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

Lymphangioleiomyomatosis (LAM) Clinical Trial

— EXIST-2  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00790400
• Other study ID #: CRAD001M2302
• Secondary ID: 2008-002113-48
• Status: Completed
• Phase: Phase 3
• First received: November 10, 2008
• Last updated: January 26, 2016
• Start date: April 2009
• Est. completion date: September 2015

Study information

• Verified date: January 2016
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Health CanadaFrance: Ministry of HealthGermany: Federal Institute for Drugs and Medical DevicesItaly: Ministry of HealthJapan: Ministry of Health, Labour and Welfare, Pharmaceutical amd Medical Safety BureauNetherlands: Medical Ethics Review Committee (METC)Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsRussia: Federal Service on Surveillance in Healthcare and Social Development of Russian FederationSpain: Ministerio de Sanidad y Politica SocialUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyJapan: Ministry of Health, Labour and Welfare, Pharmaceutical and Medical Safety Bureau
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 118
• Est. completion date: September 2015
• Est. primary completion date: September 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Non-interventional follow-up inclusion:

• No angiomyolipoma progression at time of study treatment discontinuation and no plan to continue treating their angiomyolipoma(s) with systemic therapy

• Non-interventional follow-up phase consent

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

Non-interventional follow-up phase exclusion:

• Starting treatment with any mTOR inhibitor

• Embolization immediately after discontinuing study treatment

• Surgical resection of angiomyolipoma after discontinuing study treatment

• Prior kidney CT/MRI already performed 1-year after discontinuation of everolimus

Other protocol-defined inclusion/exclusion criteria may apply

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Angiomyolipoma
• Lymphangioleiomyomatosis
• Lymphangioleiomyomatosis (LAM)
• Sclerosis
• Tuberous Sclerosis
• Tuberous Sclerosis Complex (TSC)

Intervention

Drug:
• Everolimus (RAD001)
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.
• Placebo
Matching placebo was provided as a matching tablet and was also blister-packed under aluminum foil in units of ten.

Locations

Country	Name	City	State
Canada	Novartis Investigative Site	Torono	Ontario
France	Novartis Investigative Site	Lyon
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	München
Italy	Novartis Investigative Site	Roma
Italy	Novartis Investigative Site	Siena	SI
Italy	Novartis Investigative Site	Torino	TO
Japan	Novartis Investigative Site	Sapporo-city	Hokkaido
Japan	Novartis Investigative Site	Suita-city	Osaka
Japan	Novartis Investigative Site	Yamagata
Netherlands	Novartis Investigative Site	Utrecht
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Warszawa
Russian Federation	Novartis Investigative Site	Moscow
Spain	Novartis Investigative Site	Barcelona	Catalunya
United Kingdom	Novartis Investigative Site	Brighton	East Sussex
United Kingdom	Novartis Investigative Site	Cardiff	Wales
United Kingdom	Novartis Investigative Site	Craigavon	Northern Ireland
United Kingdom	Novartis Investigative Site	London
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital Massachussetts General Hospita	Boston	Massachusetts
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	LeBonheur Childrens Medical Group SC-2	Memphis	Tennessee
United States	Barrow Tuberous Sclerosis Center	Phoenix	Arizona
United States	Minnesota Epilepsy Group - PA	St. Paul	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Italy,  Japan,  Netherlands,  Poland,  Russian Federation,  Spain,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Angiomyolipoma Response Rate as Per Central Radiology Review (Double-blind Period)	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	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 analysis cut-off date (30-June-2011).	No
Secondary	Time to Angiomyolipoma Progression as Per Central Radiology Review (Double-blind Period)	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	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 analysis cut-off date (30-June-2011).	No
Secondary	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).	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 analysis cut-off date (30-June-2011).	No
Secondary	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.	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 analysis cut-off date (30-June-2011).	Yes
Secondary	Change From Baseline in Plasma Angiogenic Molecules		Baseline, 12 Months	No