Trial Outcomes & Findings for A Study to Determine the Safety and Effectiveness of RAD001 (Everolimus) in Patients With Lymphangioleiomyomatosis (NCT NCT01059318)

Last Updated: 2020-11-19

Results Overview

Blood samples (1 mL) for determination of VEGF-D were collected from a forearm vein (direct venipuncture or from an indwelling cannula) and 2 aliquots of serum were collected. VEGF-D levels were determined from only 1 of the 2 serum aliquots, with the second acting as a back-up. A serum VEGF-D \>800 pg/mL level supports a diagnosis of Lymphangioleiomyomatosis (LAM)

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

24 participants

Primary outcome timeframe

Baseline, 26 weeks

Results posted on

2020-11-19

Participant Flow

Participant milestones

Participant milestones
Measure	Everolimus All patients received a starting dose of everolimus 2.5mg/day for 4 weeks, followed by a dose of 5 mg/day for 4 weeks and finally a dose of 10mg/day for 18 weeks. The 26 week treatment period was followed by an optional extension period wherein patients continued therapy until the last patient had completed 26-weeks of treatment. The longest period a patient participated in the study was 62 weeks. Everolimus : Everolimus was formulated as tablets in strengths of 2.5mg, 5mg and 10mg.
Core Study (26 Week) STARTED	24
Core Study (26 Week) Everolimus 2.5 mg for 4 Weeks	24
Core Study (26 Week) Everolimus 5 mg for 4 Weeks	24
Core Study (26 Week) Everolimus 10 mg for 18 Weeks	24
Core Study (26 Week) Pharmacokinetics (PK) Analysis Set	16
Core Study (26 Week) COMPLETED	20
Core Study (26 Week) NOT COMPLETED	4
Extension (36 Week) STARTED	20
Extension (36 Week) COMPLETED	17
Extension (36 Week) NOT COMPLETED	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Everolimus All patients received a starting dose of everolimus 2.5mg/day for 4 weeks, followed by a dose of 5 mg/day for 4 weeks and finally a dose of 10mg/day for 18 weeks. The 26 week treatment period was followed by an optional extension period wherein patients continued therapy until the last patient had completed 26-weeks of treatment. The longest period a patient participated in the study was 62 weeks. Everolimus : Everolimus was formulated as tablets in strengths of 2.5mg, 5mg and 10mg.
Core Study (26 Week) Adverse Event	3
Core Study (26 Week) Withdrawal by Subject	1
Extension (36 Week) Adverse Event	3

Baseline Characteristics

A Study to Determine the Safety and Effectiveness of RAD001 (Everolimus) in Patients With Lymphangioleiomyomatosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Everolimus n=24 Participants All patients received a starting dose of everolimus 2.5mg/day for 4 weeks, followed by a dose of 5 mg/day for 4 weeks and finally a dose of 10mg/day for 18 weeks. The 26 week treatment period was followed by an optional extension period wherein patients continued therapy until the last patient had completed 26-weeks of treatment. The longest period a patient participated in the study was 62 weeks. Everolimus : Everolimus was formulated as tablets in strengths of 2.5mg, 5mg and 10mg.
Age, Continuous	44 years STANDARD_DEVIATION 13.4 • n=5 Participants
Sex: Female, Male Female	24 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 26 weeks

Population: Pharmacodynamic analysis included patients who received study drug without any major protocol violation. Same patients in different dose groups were included in this analysis with available data.

Outcome measures

Outcome measures
Measure	Everolimus 2.5 mg/Day n=21 Participants All patients received a starting dose of everolimus 2.5mg/day for first 4 weeks.	Everolimus 5 mg/Day n=22 Participants Patients from 2.5 mg/day up-titrated after 4 weeks and followed by a dose of 5 mg/day for another 4 weeks.	Everolimus 10 mg/Day n=22 Participants Patients who had received 2.5 mg/day for first 4 weeks, up titrated to 5 mg/day and continued for another 4 weeks, again up-titrated to 10 mg/day for 18 weeks.
Change From Baseline in Vascular Endothelial Growth Factor-D (VEGF-D) Concentrations	-464.3 pg/mL Standard Deviation 745.23	-1113.2 pg/mL Standard Deviation 1468.9	-1771.7 pg/mL Standard Deviation 2091.6

PRIMARY outcome

Timeframe: pre-dose and at 2 hour post dose at week 26

Population: Pharmacokinetics analysis set. Patients with measurable data at particular time points were included in this analysis.

Venous blood samples (2 mL) for pharmacokinetic evaluation were collected pre dose and 2 hours post dose at preselected visits.

