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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:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00790400
First received: November 10, 2008
Last updated: January 14, 2014
Last verified: January 2014

November 10, 2008
January 14, 2014
April 2009
June 2011   (final data collection date for primary outcome measure)
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

• Angiomyolipoma response rate through MRIs at screening, 12, 24 and 48 weeks and annually thereafter [ Time Frame: Screening, 12, 24, 48 weeks and annually for 4 years ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00790400 on ClinicalTrials.gov Archive Site
  • 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 ]
  • • Time to angiomyolipoma progression through MRIs at screening, 12, 24 and 48 weeks and annually thereafter [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (5 years). ] [ Designated as safety issue: Yes ]
  • • Skin lesion response rate tracked by digital photographs [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (5 years). ] [ Designated as safety issue: Yes ]
  • • Change from baseline in biomarkers collected during the first years of study [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (5 years). ] [ Designated as safety issue: Yes ]
  • • Changes in renal function by assessing creatinine clearance levels throughout the study [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (5 years). ] [ Designated as safety issue: Yes ]
  • • Safety assessed on a continuous basis throughout study [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (5 years). ] [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)
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)

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

Not Provided
Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Tuberous Sclerosis Complex (TSC)
  • Lymphangioleiomyomatosis (LAM)
  • 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
  • Drug: Placebo
    Matching placebo was provided as a matching tablet and was also blister-packed under aluminum foil in units of ten.
  • Experimental: Everolimus
    Study drug was given by continuous oral daily dosing of two 5 mg tablets.
    Intervention: Drug: Everolimus (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.)
    Intervention: Drug: Placebo
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
118
January 2015
June 2011   (final data collection date for primary outcome measure)

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

Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States,   Canada,   France,   Germany,   Italy,   Japan,   Netherlands,   Poland,   Russian Federation,   Spain,   United Kingdom
 
NCT00790400
CRAD001M2302, 2008-002113-48
Yes
Novartis ( Novartis Pharmaceuticals )
Novartis Pharmaceuticals
Not Provided
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Novartis
January 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP