Trial Outcomes & Findings for Efficacy, Safety and Tolerability of Everolimus in Preventing End-stage Renal Disease in Patients With Autosomal Dominant Polycystic Kidney Disease (NCT NCT00414440)

NCT ID: NCT00414440

Last Updated: 2015-01-14

Results Overview

Everolimus (RAD001) compared to placebo with respect to the change from baseline in total kidney volume at Month 24.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 431 participants
• Primary outcome timeframe: Baseline, Month 24
• Results posted on: 2015-01-14

Participant Flow

Participant milestones

Measure	Everolimus Patients in the everolimus group initially received 5 mg/day everolimus divided in 2 equal doses (i.e. 2.5 mg b.i.d.). Dose adjustments were performed to achieve a blood trough level of 3-8 ng/mL (maximum daily dose: 10 mg/day \[5 mg b.i.d.\]).	Placebo Placebo tablets equivalent to the dosage of everolimus 5 mg/day, divided in 2 equal doses.
Core Period STARTED	214	217
Core Period COMPLETED	144	185
Core Period NOT COMPLETED	70	32
Extension Period STARTED	214	217
Extension Period COMPLETED	64	77
Extension Period NOT COMPLETED	150	140

Reasons for withdrawal

Measure	Everolimus Patients in the everolimus group initially received 5 mg/day everolimus divided in 2 equal doses (i.e. 2.5 mg b.i.d.). Dose adjustments were performed to achieve a blood trough level of 3-8 ng/mL (maximum daily dose: 10 mg/day \[5 mg b.i.d.\]).	Placebo Placebo tablets equivalent to the dosage of everolimus 5 mg/day, divided in 2 equal doses.
Core Period Withdrawal by Subject	70	32
Extension Period Lost to Follow-up	44	52
Extension Period Did not consent to continue follow up	61	54
Extension Period Other	1	1
Extension Period Administrative	16	16
Extension Period Death	1	2
Extension Period Withdrawal by Subject	9	7
Extension Period Not included in follow up period	18	8

Baseline Characteristics

Efficacy, Safety and Tolerability of Everolimus in Preventing End-stage Renal Disease in Patients With Autosomal Dominant Polycystic Kidney Disease

Baseline characteristics by cohort

Measure	Everolimus n=214 Participants Patients in the everolimus group initially received 5 mg/day everolimus divided in 2 equal doses (i.e. 2.5 mg b.i.d.). Dose adjustments were performed to achieve a blood trough level of 3-8 ng/mL (maximum daily dose: 10 mg/day \[5 mg b.i.d.\]).	Placebo n=217 Participants Placebo tablets equivalent to the dosage of everolimus 5 mg/day, divided in 2 equal doses.	Total n=431 Participants Total of all reporting groups
Age, Continuous	44.6 years STANDARD_DEVIATION 10.1 • n=93 Participants	44.5 years STANDARD_DEVIATION 10.4 • n=4 Participants	44.5 years STANDARD_DEVIATION 10.3 • n=27 Participants
Sex: Female, Male Female	105 Participants n=93 Participants	117 Participants n=4 Participants	222 Participants n=27 Participants
Sex: Female, Male Male	109 Participants n=93 Participants	100 Participants n=4 Participants	209 Participants n=27 Participants
Race/Ethnicity, Customized Asian Oriental	4 participants n=93 Participants	0 participants n=4 Participants	4 participants n=27 Participants
Race/Ethnicity, Customized Black or African American	1 participants n=93 Participants	0 participants n=4 Participants	1 participants n=27 Participants
Race/Ethnicity, Customized White	208 participants n=93 Participants	217 participants n=4 Participants	425 participants n=27 Participants
Race/Ethnicity, Customized Other, Unknown or Not Reported	1 participants n=93 Participants	0 participants n=4 Participants	1 participants n=27 Participants

PRIMARY outcome

Timeframe: Baseline, Month 24

Population: mITT set

Everolimus (RAD001) compared to placebo with respect to the change from baseline in total kidney volume at Month 24.

Outcome measures

Measure	Everolimus n=214 Participants Patients in the everolimus group initially received 5 mg/day everolimus divided in 2 equal doses (i.e. 2.5 mg b.i.d.). Dose adjustments were performed to achieve a blood trough level of 3-8 ng/mL (maximum daily dose: 10 mg/day \[5 mg b.i.d.\]).	Placebo n=217 Participants Placebo tablets equivalent to the dosage of everolimus 5 mg/day, divided in 2 equal doses.
Primary Efficacy Analysis of Total Kidney Volume (mITT Set, Multiple Imputation)	230.1 mL Interval 172.4 to 287.9	300.8 mL Interval 247.5 to 354.1

