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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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 Lym

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 Summary:
Sponsor: Novartis Pharmaceuticals

Current Primary Outcome: Angiomyolipoma Response Rate as Per Central Radiology Review [ 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 up to 5.7 years ]

Original Primary Outcome: • 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 ]

Current Secondary Outcome:

• Time to Angiomyolipoma Progression as Per Central Radiology Review [ 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 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.

• 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 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.
• Percentage of Participants With Renal Impairment [ Time Frame: 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.
• Change From Baseline in Plasma Angiogenic Molecules - Vascular Endothelial Growth Factor (VEGF) Marker [ Time Frame: 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) [ Time Frame: 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.
• Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose [ Time Frame: 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.
• Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response [ 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 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 [ Time Frame: From date of randomization until the earliest date of first documente
  
  

  Original Secondary Outcome:

  • • 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). ]
  • • 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). ]
  • • 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). ]
  • • 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). ]
  • • 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). ]
  
  
  Information By: Novartis
  

  Dates:
  Date Received: November 10, 2008
  Date Started: April 2009
  Date Completion:
  Last Updated: January 3, 2017
  Last Verified: January 2017