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

Phase 3

Completed

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

Interventions: Drug: Everolimus (RAD001)
Drug: Everolimus Placebo

Registration Number: NCT00790400

Lead Sponsor: Novartis Pharmaceuticals

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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 118

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Everolimus	Everolimus (RAD001)	Study drug was given by continuous oral daily dosing of two 5 mg tablets.
Placebo	Everolimus Placebo	Placebo was given by continuous oral daily dosing of two 5 mg tablets.

Primary Outcome Measures

Name	Time	Method
Angiomyolipoma Response Rate as Per Central Radiology Review	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	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.

Secondary Outcome Measures

Name	Time	Method
Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)	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	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.
Change From Baseline in Plasma Angiogenic Molecules - Vascular Endothelial Growth Factor (VEGF) Marker	4 weeks, 12 weeks, 24 weeks, 36 weeks 48 weeks, 60 weeks, 72 weeks	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.
Everolimus Trough Concentrations (Cmin)	Prior to dosing at weeks 2, 4, 12, 24, 48	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.
Time to Angiomyolipoma Progression as Per Central Radiology Review	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	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.
Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose	2 hours post-dose administration at Weeks 2, 4, 12, 24, 48	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.
Percentage of Participants With Renal Impairment	Day 1 up to 28 days after end of treatment	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.
Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response	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	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.
Duration of Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response	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 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.
Duration of Skin Lesion Response - Only Everolimus Patients With Best Overall Skin Lesion Response of Complete Clinical Response (CCR) or Partial Response (PR)	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 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.

Trial Locations

Locations (7): Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Minnesota Epilepsy Group
🇺🇸
St. Paul, Minnesota, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
Barrow Tuberous Sclerosis Center
🇺🇸
Phoenix, Arizona, United States
Novartis Investigative Site
🇬🇧
London, United Kingdom
Massachusetts General Hospital Massachussetts General Hospita
🇺🇸
Boston, Massachusetts, United States
LeBonheur Childrens Medical Group SC-2
🇺🇸
Memphis, Tennessee, United States