SECONDARY outcome

Timeframe: Months 24, 36, 48 and 60

Population: ITT

Course of calculated GFR (mL/min/1.73 m^2) at Months 24, 36, 48 and 60

Outcome measures

Measure	Everolimus n=214 Participants Patients in the everolimus group initially received 5 mg/day everolimus divided in 2 equal doses (i.e. 2.5 mg b.i.d.). Dose adjustments were performed to achieve a blood trough level of 3-8 ng/mL (maximum daily dose: 10 mg/day \[5 mg b.i.d.\]).	Placebo n=217 Participants Placebo tablets equivalent to the dosage of everolimus 5 mg/day, divided in 2 equal doses.
Course of Calculated GFR (mL/Min/1.73 m^2) From Month 24 to Month 60 Month 24	43.9 mL/min/1.73 m^2 Standard Deviation 23.9	48.8 mL/min/1.73 m^2 Standard Deviation 20.8
Course of Calculated GFR (mL/Min/1.73 m^2) From Month 24 to Month 60 Month 36	42.6 mL/min/1.73 m^2 Standard Deviation 23.5	44.9 mL/min/1.73 m^2 Standard Deviation 22.2
Course of Calculated GFR (mL/Min/1.73 m^2) From Month 24 to Month 60 Month 48	39.6 mL/min/1.73 m^2 Standard Deviation 22.2	42.7 mL/min/1.73 m^2 Standard Deviation 22.5
Course of Calculated GFR (mL/Min/1.73 m^2) From Month 24 to Month 60 Month 60	37.7 mL/min/1.73 m^2 Standard Deviation 23.8	37.6 mL/min/1.73 m^2 Standard Deviation 21.6

SECONDARY outcome

Timeframe: Months 24, 36, 48 and 60

Population: ITT

Change in renal function was assessed by the estimated Glomerular Filtration Rate (eGFR) using the abbreviated (4 variables) Modification of Diet in Renal Disease (MDRD-4) formula which was developed by the MDRD Study Group and has been validated in patients with chronic kidney disease. The MDRD-4 formula used for the eGFR calculation is: eGFR (mL/min/1.73m^2) = 186.3*(C^-1.154)*(A^-0.203)*G*R, where C is the serum concentration of creatinine (mg/dL), A is age (years), G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1. The changes in renal function were analyzed via analysis of covariance (ANCOVA) with treatment, pre-transplant hepatitis C virus status and randomization eGFR as covariates. Based on these ANCOVA analyses, the least-squares mean and standard errors of change were reported.

Outcome measures

Measure	Everolimus n=64 Participants Patients in the everolimus group initially received 5 mg/day everolimus divided in 2 equal doses (i.e. 2.5 mg b.i.d.). Dose adjustments were performed to achieve a blood trough level of 3-8 ng/mL (maximum daily dose: 10 mg/day \[5 mg b.i.d.\]).	Placebo n=75 Participants Placebo tablets equivalent to the dosage of everolimus 5 mg/day, divided in 2 equal doses.
Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR >70 mL/min/1.73 m^2 n=11, 18	-14.8 mL/min/1.73 m^2 Standard Deviation 22.7	-20.5 mL/min/1.73 m^2 Standard Deviation 11.1
Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR ≤70 mL/min/1.73 m^2 n=53, 57	-16.1 mL/min/1.73 m^2 Standard Deviation 17.6	-15.6 mL/min/1.73 m^2 Standard Deviation 15.2
Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR >60 mL/min/1.73 m^2 n=21.26	-17.0 mL/min/1.73 m^2 Standard Deviation 17.3	-20.0 mL/min/1.73 m^2 Standard Deviation 13.6
Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR ≤60 mL/min/1.73 m^2 n=43,49	-15.3 mL/min/1.73 m^2 Standard Deviation 19.0	-15.1 mL/min/1.73 m^2 Standard Deviation 14.7
Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR >50 mL/min/1.73 m^2 n=36,39	-19.0 mL/min/1.73 m^2 Standard Deviation 17.3	-19.4 mL/min/1.73 m^2 Standard Deviation 12.6
Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR ≤50 mL/min/1.73 m^2 n=28, 36	-11.8 mL/min/1.73 m^2 Standard Deviation 19.2	-14.0 mL/min/1.73 m^2 Standard Deviation 15.8

SECONDARY outcome

Timeframe: Baseline, Months 12 and 24

Population: ITT, observed cases

Changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP), at baseline and then months 12 and 24

