Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)

Study Overview
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Brief Summary
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This study will evaluate the safety and efficacy of RAD001 in treating patients with Angiomyolipoma associated with Tuberous Sclerosis Complex or Sporadic Lymphangioleiomyomatosis.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study of RAD0001 in the Treatment of Angiomyolipoma in Patients With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)

Conditions
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Tuberous Sclerosis Complex (TSC), Lymphangioleiomyomatosis (LAM)

Intervention / Treatment
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* Drug: Everolimus (RAD001)
* Drug: Everolimus Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or Female 18 years or older Clinically definite diagnosis of Tuberous Sclerosis Complex according to the modified Gomez criteria or sporadic LAM (biopsy-proven or compatible chest CT scan) Clinically definite diagnosis of renal angiomyolipoma At least one Angiomyolipoma of ≥ 3 cm in its longest diameter using CT or MRI Females of child bearing potential must use birth control and have documentation of negative pregnancy test Written informed consent according to local guidelines Exclusion Criteria: Recent heart attack, cardiac related chest pain or stroke Severely impaired lung function Bleeding related to angiomyolipoma or embolization during 6 months prior to randomization Clinically significant chylous ascites Clinically significant hematological or hepatic abnormality Severe liver dysfunction Severe kidney dysfunction Pregnancy or breast feeding Current infection History of organ transplant Surgery within two months prior to study enrollment Prior therapy with a medication in the same class as Everolimus Recent use of an investigational drug Bleeding diathesis or on oral anti-vitamin K medication Uncontrolled high cholesterol Uncontrolled diabetes HIV Inability to attend scheduled clinic visits Patients with metal implants thus prohibiting MRI evaluations Angiomyolipoma which requires surgery at the time of randomization History of malignancy Severe or uncontrolled medical conditions which would cause an unacceptable safety risk or compromise compliance with the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus<br>Study drug was given by continuous oral daily dosing of two 5 mg tablets. | Drug: Everolimus (RAD001)<br>* Everolimus is used in 5 mg strength tablets, blister-packed under aluminum foil in units of ten tablets and dosed on a daily basis. 10mg daily dosing throughout the trial.<br>* Other names: RAD001;|
| Placebo Comparator: Placebo<br>Placebo was given by continuous oral daily dosing of two 5 mg tablets. | Drug: Everolimus Placebo<br>* Matching placebo was provided as a matching tablet and was also blister-packed under aluminum foil in units of ten.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Angiomyolipoma Response Rate as Per Central Radiology Review | Angiomyolipoma response defined as the combination of the following criteria: reduction in angiomyolipoma volume of ≥ 50% relative to baseline, where angiomyolipoma volume was sum of volumes of all target lesions identified at baseline, and with a confirmatory scan performed approximately 12 weeks later (no sooner than 8 weeks later); no new angiomyolipoma lesions ≥ 1.0 cm in longest diameter were identified; there were no kidney increases in volume > 20% from nadir. The patient did not have any angiomyolipoma-related bleeding of ≥ grade 2. For the everolimus (core/extension periods) treatment group, the baseline means the latest value on or before starting everolimus. | From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to 5.7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Angiomyolipoma Progression as Per Central Radiology Review | Time to angiomyolipoma progression (TTAP) is defined as time from date of randomization to date of first documented angiomyolipoma progression. Angiomyolipoma progression was defined as one or more of the following: Increase from nadir of ≥ 25% in angiomyolipoma volume to value greater than baseline; the appearance of a new angiomyolipoma ≥ 1.0 cm in longest diameter; an increase from nadir of 20% or more in the volume of either kidney to a value greater than baseline; angiomyolipoma-related bleeding grade ≥ 2. For the everolimus (core/extension periods) treatment group, the time to angiomyolipoma progression is defined starting from the start of everolimus. The baseline means the latest value on or before starting everolimus. | From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to about 5.7 years | 
| Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline) | Skin lesion response rate in the double-blind period was determined only among patients with at least one skin lesion at baseline, and is the percentage of this group of patients with a best overall skin lesion response on the Physician's Global Assessment of Clinical Condition (PGA) of either complete clinical response (CCR) or partial response (PR). A complete clinical response (CCR) requires a grading of 0 indicating the absence of disease (histological confirmation is not required). Grades 1, 2, and 3 constitute partial response, indicating improvement of at least 50 percent, but less than 100 percent improvement. For the everolimus (core/extension periods) treatment group, the baseline means the latest value on or before starting everolimus. | From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to 5.7 years | 
| Percentage of Participants With Renal Impairment | Renal Impairment was measured by glomerular filtration rate which was calculated using the Modification of Diet in Renal Disease formula. Percentage of participants with renal impairment was reported. Severe renal impairment was defined as a GFR of <30ml/min/1.73m2. | Day 1 up to 28 days after end of treatment | 
| Change From Baseline in Plasma Angiogenic Molecules - Vascular Endothelial Growth Factor (VEGF) Marker | Blood samples for biomarker assessment were collected immediately prior to study administration. On-treatment samples was compared to baseline samples with the change from baseline. | 4 weeks, 12 weeks, 24 weeks, 36 weeks 48 weeks, 60 weeks, 72 weeks | 
| Everolimus Trough Concentrations (Cmin) | Cmin values collected prior to dose administration on the same study day and at 20-28 hours after previous dose, at steady state, and patient did not vomit within 4 hours of previous dose. Samples collected during the first 4 days of dosing were excluded from all analyses. | Prior to dosing at weeks 2, 4, 12, 24, 48 | 
| Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose | C2h values collected 1-3 hours after dose administration on the same study day, at steady state, and patient did not vomit between taking previous dose and blood collection. Samples collected during the first 4 days of dosing will be excluded from all analyses. | 2 hours post-dose administration at Weeks 2, 4, 12, 24, 48 | 
| Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response | Time to angiomyolipoma response was defined as the time from the date of randomization until the date of the first documented angiomyolipoma response. Angiomyolipoma response defined as the combination of the following criteria: reduction in angiomyolipoma volume of ≥ 50% relative to baseline, where angiomyolipoma volume was sum of volumes of all target lesions identified at baseline, and with a confirmatory scan performed approximately 12 weeks later (no sooner than 8 weeks later); no new angiomyolipoma lesions ≥ 1.0 cm in longest diameter were identified; no kidney increases in volume > 20% from nadir; no angiomyolipoma-related bleeding of ≥ grade 2. For the everolimus (core/extension periods) treatment group, the time to angiomyolipoma response is from the start of everolimus. The baseline in the response definition means the latest value on or before starting everolimus. | From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to 5.7 years | 
| Duration of Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response | Duration of angiomyolipoma response was defined as the time from the date of the first documented angiomyolipoma response until the date of the first documented angiomyolipoma progression . Angiomyolipoma response was defined as the combination of the following criteria: reduction in angiomyolipoma volume of ≥ 50% relative to baseline, where angiomyolipoma volume was sum of volumes of all target lesions identified at baseline, and with a confirmatory scan performed approximately 12 weeks later (no sooner than 8 weeks later); no new angiomyolipoma lesions ≥ 1.0 cm in longest diameter were identified; there were no kidney increases in volume > 20% from nadir. The patient did not have any angiomyolipoma-related bleeding of ≥ grade 2. | From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to about 5.7 years | 
| Duration of Skin Lesion Response - Only Everolimus Patients With Best Overall Skin Lesion Response of Complete Clinical Response (CCR) or Partial Response (PR) | Duration of skin lesion response is defined as the time from the date of the first skin lesion response until the date of the first skin lesion progression, according to the PGA (physician's global assessment of clinical condition). A progression is when the disease is worse than at baseline evaluation by >=25% or more. | From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to about 5.7 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TSC, Angiomyolipoma, AML, Tuberous Sclerosis Complex, mTOR, RAD001, Mammalian Target of Rapamycin, Everolimus, Afinitor, SEGA, Subependymal Giant Cell Astrocytoma, Seizures, Tuberous sclerosis complex (TSC), Tuberous sclerosis, benign tumors of brain, kidney, heart, eyes, lungs, skinTSC1, TSC2, hamaratin, tuberin, tumor growth suppressors, gyri, tubers, Sporadic Lymphangioleiomyomatosis., Lymphangioleiomyomatosis (LAM), rare lung disease