased | 1/204 (0.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Ammonia increased | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Aspartate aminotransferase increased | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Blood bilirubin increased | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Blood creatinine increased | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Blood potassium decreased | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| C-reactive protein increased | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Haemoglobin decreased | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Weight decreased | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 2/204 (1%) | 0/203 (0%) | 3/225 (1.3%) | |||
| Dehydration | 5/204 (2.5%) | 2/203 (1%) | 2/225 (0.9%) | |||
| Diabetes mellitus | 1/204 (0.5%) | 1/203 (0.5%) | 3/225 (1.3%) | |||
| Diabetes mellitus inadequate control | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Diabetic ketoacidosis | 0/204 (0%) | 0/203 (0%) | 2/225 (0.9%) | |||
| Electrolyte imbalance | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Fluid overload | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Gout | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Hypercalcaemia | 2/204 (1%) | 3/203 (1.5%) | 0/225 (0%) | |||
| Hyperglycaemia | 2/204 (1%) | 2/203 (1%) | 3/225 (1.3%) | |||
| Hyperkalaemia | 1/204 (0.5%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Hypoglycaemia | 0/204 (0%) | 1/203 (0.5%) | 4/225 (1.8%) | |||
| Hypokalaemia | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Hyponatraemia | 1/204 (0.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Hypophagia | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Hypophosphataemia | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Ketoacidosis | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Metabolic acidosis | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Polydipsia | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 0/204 (0%) | 1/203 (0.5%) | 1/225 (0.4%) | |||
| Back pain | 1/204 (0.5%) | 2/203 (1%) | 2/225 (0.9%) | |||
| Bone pain | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Flank pain | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Neck pain | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Pain in extremity | 0/204 (0%) | 2/203 (1%) | 0/225 (0%) | |||
| Polyarthritis | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Rhabdomyolysis | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Spinal osteoarthritis | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Spinal pain | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Bladder cancer | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Cancer pain | 0/204 (0%) | 2/203 (1%) | 0/225 (0%) | |||
| Gastrinoma | 0/204 (0%) | 0/203 (0%) | 2/225 (0.9%) | |||
| Malignant melanoma | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Neuroendocrine tumour | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Pancreatic neuroendocrine tumour metastatic | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Nervous system disorders | ||||||
| Ataxia | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Cerebrovascular accident | 1/204 (0.5%) | 0/203 (0%) | 3/225 (1.3%) | |||
| Depressed level of consciousness | 0/204 (0%) | 2/203 (1%) | 1/225 (0.4%) | |||
| Dizziness | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Epiduritis | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Hepatic encephalopathy | 1/204 (0.5%) | 0/203 (0%) | 2/225 (0.9%) | |||
| Hypoglycaemic coma | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Loss of consciousness | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Memory impairment | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Mental impairment | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Sciatica | 1/204 (0.5%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Syncope | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Tremor | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Unresponsive to stimuli | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Pregnancy, puerperium and perinatal conditions | ||||||
| Abortion spontaneous | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Psychiatric disorders | ||||||
| Confusional state | 3/204 (1.5%) | 3/203 (1.5%) | 2/225 (0.9%) | |||
| Listless | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Mental status changes | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Renal and urinary disorders | ||||||
| Calculus urinary | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Haematuria | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Nephrolithiasis | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Pollakiuria | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Polyuria | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Pyelocaliectasis | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Renal colic | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Renal failure | 3/204 (1.5%) | 1/203 (0.5%) | 1/225 (0.4%) | |||
| Renal failure acute | 2/204 (1%) | 3/203 (1.5%) | 4/225 (1.8%) | |||
| Renal impairment | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Renal tubular necrosis | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Acute respiratory distress syndrome | 1/204 (0.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Bronchial hyperreactivity | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Cough | 2/204 (1%) | 1/203 (0.5%) | 1/225 (0.4%) | |||
| Dyspnoea | 6/204 (2.9%) | 2/203 (1%) | 2/225 (0.9%) | |||
| Haemoptysis | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Hypoxia | 1/204 (0.5%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Interstitial lung disease | 3/204 (1.5%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Lung infiltration | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Nasal obstruction | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Pleural effusion | 2/204 (1%) | 1/203 (0.5%) | 1/225 (0.4%) | |||
| Pleurisy | 0/204 (0%) | 1/203 (0.5%) | 1/225 (0.4%) | |||
| Pneumonitis | 7/204 (3.4%) | 0/203 (0%) | 2/225 (0.9%) | |||
| Pneumothorax | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Pulmonary congestion | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Pulmonary embolism | 5/204 (2.5%) | 1/203 (0.5%) | 1/225 (0.4%) | |||
| Pulmonary hypertension | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Pulmonary oedema | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Respiratory failure | 2/204 (1%) | 1/203 (0.5%) | 2/225 (0.9%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Rash | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Stasis dermatitis | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Vascular disorders | ||||||
| Aneurysm ruptured | 0/204 (0%) | 0/203 (0%) | 1/225 (0.4%) | |||
| Hypertensive crisis | 0/204 (0%) | 1/203 (0.5%) | 0/225 (0%) | |||
| Hypotension | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
| Venous thrombosis | 1/204 (0.5%) | 0/203 (0%) | 0/225 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Everolimus 10mg/Day | Placebo | Open Label - Everolimus 10mg | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 201/204 (98.5%) | 190/203 (93.6%) | 218/225 (96.9%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 48/204 (23.5%) | 18/203 (8.9%) | 55/225 (24.4%) | |||
| Leukopenia | 12/204 (5.9%) | 4/203 (2%) | 9/225 (4%) | |||
| Lymphopenia | 15/204 (7.4%) | 6/203 (3%) | 10/225 (4.4%) | |||
| Neutropenia | 14/204 (6.9%) | 4/203 (2%) | 24/225 (10.7%) | |||
| Thrombocytopenia | 29/204 (14.2%) | 2/203 (1%) | 20/225 (8.9%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal distension | 18/204 (8.8%) | 14/203 (6.9%) | 19/225 (8.4%) | |||
| Abdominal pain | 47/204 (23%) | 48/203 (23.6%) | 55/225 (24.4%) | |||
| Abdominal pain upper | 30/204 (14.7%) | 15/203 (7.4%) | 29/225 (12.9%) | |||
| Aphthous stomatitis | 25/204 (12.3%) | 8/203 (3.9%) | 22/225 (9.8%) | |||
| Ascites | 13/204 (6.4%) | 4/203 (2%) | 7/225 (3.1%) | |||
| Constipation | 30/204 (14.7%) | 26/203 (12.8%) | 32/225 (14.2%) | |||
| Diarrhoea | 97/204 (47.5%) | 47/203 (23.2%) | 96/225 (42.7%) | |||
| Dry mouth | 23/204 (11.3%) | 9/203 (4.4%) | 8/225 (3.6%) | |||
| Dyspepsia | 13/204 (6.4%) | 13/203 (6.4%) | 8/225 (3.6%) | |||
| Flatulence | 10/204 (4.9%) | 8/203 (3.9%) | 14/225 (6.2%) | |||
| Gastrooesophageal reflux disease | 5/204 (2.5%) | 6/203 (3%) | 13/225 (5.8%) | |||
| Haemorrhoids | 6/204 (2.9%) | 4/203 (2%) | 17/225 (7.6%) | |||
| Mouth ulceration | 14/204 (6.9%) | 4/203 (2%) | 15/225 (6.7%) | |||
| Nausea | 66/204 (32.4%) | 64/203 (31.5%) | 80/225 (35.6%) | |||
| Stomatitis | 110/204 (53.9%) | 27/203 (13.3%) | 105/225 (46.7%) | |||
| Toothache | 11/204 (5.4%) | 5/203 (2.5%) | 10/225 (4.4%) | |||
| Vomiting | 61/204 (29.9%) | 41/203 (20.2%) | 70/225 (31.1%) | |||
| General disorders | ||||||
| Asthenia | 35/204 (17.2%) | 40/203 (19.7%) | 41/225 (18.2%) | |||
| Chills | 11/204 (5.4%) | 1/203 (0.5%) | 14/225 (6.2%) | |||
| Fatigue | 91/204 (44.6%) | 53/203 (26.1%) | 73/225 (32.4%) | |||