Outcome measures

Measure	Everolimus n=213 mean Patients in the everolimus group initially received 5 mg/day everolimus divided in 2 equal doses (i.e. 2.5 mg b.i.d.). Dose adjustments were performed to achieve a blood trough level of 3-8 ng/mL (maximum daily dose: 10 mg/day \[5 mg b.i.d.\]).	Placebo n=216 mean Placebo tablets equivalent to the dosage of everolimus 5 mg/day, divided in 2 equal doses.
Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Baseline DBP	88 mmHG Standard Deviation 11	88 mmHG Standard Deviation 10
Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Month 12 DBP	86 mmHG Standard Deviation 10	86 mmHG Standard Deviation 10
Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Month 24 DBP	85 mmHG Standard Deviation 10	85 mmHG Standard Deviation 10
Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Baseline SBP	136 mmHG Standard Deviation 16	135 mmHG Standard Deviation 17
Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Month 12 SBP	134 mmHG Standard Deviation 15	134 mmHG Standard Deviation 16
Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Month 24 SBP	134 mmHG Standard Deviation 17	134 mmHG Standard Deviation 15

SECONDARY outcome

Timeframe: Months 3, 6, 9, 12, 18 and 24

Population: ITT set, observed cases

Change in renal function was assessed by the Glomerular Filtration Rate (GFR) using the abbreviated (4 variables) Modification of Diet in Renal Disease (MDRD-4) formula which was developed by the MDRD Study Group and has been validated in patients with chronic kidney disease. The MDRD-4 formula used for the eGFR calculation is: eGFR (mL/min/1.73m^2) = 186.3*(C^-1.154)*(A^-0.203)*G*R, where C is the serum concentration of creatinine (mg/dL), A is age (years), G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1. The changes in renal function were analyzed via analysis of covariance (ANCOVA) with treatment, pre-transplant hepatitis C virus status and randomization eGFR as covariates. Based on these ANCOVA analyses, the least-squares mean and standard errors of change were reported.

Outcome measures

Measure	Everolimus n=213 calculated GFR Patients in the everolimus group initially received 5 mg/day everolimus divided in 2 equal doses (i.e. 2.5 mg b.i.d.). Dose adjustments were performed to achieve a blood trough level of 3-8 ng/mL (maximum daily dose: 10 mg/day \[5 mg b.i.d.\]).	Placebo n=216 calculated GFR Placebo tablets equivalent to the dosage of everolimus 5 mg/day, divided in 2 equal doses.
Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit Week 1	2.0 mL/min/1.73m^2 Standard Deviation 5.9	-0.9 mL/min/1.73m^2 Standard Deviation 6.1
Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit Month 6	-2.3 mL/min/1.73m^2 Standard Deviation 7.7	-2.2 mL/min/1.73m^2 Standard Deviation 6.7
Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit Month 9	-4.6 mL/min/1.73m^2 Standard Deviation 8.2	-2.4 mL/min/1.73m^2 Standard Deviation 6.0
Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit Week 2	1.7 mL/min/1.73m^2 Standard Deviation 5.9	-0.9 mL/min/1.73m^2 Standard Deviation 6.5
Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit Week 4	0.6 mL/min/1.73m^2 Standard Deviation 6.3	-1.2 mL/min/1.73m^2 Standard Deviation 6.7
Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit Month 3	-0.5 mL/min/1.73m^2 Standard Deviation 8.2	-2.4 mL/min/1.73m^2 Standard Deviation 6.7
Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit Month 12	-5.4 mL/min/1.73m^2 Standard Deviation 7.5	-3.2 mL/min/1.73m^2 Standard Deviation 6.9
Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit Month 18	-7.7 mL/min/1.73m^2 Standard Deviation 8.5	-5.5 mL/min/1.73m^2 Standard Deviation 6.7
Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit Month 24	-8.9 mL/min/1.73m^2 Standard Deviation 8.8	-7.7 mL/min/1.73m^2 Standard Deviation 6.6

Adverse Events

Everolimus

Serious events: 80 serious events

Other events: 205 other events

Deaths: 0 deaths

Placebo

Serious events: 51 serious events

Other events: 185 other events

Deaths: 0 deaths

Serious adverse events

Measure	Everolimus n=214 participants at risk Patients in the everolimus group initially received 5 mg/day everolimus divided in 2 equal doses (i.e. 2.5 mg b.i.d.). Dose adjustments were performed to achieve a blood trough level of 3-8 ng/mL (maximum daily dose: 10 mg/day \[5 mg b.i.d.\]).	Placebo n=217 participants at risk Placebo tablets equivalent to the dosage of everolimus 5 mg/day, divided in 2 equal doses
Blood and lymphatic system disorders ANAEMIA	0.93% 2/214	0.00% 0/217
Blood and lymphatic system disorders IRON DEFICIENCY ANAEMIA	0.47% 1/214	0.00% 0/217
Blood and lymphatic system disorders LEUKOCYTOSIS	0.47% 1/214	0.00% 0/217
Blood and lymphatic system disorders LYMPH NODE PAIN	0.47% 1/214	0.00% 0/217
Blood and lymphatic system disorders LYMPHADENOPATHY	0.47% 1/214	0.00% 0/217
Blood and lymphatic system disorders NEUTROPENIA	0.47% 1/214	0.00% 0/217
Cardiac disorders ANGINA PECTORIS	0.00% 0/214	0.46% 1/217
Cardiac disorders ATRIAL FIBRILLATION	0.93% 2/214	0.00% 0/217
Cardiac disorders ATRIAL FLUTTER	0.47% 1/214	0.00% 0/217
Cardiac disorders BRADYARRHYTHMIA	0.00% 0/214	0.46% 1/217
Cardiac disorders BRADYCARDIA	0.47% 1/214	0.00% 0/217
Cardiac disorders CARDIAC FAILURE	0.47% 1/214	0.00% 0/217
Cardiac disorders CARDIOGENIC SHOCK	0.47% 1/214	0.00% 0/217
Cardiac disorders CORONARY ARTERY DISEASE	0.00% 0/214	1.4% 3/217
Cardiac disorders LEFT VENTRICULAR FAILURE	0.47% 1/214	0.00% 0/217
Cardiac disorders MITRAL VALVE INCOMPETENCE	0.47% 1/214	0.00% 0/217
Cardiac disorders MYOPERICARDITIS	0.47% 1/214	0.00% 0/217
Cardiac disorders PERICARDIAL EFFUSION	0.93% 2/214	0.00% 0/217
Congenital, familial and genetic disorders POLYCYSTIC LIVER DISEASE	0.00% 0/214	0.46% 1/217
Ear and labyrinth disorders ACUTE VESTIBULAR SYNDROME	0.00% 0/214	0.46% 1/217
Ear and labyrinth disorders VERTIGO	0.00% 0/214	0.46% 1/217
Endocrine disorders GOITRE	0.00% 0/214	0.46% 1/217
Eye disorders RETINAL DETACHMENT	0.47% 1/214	0.00% 0/217
Gastrointestinal disorders ABDOMINAL PAIN	0.93% 2/214	0.46% 1/217
Gastrointestinal disorders ABDOMINAL PAIN UPPER	0.93% 2/214	0.46% 1/217
Gastrointestinal disorders ABDOMINAL TENDERNESS	0.47% 1/214	0.00% 0/217
Gastrointestinal disorders APHTHOUS STOMATITIS	0.93% 2/214	0.00% 0/217
Gastrointestinal disorders ASCITES	0.47% 1/214	0.00% 0/217
Gastrointestinal disorders COLITIS	0.00% 0/214	0.46% 1/217
Gastrointestinal disorders COLONIC POLYP	0.47% 1/214	0.00% 0/217
Gastrointestinal disorders CROHN'S DISEASE	0.00% 0/214	0.46% 1/217
Gastrointestinal disorders DIARRHOEA	1.4% 3/214	0.46% 1/217
Gastrointestinal disorders GASTRIC HAEMORRHAGE	0.47% 1/214	0.00% 0/217
Gastrointestinal disorders GASTRITIS	0.47% 1/214	0.00% 0/217
Gastrointestinal disorders GASTRODUODENITIS	0.00% 0/214	0.46% 1/217
Gastrointestinal disorders HAEMORRHOIDAL HAEMORRHAGE	0.47% 1/214	0.00% 0/217
Gastrointestinal disorders INGUINAL HERNIA	0.93% 2/214	1.8% 4/217
Gastrointestinal disorders OESOPHAGITIS	0.47% 1/214	0.00% 0/217
Gastrointestinal disorders RECTAL HAEMORRHAGE	0.47% 1/214	0.00% 0/217
Gastrointestinal disorders SUBILEUS	0.47% 1/214	0.00% 0/217
Gastrointestinal disorders UMBILICAL HERNIA	1.4% 3/214	0.92% 2/217
Gastrointestinal disorders VOMITING	0.47% 1/214	0.00% 0/217
General disorders ASTHENIA	0.93% 2/214	0.92% 2/217
General disorders BLOODY DISCHARGE	0.00% 0/214	0.46% 1/217
General disorders CHEST PAIN	0.47% 1/214	0.46% 1/217
General disorders DISEASE PROGRESSION	1.9% 4/214	0.92% 2/217
General disorders DRUG WITHDRAWAL SYNDROME	0.00% 0/214	0.46% 1/217
General disorders OEDEMA	0.47% 1/214	0.00% 0/217
General disorders OEDEMA PERIPHERAL	0.47% 1/214	0.00% 0/217
General disorders PYREXIA	0.47% 1/214	0.46% 1/217
Hepatobiliary disorders CHOLECYSTITIS	0.47% 1/214	0.00% 0/217
Hepatobiliary disorders HEPATIC CYST	0.47% 1/214	0.46% 1/217
Hepatobiliary disorders HEPATIC CYST RUPTURED	0.47% 1/214	0.46% 1/217
Hepatobiliary disorders HEPATOMEGALY	0.47% 1/214	0.00% 0/217
Hepatobiliary disorders PORTAL VEIN THROMBOSIS	0.47% 1/214	0.00% 0/217
Immune system disorders ANAPHYLACTIC SHOCK	0.47% 1/214	0.00% 0/217
Immune system disorders HOUSE DUST ALLERGY	0.47% 1/214	0.00% 0/217
Immune system disorders HYPERSENSITIVITY	0.47% 1/214	0.00% 0/217
Infections and infestations ACUTE TONSILLITIS	0.47% 1/214	0.00% 0/217
Infections and infestations ANOGENITAL WARTS	0.00% 0/214	0.46% 1/217
Infections and infestations APPENDICITIS	0.47% 1/214	0.00% 0/217
Infections and infestations BRONCHITIS	0.47% 1/214	0.00% 0/217
Infections and infestations DIVERTICULITIS	0.00% 0/214	0.46% 1/217
Infections and infestations ENTEROCOLITIS INFECTIOUS	0.47% 1/214	0.00% 0/217
Infections and infestations ERYSIPELAS	0.00% 0/214	0.46% 1/217
Infections and infestations GASTROENTERITIS	1.4% 3/214	0.00% 0/217
Infections and infestations GASTROINTESTINAL INFECTION	0.47% 1/214	0.46% 1/217
Infections and infestations HEPATIC CYST INFECTION	0.00% 0/214	0.46% 1/217
Infections and infestations HERPES SIMPLEX	0.47% 1/214	0.00% 0/217
Infections and infestations HERPES ZOSTER	0.93% 2/214	0.00% 0/217
Infections and infestations HERPES ZOSTER OPHTHALMIC	0.47% 1/214	0.00% 0/217
Infections and infestations INFECTION	0.93% 2/214	0.00% 0/217
Infections and infestations INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE	0.00% 0/214	0.46% 1/217
Infections and infestations LYMPH NODE TUBERCULOSIS	0.47% 1/214	0.00% 0/217
Infections and infestations LYMPHADENITIS BACTERIAL	0.47% 1/214	0.00% 0/217
Infections and infestations OTITIS MEDIA CHRONIC	0.47% 1/214	0.00% 0/217
Infections and infestations PAPILLOMA VIRAL INFECTION	0.00% 0/214	0.46% 1/217
Infections and infestations PNEUMONIA	2.3% 5/214	0.46% 1/217
Infections and infestations PYELONEPHRITIS	0.47% 1/214	0.92% 2/217
Infections and infestations PYELONEPHRITIS ACUTE	0.00% 0/214	0.46% 1/217
Infections and infestations RENAL CYST INFECTION	0.93% 2/214	1.8% 4/217
Infections and infestations RESPIRATORY TRACT INFECTION	0.00% 0/214	0.92% 2/217
Infections and infestations SINUSITIS	0.93% 2/214	0.00% 0/217
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	0.47% 1/214	0.46% 1/217
Infections and infestations UROSEPSIS	0.47% 1/214	0.00% 0/217
Infections and infestations VESTIBULAR NEURONITIS	0.47% 1/214	0.00% 0/217
Infections and infestations VIRAL INFECTION	0.00% 0/214	0.46% 1/217
Injury, poisoning and procedural complications ARTHROPOD STING	0.47% 1/214	0.00% 0/217
Injury, poisoning and procedural complications CONJUNCTIVAL ABRASION	0.00% 0/214	0.46% 1/217
Injury, poisoning and procedural complications CORNEAL ABRASION	0.00% 0/214	0.46% 1/217
Injury, poisoning and procedural complications FOOT FRACTURE	0.47% 1/214	0.00% 0/217
Injury, poisoning and procedural complications FOREIGN BODY IN EYE	0.00% 0/214	0.46% 1/217
Injury, poisoning and procedural complications INCISIONAL HERNIA	0.00% 0/214	0.92% 2/217
Injury, poisoning and procedural complications LIGAMENT INJURY	0.00% 0/214	0.46% 1/217
Injury, poisoning and procedural complications MENISCUS LESION	0.00% 0/214	0.46% 1/217
Injury, poisoning and procedural complications POST PROCEDURAL HAEMORRHAGE	0.47% 1/214	0.00% 0/217
Injury, poisoning and procedural complications STERNAL FRACTURE	0.00% 0/214	0.46% 1/217
Investigations BLOOD CREATINE PHOSPHOKINASE INCREASED	0.47% 1/214	0.46% 1/217
Investigations BLOOD CREATININE INCREASED	0.93% 2/214	0.00% 0/217
Investigations C-REACTIVE PROTEIN INCREASED	1.4% 3/214	0.00% 0/217
Investigations WEIGHT DECREASED	1.9% 4/214	0.00% 0/217
Metabolism and nutrition disorders DIABETES MELLITUS	0.47% 1/214	0.00% 0/217
Metabolism and nutrition disorders GOUT	0.47% 1/214	0.00% 0/217
Metabolism and nutrition disorders HYPOKALAEMIA	0.47% 1/214	0.00% 0/217
Musculoskeletal and connective tissue disorders ANKYLOSING SPONDYLITIS	0.00% 0/214	0.46% 1/217
Musculoskeletal and connective tissue disorders ARTHRALGIA	0.93% 2/214	0.00% 0/217
Musculoskeletal and connective tissue disorders ARTHRITIS REACTIVE	0.47% 1/214	0.00% 0/217
Musculoskeletal and connective tissue disorders BACK PAIN	0.47% 1/214	0.00% 0/217
Musculoskeletal and connective tissue disorders FLANK PAIN	0.93% 2/214	0.46% 1/217
Musculoskeletal and connective tissue disorders FOOT DEFORMITY	0.47% 1/214	0.00% 0/217
Musculoskeletal and connective tissue disorders INTERVERTEBRAL DISC PROTRUSION	0.47% 1/214	0.00% 0/217
Musculoskeletal and connective tissue disorders MUSCULAR WEAKNESS	0.47% 1/214	0.00% 0/217
Musculoskeletal and connective tissue disorders MYALGIA	1.9% 4/214	0.46% 1/217
Musculoskeletal and connective tissue disorders MYOSITIS	0.47% 1/214	0.00% 0/217
Musculoskeletal and connective tissue disorders POLYARTHRITIS	0.47% 1/214	0.00% 0/217
Musculoskeletal and connective tissue disorders RHABDOMYOLYSIS	0.47% 1/214	0.46% 1/217
Neoplasms benign, malignant and unspecified (incl cysts and polyps) ADENOCARCINOMA PANCREAS	0.47% 1/214	0.00% 0/217
Neoplasms benign, malignant and unspecified (incl cysts and polyps) BENIGN OVARIAN TUMOUR	0.47% 1/214	0.00% 0/217
Neoplasms benign, malignant and unspecified (incl cysts and polyps) BREAST CANCER	0.47% 1/214	0.46% 1/217
Neoplasms benign, malignant and unspecified (incl cysts and polyps) CHOLESTEATOMA	0.47% 1/214	0.00% 0/217
Neoplasms benign, malignant and unspecified (incl cysts and polyps) PANCREATIC CARCINOMA	0.00% 0/214	0.46% 1/217
Neoplasms benign, malignant and unspecified (incl cysts and polyps) PLASMACYTOMA	0.47% 1/214	0.00% 0/217
Neoplasms benign, malignant and unspecified (incl cysts and polyps) THYROID NEOPLASM	0.00% 0/214	0.46% 1/217
Neoplasms benign, malignant and unspecified (incl cysts and polyps) UTERINE LEIOMYOMA	0.47% 1/214	0.46% 1/217
Nervous system disorders CEREBRAL ATROPHY	0.47% 1/214	0.00% 0/217
Nervous system disorders CEREBRAL HAEMORRHAGE	0.47% 1/214	0.00% 0/217
Nervous system disorders CEREBROVASCULAR ACCIDENT	0.47% 1/214	0.46% 1/217
Nervous system disorders HEMIPARESIS	0.00% 0/214	0.46% 1/217
Nervous system disorders MIGRAINE	0.00% 0/214	0.46% 1/217
Nervous system disorders MIGRAINE WITH AURA	0.00% 0/214	0.46% 1/217
Nervous system disorders NEUROPATHY PERIPHERAL	0.00% 0/214	0.46% 1/217
Nervous system disorders RUPTURED CEREBRAL ANEURYSM	0.47% 1/214	0.00% 0/217
Nervous system disorders SYNCOPE	0.00% 0/214	0.92% 2/217
Pregnancy, puerperium and perinatal conditions PREGNANCY	0.47% 1/214	0.00% 0/217
Psychiatric disorders ACUTE PSYCHOSIS	0.47% 1/214	0.00% 0/217
Psychiatric disorders DEPRESSED MOOD	0.47% 1/214	0.00% 0/217
Psychiatric disorders DEPRESSION	0.47% 1/214	0.46% 1/217
Psychiatric disorders PARANOIA	0.47% 1/214	0.00% 0/217
Psychiatric disorders PSYCHOTIC DISORDER	0.00% 0/214	0.46% 1/217
Psychiatric disorders SUICIDE ATTEMPT	0.47% 1/214	0.00% 0/217
Renal and urinary disorders CALCULUS URETERIC	0.47% 1/214	0.00% 0/217
Renal and urinary disorders HAEMATURIA	0.93% 2/214	0.00% 0/217
Renal and urinary disorders NEPHROTIC SYNDROME	0.47% 1/214	0.00% 0/217
Renal and urinary disorders RENAL COLIC	0.93% 2/214	0.46% 1/217
Renal and urinary disorders RENAL CYST RUPTURED	0.00% 0/214	0.46% 1/217
Renal and urinary disorders RENAL FAILURE	0.47% 1/214	0.00% 0/217
Renal and urinary disorders RENAL FAILURE ACUTE	2.3% 5/214	0.46% 1/217
Renal and urinary disorders RENAL HAEMORRHAGE	1.4% 3/214	0.92% 2/217
Renal and urinary disorders RENAL IMPAIRMENT	0.93% 2/214	0.46% 1/217
Reproductive system and breast disorders BREAST DISCHARGE	0.00% 0/214	0.46% 1/217
Reproductive system and breast disorders BREAST FIBROSIS	0.00% 0/214	0.46% 1/217
Reproductive system and breast disorders BREAST HYPERPLASIA	0.00% 0/214	0.46% 1/217
Reproductive system and breast disorders COLPOCELE	0.00% 0/214	0.46% 1/217
Reproductive system and breast disorders DYSMENORRHOEA	0.47% 1/214	0.00% 0/217
Reproductive system and breast disorders MENORRHAGIA	0.47% 1/214	0.00% 0/217
Reproductive system and breast disorders MENSTRUATION IRREGULAR	0.47% 1/214	0.00% 0/217
Reproductive system and breast disorders OVARIAN CYST	3.3% 7/214	0.00% 0/217
Reproductive system and breast disorders PELVIC FLUID COLLECTION	0.47% 1/214	0.00% 0/217
Reproductive system and breast disorders POLYCYSTIC OVARIES	0.47% 1/214	0.00% 0/217
Reproductive system and breast disorders VAGINAL HAEMORRHAGE	0.93% 2/214	0.00% 0/217
Respiratory, thoracic and mediastinal disorders CHRONIC OBSTRUCTIVE PULMONARY DISEASE	0.47% 1/214	0.00% 0/217
Respiratory, thoracic and mediastinal disorders COUGH	0.47% 1/214	0.46% 1/217
Respiratory, thoracic and mediastinal disorders DYSPNOEA	0.47% 1/214	0.00% 0/217
Respiratory, thoracic and mediastinal disorders DYSPNOEA EXERTIONAL	0.47% 1/214	0.00% 0/217
Respiratory, thoracic and mediastinal disorders LUNG DISORDER	0.47% 1/214	0.00% 0/217
Respiratory, thoracic and mediastinal disorders PAINFUL RESPIRATION	0.47% 1/214	0.00% 0/217
Respiratory, thoracic and mediastinal disorders PLEURAL EFFUSION	0.47% 1/214	0.00% 0/217
Respiratory, thoracic and mediastinal disorders PLEURISY	0.47% 1/214	0.00% 0/217
Respiratory, thoracic and mediastinal disorders PNEUMONITIS	0.93% 2/214	0.00% 0/217
Respiratory, thoracic and mediastinal disorders PULMONARY EMBOLISM	0.00% 0/214	0.46% 1/217
Respiratory, thoracic and mediastinal disorders PULMONARY OEDEMA	0.47% 1/214	0.00% 0/217
Skin and subcutaneous tissue disorders ANGIOEDEMA	3.7% 8/214	0.00% 0/217
Skin and subcutaneous tissue disorders HYPOAESTHESIA FACIAL	0.00% 0/214	0.46% 1/217
Vascular disorders ANGIODYSPLASIA	0.47% 1/214	0.00% 0/217
Vascular disorders DEEP VEIN THROMBOSIS	0.00% 0/214	0.92% 2/217
Vascular disorders HYPERTENSION	0.00% 0/214	0.46% 1/217
Vascular disorders HYPERTENSIVE CRISIS	0.00% 0/214	0.46% 1/217
Vascular disorders HYPOTENSION	0.47% 1/214	0.00% 0/217
Vascular disorders ILIAC ARTERY STENOSIS	0.00% 0/214	0.46% 1/217
Vascular disorders INTERMITTENT CLAUDICATION	0.00% 0/214	0.46% 1/217
Vascular disorders PERIPHERAL ARTERIAL OCCLUSIVE DISEASE	0.00% 0/214	0.46% 1/217
Vascular disorders THROMBOSIS	0.47% 1/214	0.00% 0/217
Vascular disorders VARICOSE VEIN	0.00% 0/214	0.46% 1/217
Vascular disorders VASCULITIS	0.00% 0/214	0.46% 1/217
Vascular disorders VENOUS THROMBOSIS LIMB	0.47% 1/214	0.00% 0/217

