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| ID | Type | Description | Link |
|---|---|---|---|
| 2010-019825-32 | EudraCT Number |
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This was an exploratory study to determine whether escalating doses of RAD001 (everolimus) were safe and effective in patients with Lymphangioleiomyomatosis
In addition to the data collected in this study, historical data from 43 patients treated with placebo from the multicenter trial of sirolimus in LAM (MILES) study (NCT00414648) were down weighted to an effective sample size of 18 for comparison of FEV1 and FVC endpoints. Reference to the publication of the MILES study has been provided under "Result Publication".
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Everolimus | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Everolimus | Drug | Everolimus was formulated as tablets in strengths of 2.5mg, 5mg and 10mg. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Vascular Endothelial Growth Factor-D (VEGF-D) Concentrations | 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) | Baseline, 26 weeks |
| Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State | Venous blood samples (2 mL) for pharmacokinetic evaluation were collected pre dose and 2 hours post dose at preselected visits. | pre-dose and at 2 hour post dose at week 26 |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Forced Vital Capacity (FVC) | 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. |
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Inclusion Criteria:
Exclusion Criteria:
Other protocol-defined inclusion/exclusion criteria may apply
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| Name | Affiliation | Role |
|---|---|---|
| Novartis | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Center for LAM Research and Clinical Care | Boston | Massachusetts | 02115 | United States | ||
| University of Cincinnati, Department of Internal Medicine, Pulmonary, Critical Care & Sleep Medicine, |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21410393 | Result | McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011 Apr 28;364(17):1595-606. doi: 10.1056/NEJMoa1100391. Epub 2011 Mar 16. | |
| 26113676 |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Core Study (26 Week) |
|
| |||||||||||||||||||||||||||||||||
| Extension (36 Week) |
|
Everolimus arm has all patients who received study drug that is the safety analysis set.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline in Vascular Endothelial Growth Factor-D (VEGF-D) Concentrations | 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) | 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. | Posted | Mean | Standard Deviation | pg/mL | Baseline, 26 weeks |
|
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Safety set includes all the patients who had received at least one dose of study drug.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cardiac failure | Cardiac disorders | MedDRA | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Novartis Pharmaceuticals | 862-778-8300 | trialandresults.registries@novartis.com |
| ID | Term |
|---|---|
| D018192 | Lymphangioleiomyomatosis |
| ID | Term |
|---|---|
| D008203 | Lymphangiomyoma |
| D018190 | Neoplasm, Lymphatic Tissue |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| D000068338 | Everolimus |
| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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| Baseline, 26 weeks |
| Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | 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. | Baseline, 26 weeks |
| Change From Baseline in Extended Pulmonary Function Testing | Extended pulmonary function testing such as Total Lung Capacity (TLC), Thoracic Gas Volume (TGV), Residual Volume (RV) were measured using a body plethysmograph | Baseline, 26 weeks |
| Change From Baseline in Carbon Monoxide Diffusing Capacity (DLCO) | Carbon Monoxide Diffusing Capacity (DLCO) one of the extended pulmonary function testing which was also measured using a body plethysmograph. | Baseline, 26 weeks |
| Change From Baseline in 6-minute Walk Test Score to Measure Exercise Capacity | 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. | Baseline, 26 weeks |
| Change From Baseline in Oxygen Saturation | Oxygen saturation means the amount of oxygen in blood stream. Oxygen saturation was measured by using a Pulse Oximeter. | Baseline, 26 weeks |
| Cincinnati |
| Ohio |
| 45267 |
| United States |
| Novartis Investigative Site | Lyon | France |
| Novartis Investigative Site | Milan | Italy |
| Derived |
| Goldberg HJ, Harari S, Cottin V, Rosas IO, Peters E, Biswal S, Cheng Y, Khindri S, Kovarik JM, Ma S, McCormack FX, Henske EP. Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study. Eur Respir J. 2015 Sep;46(3):783-94. doi: 10.1183/09031936.00210714. Epub 2015 Jun 25. |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| OG001 | 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. |
| OG002 | 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. |
|
|