Outcome measures

Outcome measures
Measure	Everolimus 2.5 mg/Day n=16 Participants All patients received a starting dose of everolimus 2.5mg/day for first 4 weeks.	Everolimus 5 mg/Day n=16 Participants Patients from 2.5 mg/day up-titrated after 4 weeks and followed by a dose of 5 mg/day for another 4 weeks.	Everolimus 10 mg/Day n=16 Participants Patients who had received 2.5 mg/day for first 4 weeks, up titrated to 5 mg/day and continued for another 4 weeks, again up-titrated to 10 mg/day for 18 weeks.
Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State Trough (C0, ss)	3.1 ng/mL Standard Deviation 1.33	5.8 ng/mL Standard Deviation 3.02	11.0 ng/mL Standard Deviation 3.45
Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State Peak (C2, ss)	12.1 ng/mL Standard Deviation 3.56	22.6 ng/mL Standard Deviation 7.22	45.7 ng/mL Standard Deviation 12.52

SECONDARY outcome

Timeframe: Baseline, 26 weeks

Population: Pharmacodynamic analysis set for everolimus reporting arm. Patients with both baseline and 26 weeks assessment were included in this analysis.

All spirometry evaluation followed recommendations of the Standardization of Lung Function Testing. All spirometry maneuvers were performed in sitting position whilst wearing nose clips. At least three acceptable maneuvers were performed for each time point, and results met within-test and between-test criteria for acceptability. The highest value was obtained of FVC from any of the three maneuvers that met acceptability criteria. Change from baseline in FVC was compared between everolimus and historical placebo data from multicenter trial of sirolimus in LAM. (MILES NCT00414648) due to absence of placebo group in this current study on a rare lung disease. These two studies had different study designs, so the change from baseline to 6 months (26 weeks) in MILES study was estimated from the publicly reported rate of change per month to provide a meaningful comparison. This historical control be can be viewed on the Novartis Clinical Trial Results website.

Outcome measures

Outcome measures
Measure	Everolimus 2.5 mg/Day n=23 Participants All patients received a starting dose of everolimus 2.5mg/day for first 4 weeks.	Everolimus 5 mg/Day Patients from 2.5 mg/day up-titrated after 4 weeks and followed by a dose of 5 mg/day for another 4 weeks.	Everolimus 10 mg/Day Patients who had received 2.5 mg/day for first 4 weeks, up titrated to 5 mg/day and continued for another 4 weeks, again up-titrated to 10 mg/day for 18 weeks.
Change From Baseline in Forced Vital Capacity (FVC)	10 mL Interval -111.0 to 132.0	—	—

SECONDARY outcome

Timeframe: Baseline, 26 weeks

Population: Pharmacodynamic analysis set for everolimus reporting arm. Patients with both baseline and 26 weeks assessment were included in this analysis.

All spirometry evaluation followed the recommendations of the Standardization of Lung Function Testing. All spirometry maneuvers were performed in the sitting position whilst wearing nose clips. At least three acceptable maneuvers were performed for each time point, and the results met within-test and between-test criteria for acceptability. The highest value was obtained of FEV1 from any of the three maneuvers that met acceptability criteria. Change from baseline in FEV1 was compared between everolimus and historical placebo data from the MILES study (NCT00414648) due to the absence of a placebo group in this current study on a rare lung disease. These two studies had different study designs, so the change from baseline to 6 months (26 weeks) in MILES study was estimated from the publicly reported rate of change per month in order to provide a meaningful comparison. This historical control can be viewed on the Novartis Clinical Trial Results website.

Outcome measures

Outcome measures
Measure	Everolimus 2.5 mg/Day n=23 Participants All patients received a starting dose of everolimus 2.5mg/day for first 4 weeks.	Everolimus 5 mg/Day Patients from 2.5 mg/day up-titrated after 4 weeks and followed by a dose of 5 mg/day for another 4 weeks.	Everolimus 10 mg/Day Patients who had received 2.5 mg/day for first 4 weeks, up titrated to 5 mg/day and continued for another 4 weeks, again up-titrated to 10 mg/day for 18 weeks.
Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)	114 mL Interval 11.0 to 217.0	—	—

SECONDARY outcome

Timeframe: Baseline, 26 weeks

Population: Pharmacodynamic analysis set. Patients with both baseline and 26 weeks assessment were included in the analysis.

Extended pulmonary function testing such as Total Lung Capacity (TLC), Thoracic Gas Volume (TGV), Residual Volume (RV) were measured using a body plethysmograph

Outcome measures

Outcome measures
Measure	Everolimus 2.5 mg/Day n=22 Participants All patients received a starting dose of everolimus 2.5mg/day for first 4 weeks.	Everolimus 5 mg/Day Patients from 2.5 mg/day up-titrated after 4 weeks and followed by a dose of 5 mg/day for another 4 weeks.	Everolimus 10 mg/Day Patients who had received 2.5 mg/day for first 4 weeks, up titrated to 5 mg/day and continued for another 4 weeks, again up-titrated to 10 mg/day for 18 weeks.
Change From Baseline in Extended Pulmonary Function Testing TLC	0.199 Liters (L) Standard Deviation 0.8645	—	—
Change From Baseline in Extended Pulmonary Function Testing TGV	0.267 Liters (L) Standard Deviation 1.0368	—	—
Change From Baseline in Extended Pulmonary Function Testing RV	0.169 Liters (L) Standard Deviation 0.9055	—	—

SECONDARY outcome

Timeframe: Baseline, 26 weeks

Population: Pharmacodynamic analysis set. Patients with both baseline and 26 weeks assessment were included in the analysis.