Other adverse events

Measure	Everolimus n=214 participants at risk Patients in the everolimus group initially received 5 mg/day everolimus divided in 2 equal doses (i.e. 2.5 mg b.i.d.). Dose adjustments were performed to achieve a blood trough level of 3-8 ng/mL (maximum daily dose: 10 mg/day \[5 mg b.i.d.\]).	Placebo n=217 participants at risk Placebo tablets equivalent to the dosage of everolimus 5 mg/day, divided in 2 equal doses
Blood and lymphatic system disorders ANAEMIA	16.4% 35/214	5.1% 11/217
Blood and lymphatic system disorders LEUKOPENIA	17.8% 38/214	2.8% 6/217
Blood and lymphatic system disorders THROMBOCYTOPENIA	14.0% 30/214	0.92% 2/217
Gastrointestinal disorders ABDOMINAL DISCOMFORT	5.6% 12/214	3.7% 8/217
Gastrointestinal disorders ABDOMINAL PAIN	11.2% 24/214	6.0% 13/217
Gastrointestinal disorders ABDOMINAL PAIN UPPER	6.5% 14/214	6.0% 13/217
Gastrointestinal disorders APHTHOUS STOMATITIS	38.8% 83/214	5.5% 12/217
Gastrointestinal disorders DIARRHOEA	22.4% 48/214	15.7% 34/217
Gastrointestinal disorders NAUSEA	9.3% 20/214	5.5% 12/217
Gastrointestinal disorders VOMITING	5.1% 11/214	6.5% 14/217
General disorders ASTHENIA	5.1% 11/214	2.8% 6/217
General disorders FATIGUE	9.3% 20/214	8.8% 19/217
General disorders OEDEMA	11.7% 25/214	5.5% 12/217
General disorders OEDEMA PERIPHERAL	19.6% 42/214	9.2% 20/217
General disorders PYREXIA	5.6% 12/214	4.1% 9/217
Infections and infestations BRONCHITIS	9.8% 21/214	10.6% 23/217
Infections and infestations GASTROENTERITIS	5.1% 11/214	1.8% 4/217
Infections and infestations NASOPHARYNGITIS	38.8% 83/214	38.2% 83/217
Infections and infestations ORAL HERPES	7.0% 15/214	1.8% 4/217
Infections and infestations SINUSITIS	6.5% 14/214	6.0% 13/217
Infections and infestations URINARY TRACT INFECTION	10.3% 22/214	8.8% 19/217
Investigations BLOOD CREATINE PHOSPHOKINASE INCREASED	15.0% 32/214	6.9% 15/217
Investigations BLOOD CREATININE INCREASED	17.8% 38/214	6.0% 13/217
Metabolism and nutrition disorders HYPERCHOLESTEROLAEMIA	21.5% 46/214	3.7% 8/217
Metabolism and nutrition disorders HYPERLIPIDAEMIA	13.1% 28/214	2.3% 5/217
Metabolism and nutrition disorders HYPERTRIGLYCERIDAEMIA	7.0% 15/214	3.7% 8/217
Metabolism and nutrition disorders HYPERURICAEMIA	3.3% 7/214	6.0% 13/217
Metabolism and nutrition disorders IRON DEFICIENCY	5.6% 12/214	0.92% 2/217
Musculoskeletal and connective tissue disorders ARTHRALGIA	6.1% 13/214	2.3% 5/217
Musculoskeletal and connective tissue disorders BACK PAIN	7.0% 15/214	7.8% 17/217
Musculoskeletal and connective tissue disorders FLANK PAIN	7.9% 17/214	10.6% 23/217
Musculoskeletal and connective tissue disorders MUSCLE SPASMS	4.7% 10/214	5.5% 12/217
Musculoskeletal and connective tissue disorders MYALGIA	6.5% 14/214	1.4% 3/217
Nervous system disorders HEADACHE	17.3% 37/214	12.4% 27/217
Renal and urinary disorders HAEMATURIA	6.1% 13/214	4.1% 9/217
Renal and urinary disorders PROTEINURIA	13.1% 28/214	6.9% 15/217
Respiratory, thoracic and mediastinal disorders COUGH	11.2% 24/214	8.8% 19/217
Respiratory, thoracic and mediastinal disorders OROPHARYNGEAL PAIN	5.6% 12/214	4.1% 9/217
Skin and subcutaneous tissue disorders ACNE	14.0% 30/214	2.8% 6/217
Skin and subcutaneous tissue disorders RASH	8.4% 18/214	3.7% 8/217
Vascular disorders HYPERTENSION	15.4% 33/214	13.4% 29/217

Additional Information

Study Director

Novartis

Phone: +1 (862) 778-8300

Results disclosure agreements

• Principal investigator is a sponsor employee Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. 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; or disclosure of the trial results in their entirety.
• Publication restrictions are in place

Restriction type: OTHER