| Primary | Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State | Venous blood samples (2 mL) for pharmacokinetic evaluation were collected pre dose and 2 hours post dose at preselected visits. | Pharmacokinetics analysis set. Patients with measurable data at particular time points were included in this analysis. | Posted | Mean | Standard Deviation | ng/mL | pre-dose and at 2 hour post dose at week 26 |
|
|
|
| Secondary | Change From Baseline in Forced Vital Capacity (FVC) | 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. | Pharmacodynamic analysis set for everolimus reporting arm. Patients with both baseline and 26 weeks assessment were included in this analysis. | Posted | Mean | 95% Confidence Interval | mL | Baseline, 26 weeks |
|
|
|
|
| Secondary | Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | 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. | Pharmacodynamic analysis set for everolimus reporting arm. Patients with both baseline and 26 weeks assessment were included in this analysis. | Posted | Mean | 95% Confidence Interval | mL | Baseline, 26 weeks |
|
|
|
|
| Secondary | Change From Baseline in Extended Pulmonary Function Testing | Extended pulmonary function testing such as Total Lung Capacity (TLC), Thoracic Gas Volume (TGV), Residual Volume (RV) were measured using a body plethysmograph | Pharmacodynamic analysis set. Patients with both baseline and 26 weeks assessment were included in the analysis. | Posted | Mean | Standard Deviation | Liters (L) | Baseline, 26 weeks |
|
|
|
| Secondary | Change From Baseline in Carbon Monoxide Diffusing Capacity (DLCO) | Carbon Monoxide Diffusing Capacity (DLCO) one of the extended pulmonary function testing which was also measured using a body plethysmograph. | Pharmacodynamic analysis set. Patients with both baseline and 26 weeks assessment were included in the analysis. | Posted | Mean | Standard Deviation | ml/min/mmHg | Baseline, 26 weeks |
|
|
|
| Secondary | Change From Baseline in 6-minute Walk Test Score to Measure Exercise Capacity | 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. | Pharmacodynamic analysis set. Patients with both baseline and 26 weeks assessment were included in the analysis. | Posted | Mean | Standard Deviation | meters (m) | Baseline, 26 weeks |
|
|
|
| Secondary | Change From Baseline in Oxygen Saturation | Oxygen saturation means the amount of oxygen in blood stream. Oxygen saturation was measured by using a Pulse Oximeter. | Pharmacodynamic analysis set. Patients with both baseline and 26 weeks assessment were included in the analysis. | Posted | Mean | Standard Deviation | percentage of oxygen | Baseline, 26 weeks |
|
|
|
| 8 |
| 24 |
| 24 |
| 24 |
| Pericarditis | Cardiac disorders | MedDRA | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | MedDRA | Systematic Assessment |
|
| Non-cardiac chest pain | General disorders | MedDRA | Systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA | Systematic Assessment |
|
| Bronchitis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Pneumocystis jiroveci infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA | Systematic Assessment |
|
| Nephrolithiasis | Renal and urinary disorders | MedDRA | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Aphthous stomatitis | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Haemorrhoids | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Mouth ulceration | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA | Systematic Assessment |
|
| Non-cardiac chest pain | General disorders | MedDRA | Systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA | Systematic Assessment |
|
| Bronchitis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Ear infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Furuncle | Infections and infestations | MedDRA | Systematic Assessment |
|
| Influenza | Infections and infestations | MedDRA | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Oral herpes | Infections and infestations | MedDRA | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Vulvovaginal mycotic infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Post-traumatic pain | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
|
| Gamma-glutamyltransferase increased | Investigations | MedDRA | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Hypercholesterolaemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Flank pain | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Dysmenorrhoea | Reproductive system and breast disorders | MedDRA | Systematic Assessment |
|
| Menorrhagia | Reproductive system and breast disorders | MedDRA | Systematic Assessment |
|
| Menometorrhagia | Reproductive system and breast disorders | MedDRA | Systematic Assessment |
|
| Pelvic pain | Reproductive system and breast disorders | MedDRA | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Upper-airway cough syndrome | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Acne | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA | Systematic Assessment |
|
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.
| D054973 |
| Perivascular Epithelioid Cell Neoplasms |
| D018204 | Neoplasms, Connective and Soft Tissue |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
| Peak (C2, ss) |
|
|
| Superiority or Other (legacy) |
| Superiority or Other (legacy) |
| Title | Measurements |
|---|---|
|