Carbon Monoxide Diffusing Capacity (DLCO) one of the extended pulmonary function testing which was also measured using a body plethysmograph.

Outcome measures

Outcome measures
Measure	Everolimus 2.5 mg/Day n=22 Participants All patients received a starting dose of everolimus 2.5mg/day for first 4 weeks.	Everolimus 5 mg/Day Patients from 2.5 mg/day up-titrated after 4 weeks and followed by a dose of 5 mg/day for another 4 weeks.	Everolimus 10 mg/Day Patients who had received 2.5 mg/day for first 4 weeks, up titrated to 5 mg/day and continued for another 4 weeks, again up-titrated to 10 mg/day for 18 weeks.
Change From Baseline in Carbon Monoxide Diffusing Capacity (DLCO)	-0.782 ml/min/mmHg Standard Deviation 1.5351	—	—

SECONDARY outcome

Timeframe: Baseline, 26 weeks

Population: Pharmacodynamic analysis set. Patients with both baseline and 26 weeks assessment were included in the analysis.

A standardized 6-minute walk test (6MWT) was performed in accordance with the guidelines of the American Thoracic Society 2002. The test was done about the same time of day to avoid diurnal variation in an environment that had an adequate temperature to avoid additional burden to the patient due to heat or cold air. The distance walked in six minutes (6MWD) was recorded.

Outcome measures

Outcome measures
Measure	Everolimus 2.5 mg/Day n=23 Participants All patients received a starting dose of everolimus 2.5mg/day for first 4 weeks.	Everolimus 5 mg/Day Patients from 2.5 mg/day up-titrated after 4 weeks and followed by a dose of 5 mg/day for another 4 weeks.	Everolimus 10 mg/Day Patients who had received 2.5 mg/day for first 4 weeks, up titrated to 5 mg/day and continued for another 4 weeks, again up-titrated to 10 mg/day for 18 weeks.
Change From Baseline in 6-minute Walk Test Score to Measure Exercise Capacity	46.9 meters (m) Standard Deviation 115.30	—	—

SECONDARY outcome

Timeframe: Baseline, 26 weeks

Population: Pharmacodynamic analysis set. Patients with both baseline and 26 weeks assessment were included in the analysis.

Oxygen saturation means the amount of oxygen in blood stream. Oxygen saturation was measured by using a Pulse Oximeter.

Outcome measures

Outcome measures
Measure	Everolimus 2.5 mg/Day n=23 Participants All patients received a starting dose of everolimus 2.5mg/day for first 4 weeks.	Everolimus 5 mg/Day Patients from 2.5 mg/day up-titrated after 4 weeks and followed by a dose of 5 mg/day for another 4 weeks.	Everolimus 10 mg/Day Patients who had received 2.5 mg/day for first 4 weeks, up titrated to 5 mg/day and continued for another 4 weeks, again up-titrated to 10 mg/day for 18 weeks.
Change From Baseline in Oxygen Saturation	0.8 percentage of oxygen Standard Deviation 2.13	—	—

Adverse Events

Everolimus

Serious events: 8 serious events

Other events: 24 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Everolimus n=24 participants at risk All patients received a starting dose of everolimus 2.5mg/day for 4 weeks, followed by a dose of 5 mg/day for 4 weeks and finally a dose of 10mg/day for 18 weeks. The 26 week treatment period was followed by an optional extension period wherein patients continued therapy until the last patient had completed 26-weeks of treatment. The longest period a patient participated in the study was 62 weeks.
Cardiac disorders Cardiac failure	4.2% 1/24 Safety set includes all the patients who had received at least one dose of study drug.
Cardiac disorders Pericarditis	4.2% 1/24 Safety set includes all the patients who had received at least one dose of study drug.
Cardiac disorders Tachycardia	4.2% 1/24 Safety set includes all the patients who had received at least one dose of study drug.
General disorders Non-cardiac chest pain	4.2% 1/24 Safety set includes all the patients who had received at least one dose of study drug.
General disorders Oedema peripheral	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
General disorders Pyrexia	4.2% 1/24 Safety set includes all the patients who had received at least one dose of study drug.
Infections and infestations Bronchitis	4.2% 1/24 Safety set includes all the patients who had received at least one dose of study drug.
Infections and infestations Pneumocystis jiroveci infection	4.2% 1/24 Safety set includes all the patients who had received at least one dose of study drug.
Infections and infestations Pneumonia	4.2% 1/24 Safety set includes all the patients who had received at least one dose of study drug.
Renal and urinary disorders Nephrolithiasis	4.2% 1/24 Safety set includes all the patients who had received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	4.2% 1/24 Safety set includes all the patients who had received at least one dose of study drug.