| Influenza like illness | 9/204 (4.4%) | 3/203 (1.5%) | 16/225 (7.1%) | |||
| Oedema peripheral | 76/204 (37.3%) | 23/203 (11.3%) | 66/225 (29.3%) | |||
| Pyrexia | 56/204 (27.5%) | 23/203 (11.3%) | 57/225 (25.3%) | |||
| Infections and infestations | ||||||
| Bronchitis | 4/204 (2%) | 3/203 (1.5%) | 15/225 (6.7%) | |||
| Influenza | 6/204 (2.9%) | 7/203 (3.4%) | 12/225 (5.3%) | |||
| Nasopharyngitis | 33/204 (16.2%) | 14/203 (6.9%) | 38/225 (16.9%) | |||
| Pneumonia | 11/204 (5.4%) | 0/203 (0%) | 13/225 (5.8%) | |||
| Sinusitis | 14/204 (6.9%) | 4/203 (2%) | 17/225 (7.6%) | |||
| Upper respiratory tract infection | 16/204 (7.8%) | 7/203 (3.4%) | 28/225 (12.4%) | |||
| Urinary tract infection | 23/204 (11.3%) | 11/203 (5.4%) | 23/225 (10.2%) | |||
| Investigations | ||||||
| Alanine aminotransferase increased | 10/204 (4.9%) | 9/203 (4.4%) | 17/225 (7.6%) | |||
| Aspartate aminotransferase increased | 12/204 (5.9%) | 11/203 (5.4%) | 28/225 (12.4%) | |||
| Blood alkaline phosphatase increased | 12/204 (5.9%) | 11/203 (5.4%) | 25/225 (11.1%) | |||
| Blood creatinine increased | 10/204 (4.9%) | 4/203 (2%) | 15/225 (6.7%) | |||
| Haemoglobin decreased | 15/204 (7.4%) | 2/203 (1%) | 16/225 (7.1%) | |||
| Weight decreased | 58/204 (28.4%) | 24/203 (11.8%) | 72/225 (32%) | |||
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 59/204 (28.9%) | 37/203 (18.2%) | 64/225 (28.4%) | |||
| Dehydration | 10/204 (4.9%) | 7/203 (3.4%) | 22/225 (9.8%) | |||
| Diabetes mellitus | 20/204 (9.8%) | 0/203 (0%) | 21/225 (9.3%) | |||
| Hypercholesterolaemia | 26/204 (12.7%) | 2/203 (1%) | 16/225 (7.1%) | |||
| Hyperglycaemia | 40/204 (19.6%) | 21/203 (10.3%) | 58/225 (25.8%) | |||
| Hyperlipidaemia | 16/204 (7.8%) | 2/203 (1%) | 10/225 (4.4%) | |||
| Hypoglycaemia | 11/204 (5.4%) | 7/203 (3.4%) | 10/225 (4.4%) | |||
| Hypokalaemia | 17/204 (8.3%) | 5/203 (2.5%) | 11/225 (4.9%) | |||
| Hypophosphataemia | 20/204 (9.8%) | 3/203 (1.5%) | 21/225 (9.3%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 31/204 (15.2%) | 14/203 (6.9%) | 34/225 (15.1%) | |||
| Back pain | 31/204 (15.2%) | 22/203 (10.8%) | 40/225 (17.8%) | |||
| Muscle spasms | 21/204 (10.3%) | 8/203 (3.9%) | 15/225 (6.7%) | |||
| Musculoskeletal chest pain | 12/204 (5.9%) | 4/203 (2%) | 15/225 (6.7%) | |||
| Musculoskeletal pain | 12/204 (5.9%) | 9/203 (4.4%) | 17/225 (7.6%) | |||
| Myalgia | 15/204 (7.4%) | 14/203 (6.9%) | 17/225 (7.6%) | |||
| Pain in extremity | 29/204 (14.2%) | 10/203 (4.9%) | 22/225 (9.8%) | |||
| Nervous system disorders | ||||||
| Dizziness | 24/204 (11.8%) | 16/203 (7.9%) | 18/225 (8%) | |||
| Dysgeusia | 38/204 (18.6%) | 11/203 (5.4%) | 46/225 (20.4%) | |||
| Headache | 62/204 (30.4%) | 30/203 (14.8%) | 52/225 (23.1%) | |||
| Psychiatric disorders | ||||||
| Depression | 14/204 (6.9%) | 3/203 (1.5%) | 18/225 (8%) | |||
| Insomnia | 28/204 (13.7%) | 17/203 (8.4%) | 27/225 (12%) | |||
| Renal and urinary disorders | ||||||
| Proteinuria | 10/204 (4.9%) | 2/203 (1%) | 13/225 (5.8%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Cough | 45/204 (22.1%) | 21/203 (10.3%) | 54/225 (24%) | |||
| Dyspnoea | 33/204 (16.2%) | 13/203 (6.4%) | 34/225 (15.1%) | |||
| Epistaxis | 44/204 (21.6%) | 3/203 (1.5%) | 38/225 (16.9%) | |||
| Oropharyngeal pain | 23/204 (11.3%) | 12/203 (5.9%) | 29/225 (12.9%) | |||
| Pleural effusion | 12/204 (5.9%) | 2/203 (1%) | 6/225 (2.7%) | |||
| Pneumonitis | 21/204 (10.3%) | 0/203 (0%) | 17/225 (7.6%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Acne | 13/204 (6.4%) | 5/203 (2.5%) | 15/225 (6.7%) | |||
| Alopecia | 8/204 (3.9%) | 9/203 (4.4%) | 12/225 (5.3%) | |||
| Dermatitis acneiform | 9/204 (4.4%) | 2/203 (1%) | 13/225 (5.8%) | |||
| Dry skin | 26/204 (12.7%) | 12/203 (5.9%) | 28/225 (12.4%) | |||
| Erythema | 11/204 (5.4%) | 3/203 (1.5%) | 4/225 (1.8%) | |||
| Nail disorder | 28/204 (13.7%) | 2/203 (1%) | 26/225 (11.6%) | |||
| Onychoclasis | 14/204 (6.9%) | 2/203 (1%) | 12/225 (5.3%) | |||
| Pruritus | 40/204 (19.6%) | 26/203 (12.8%) | 42/225 (18.7%) | |||
| Rash | 107/204 (52.5%) | 32/203 (15.8%) | 90/225 (40%) | |||
| Vascular disorders | ||||||
| Flushing | 4/204 (2%) | 6/203 (3%) | 12/225 (5.3%) | |||
| Hypertension | 24/204 (11.8%) | 9/203 (4.4%) | 29/225 (12.9%) | |||
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 |
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT00510068
Other Study ID Numbers:
- CRAD001C2324
- 2006-006819-75
First Posted:
Aug 1, 2007
Last Update Posted:
Jul 1, 2015
Last Verified:
Jun 1, 2015