Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM) (EXIST-2)
This study is ongoing, but not recruiting participants.
Sponsor:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00790400
First received: November 10, 2008
Last updated: February 5, 2015
Last verified: February 2015
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Purpose
This study will evaluate the safety and efficacy of RAD001 in treating patients with Angiomyolipoma associated with Tuberous Sclerosis Complex or Sporadic Lymphangioleiomyomatosis.
| Condition | Intervention | Phase |
|---|---|---|
|
Tuberous Sclerosis Complex (TSC) Lymphangioleiomyomatosis (LAM) |
Drug: Everolimus (RAD001) Drug: Placebo |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment |
| 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) |
Resource links provided by NLM:
MedlinePlus related topics:
Tuberous Sclerosis
Genetic and Rare Diseases Information Center resources:
Anaplastic Astrocytoma
Bourneville Syndrome
Gliosarcoma
Lymphangioleiomyomatosis
Subependymal Giant Cell Astrocytoma
Tuberous Sclerosis
U.S. FDA Resources
Further study details as provided by Novartis:
Primary Outcome Measures:
- Angiomyolipoma Response Rate as Per Central Radiology Review (Double-blind Period) [ Time Frame: 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). ] [ Designated as safety issue: No ]
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
Secondary Outcome Measures:
- Time to Angiomyolipoma Progression as Per Central Radiology Review (Double-blind Period) [ Time Frame: 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). ] [ Designated as safety issue: No ]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
- Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline) [ Time Frame: 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). ] [ Designated as safety issue: No ]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).
- Percentage of Participants With Renal Impairment [ Time Frame: 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). ] [ Designated as safety issue: Yes ]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.
- Change From Baseline in Plasma Angiogenic Molecules [ Time Frame: Baseline, 12 Months ] [ Designated as safety issue: No ]
| Enrollment: | 118 |
| Study Start Date: | April 2009 |
| Estimated Study Completion Date: | December 2015 |
| Primary Completion Date: | June 2011 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Everolimus
Study drug was given by continuous oral daily dosing of two 5 mg tablets.
|
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.
Other Name: RAD001
|
|
Placebo Comparator: Placebo
Placebo was given by continuous oral daily dosing of two 5 mg tablets. (Placebo arm closed when study was unblinded and all patients transitioned to everolimus.)
|
Drug: Placebo
Matching placebo was provided as a matching tablet and was also blister-packed under aluminum foil in units of ten.
|
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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
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
Contacts and Locations
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To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00790400
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00790400
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Locations
| United States, Alabama | |
| University of Alabama at Birmingham | |
| Birmingham, Alabama, United States, 35294 | |
| United States, Arizona | |
| Barrow Tuberous Sclerosis Center | |
| Phoenix, Arizona, United States, 85013 | |
| United States, Massachusetts | |
| Massachusetts General Hospital Massachussetts General Hospita | |
| Boston, Massachusetts, United States, 02114 | |
| United States, Minnesota | |
| Minnesota Epilepsy Group - PA | |
| St. Paul, Minnesota, United States, 55102-2383 | |
| United States, Ohio | |
| Cincinnati Children's Hospital Medical Center | |
| Cincinnati, Ohio, United States, 45229-3039 | |
| United States, Tennessee | |
| LeBonheur Childrens Medical Group SC-2 | |
| Memphis, Tennessee, United States, 38103 | |
| Canada, Ontario | |
| Novartis Investigative Site | |
| Torono, Ontario, Canada, M5G 2C4 | |
| France | |
| Novartis Investigative Site | |
| Lyon, France, 69003 | |
| Germany | |
| Novartis Investigative Site | |
| Berlin, Germany, 10098 | |
| Novartis Investigative Site | |
| Muenchen, Germany, 80336 | |
| Italy | |
| Novartis Investigative Site | |
| Milano, MI, Italy, 20142 | |
| Novartis Investigative Site | |
| Siena, SI, Italy, 53100 | |
| Novartis Investigative Site | |
| Torino, TO, Italy, 10126 | |
| Novartis Investigative Site | |
| Roma, Italy, 00137 | |
| Japan | |
| Novartis Investigative Site | |
| Sapporo-city, Hokkaido, Japan, 060-8648 | |
| Novartis Investigative Site | |
| Suita-city, Osaka, Japan, 565-0871 | |
| Novartis Investigative Site | |
| Yamagata, Japan, 990-9585 | |
| Netherlands | |
| Novartis Investigative Site | |
| Utrecht, Netherlands, 3584CX | |
| Poland | |
| Novartis Investigative Site | |
| Warszawa, Poland, 04-730 | |
| Novartis Investigative Site | |
| Warszawa, Poland, 01138 | |
| Russian Federation | |
| Novartis Investigative Site | |
| Moscow, Russian Federation, 127412 | |
| Spain | |
| Novartis Investigative Site | |
| Barcelona, Catalunya, Spain, 08025 | |
| United Kingdom | |
| Novartis Investigative Site | |
| Brighton, East Sussex, United Kingdom, BN2 5BE | |
| Novartis Investigative Site | |
| Craigavon, Northern Ireland, United Kingdom, BT63 5QQ | |
| Novartis Investigative Site | |
| Cardiff, Wales, United Kingdom, CF14 4XN | |
| Novartis Investigative Site | |
| London, United Kingdom, SW17 0QT | |
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
More Information
Additional Information:
Publications:
| Responsible Party: | Novartis ( Novartis Pharmaceuticals ) |
| ClinicalTrials.gov Identifier: | NCT00790400 History of Changes |
| Other Study ID Numbers: | CRAD001M2302, 2008-002113-48 |
| Study First Received: | November 10, 2008 |
| Results First Received: | May 23, 2012 |
| Last Updated: | February 5, 2015 |
| Health Authority: | United States: Food and Drug Administration Canada: Health Canada France: Ministry of Health Germany: Federal Institute for Drugs and Medical Devices Italy: Ministry of Health Japan: Ministry of Health, Labour and Welfare, Pharmaceutical amd Medical Safety Bureau Netherlands: Medical Ethics Review Committee (METC) Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products Russia: Federal Service on Surveillance in Healthcare and Social Development of Russian Federation Spain: Ministerio de Sanidad y Politica Social United Kingdom: Medicines and Healthcare Products Regulatory Agency Japan: Ministry of Health, Labour and Welfare, Pharmaceutical and Medical Safety Bureau |
Keywords provided by Novartis:
|
Angiomyolipoma AML Tuberous Sclerosis Complex TSC mTOR RAD001 |
Mammalian Target of Rapamycin Everolimus Afinitor SEGA Subependymal Giant Cell Astrocytoma Seizures |
Additional relevant MeSH terms:
|
Angiomyolipoma Lymphangioleiomyomatosis Sclerosis Tuberous Sclerosis Congenital Abnormalities Genetic Diseases, Inborn Hamartoma Heredodegenerative Disorders, Nervous System Immune System Diseases Immunoproliferative Disorders Lymphangiomyoma Lymphatic Diseases Lymphatic Vessel Tumors Lymphoproliferative Disorders Malformations of Cortical Development |
Neoplasms Neoplasms by Histologic Type Neoplasms, Adipose Tissue Neoplasms, Connective and Soft Tissue Neoplasms, Multiple Primary Neoplastic Syndromes, Hereditary Nervous System Diseases Nervous System Malformations Neurocutaneous Syndromes Neurodegenerative Diseases Pathologic Processes Perivascular Epithelioid Cell Neoplasms Everolimus Sirolimus Anti-Bacterial Agents |
ClinicalTrials.gov processed this record on March 03, 2015