Clinical trial NCT00790400: Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Tuberous Sclerosis Complex (TSC)
Lymphangioleiomyomatosis (LAM)
Keywords: Angiomyolipoma
AML
Tuberous Sclerosis Complex
TSC
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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2008-11-13
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Angiomyolipoma Response Rate as Per Central Radiology Review
timeFrame: 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 outcomes:
measure: Time to Angiomyolipoma Progression as Per Central Radiology Review
timeFrame: 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
measure: Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)
timeFrame: 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
measure: Percentage of Participants With Renal Impairment
timeFrame: Day 1 up to 28 days after end of treatment
measure: Change From Baseline in Plasma Angiogenic Molecules - Vascular Endothelial Growth Factor (VEGF) Marker
timeFrame: 4 weeks, 12 weeks, 24 weeks, 36 weeks 48 weeks, 60 weeks, 72 weeks
measure: Everolimus Trough Concentrations (Cmin)
timeFrame: Prior to dosing at weeks 2, 4, 12, 24, 48
measure: Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose
timeFrame: 2 hours post-dose administration at Weeks 2, 4, 12, 24, 48
measure: Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response
timeFrame: 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
measure: Duration of Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response
timeFrame: 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
measure: Duration of Skin Lesion Response - Only Everolimus Patients With Best Overall Skin Lesion Response of Complete Clinical Response (CCR) or Partial Response (PR)
timeFrame: 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
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Barrow Tuberous Sclerosis Center
state: Arizona
city: Boston
country: United States
facility: Massachusetts General Hospital Massachussetts General Hospita
state: Massachusetts
city: St. Paul
country: United States
facility: Minnesota Epilepsy Group
state: Minnesota
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Memphis
country: United States
facility: LeBonheur Childrens Medical Group SC-2
state: Tennessee
city: Torono
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Lyon
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: München
country: Germany
facility: Novartis Investigative Site
city: Siena
country: Italy
facility: Novartis Investigative Site
state: SI
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Roma
country: Italy
facility: Novartis Investigative Site
city: Sapporo-city
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Suita-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Yamagata
country: Japan
facility: Novartis Investigative Site
city: Utrecht
country: Netherlands
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Brighton
country: United Kingdom
facility: Novartis Investigative Site
state: East Sussex
city: Craigavon
country: United Kingdom
facility: Novartis Investigative Site
state: Northern Ireland
city: Cardiff
country: United Kingdom
facility: Novartis Investigative Site
state: Wales
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, de Vries PJ, Whittemore VH, Chen D, Sahmoud T, Shah G, Lincy J, Lebwohl D, Budde K. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2013 Mar 9;381(9869):817-24. doi: 10.1016/S0140-6736(12)61767-X.
citation: Bissler JJ, Nonomura N, Budde K, Zonnenberg BA, Fischereder M, Voi M, Louveau AL, Herbst F, Bebin EM, Curatolo P, Zonta A, Belousova E. Angiomyolipoma rebound tumor growth after discontinuation of everolimus in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. PLoS One. 2018 Sep 7;13(9):e0201005. doi: 10.1371/journal.pone.0201005. eCollection 2018.
citation: Bissler JJ, Budde K, Sauter M, Franz DN, Zonnenberg BA, Frost MD, Belousova E, Berkowitz N, Ridolfi A, Christopher Kingswood J. Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2. Nephrol Dial Transplant. 2019 Jun 1;34(6):1000-1008. doi: 10.1093/ndt/gfy132.
citation: Sparagana S, Franz DN, Krueger DA, Bissler JJ, Berkowitz N, Burock K, Kingswood JC. Pooled analysis of menstrual irregularities from three major clinical studies evaluating everolimus for the treatment of tuberous sclerosis complex. PLoS One. 2017 Oct 12;12(10):e0186235. doi: 10.1371/journal.pone.0186235. eCollection 2017.
citation: Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, de Vries PJ, Berkowitz N, Miao S, Segal S, Peyrard S, Budde K. Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial. Nephrol Dial Transplant. 2016 Jan;31(1):111-9. doi: 10.1093/ndt/gfv249. Epub 2015 Jul 8.