Other adverse events

Other adverse events
Measure	Everolimus n=24 participants at risk All patients received a starting dose of everolimus 2.5mg/day for 4 weeks, followed by a dose of 5 mg/day for 4 weeks and finally a dose of 10mg/day for 18 weeks. The 26 week treatment period was followed by an optional extension period wherein patients continued therapy until the last patient had completed 26-weeks of treatment. The longest period a patient participated in the study was 62 weeks.
Gastrointestinal disorders Abdominal pain upper	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Gastrointestinal disorders Aphthous stomatitis	20.8% 5/24 Safety set includes all the patients who had received at least one dose of study drug.
Gastrointestinal disorders Constipation	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Gastrointestinal disorders Diarrhoea	29.2% 7/24 Safety set includes all the patients who had received at least one dose of study drug.
Gastrointestinal disorders Haemorrhoids	12.5% 3/24 Safety set includes all the patients who had received at least one dose of study drug.
Gastrointestinal disorders Mouth ulceration	45.8% 11/24 Safety set includes all the patients who had received at least one dose of study drug.
Gastrointestinal disorders Nausea	29.2% 7/24 Safety set includes all the patients who had received at least one dose of study drug.
Gastrointestinal disorders Stomatitis	29.2% 7/24 Safety set includes all the patients who had received at least one dose of study drug.
Gastrointestinal disorders Vomiting	16.7% 4/24 Safety set includes all the patients who had received at least one dose of study drug.
General disorders Fatigue	29.2% 7/24 Safety set includes all the patients who had received at least one dose of study drug.
General disorders Non-cardiac chest pain	20.8% 5/24 Safety set includes all the patients who had received at least one dose of study drug.
General disorders Oedema peripheral	25.0% 6/24 Safety set includes all the patients who had received at least one dose of study drug.
General disorders Pyrexia	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Infections and infestations Bronchitis	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Infections and infestations Ear infection	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Infections and infestations Furuncle	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Infections and infestations Influenza	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Infections and infestations Nasopharyngitis	16.7% 4/24 Safety set includes all the patients who had received at least one dose of study drug.
Infections and infestations Oral herpes	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Infections and infestations Upper respiratory tract infection	12.5% 3/24 Safety set includes all the patients who had received at least one dose of study drug.
Infections and infestations Urinary tract infection	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Infections and infestations Vulvovaginal mycotic infection	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Injury, poisoning and procedural complications Post-traumatic pain	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Investigations Gamma-glutamyltransferase increased	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Metabolism and nutrition disorders Decreased appetite	12.5% 3/24 Safety set includes all the patients who had received at least one dose of study drug.
Metabolism and nutrition disorders Hypercholesterolaemia	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Metabolism and nutrition disorders Hypokalaemia	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	16.7% 4/24 Safety set includes all the patients who had received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Back pain	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Flank pain	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Muscle spasms	12.5% 3/24 Safety set includes all the patients who had received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Myalgia	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Nervous system disorders Headache	37.5% 9/24 Safety set includes all the patients who had received at least one dose of study drug.
Psychiatric disorders Insomnia	12.5% 3/24 Safety set includes all the patients who had received at least one dose of study drug.
Reproductive system and breast disorders Dysmenorrhoea	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Reproductive system and breast disorders Menorrhagia	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Reproductive system and breast disorders Menometorrhagia	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Reproductive system and breast disorders Pelvic pain	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	29.2% 7/24 Safety set includes all the patients who had received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Nasal congestion	16.7% 4/24 Safety set includes all the patients who had received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	29.2% 7/24 Safety set includes all the patients who had received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Upper-airway cough syndrome	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Skin and subcutaneous tissue disorders Acne	20.8% 5/24 Safety set includes all the patients who had received at least one dose of study drug.
Skin and subcutaneous tissue disorders Dry skin	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.
Skin and subcutaneous tissue disorders Pruritus	12.5% 3/24 Safety set includes all the patients who had received at least one dose of study drug.
Skin and subcutaneous tissue disorders Rash	12.5% 3/24 Safety set includes all the patients who had received at least one dose of study drug.
Vascular disorders Hypertension	8.3% 2/24 Safety set includes all the patients who had received at least one dose of study drug.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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 trial results in their entirety.
Publication restrictions are in place

Restriction type: OTHER