NCT00790400 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2017-02-17

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

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Angiomyolipoma Response Rate as Per Central Radiology Review

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outcome · POSTED

Time to Angiomyolipoma Progression as Per Central Radiology Review

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outcome · POSTED

Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)

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outcome · POSTED

Percentage of Participants With Renal Impairment

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outcome · POSTED

Change From Baseline in Plasma Angiogenic Molecules - Vascular Endothelial Growth Factor (VEGF) Marker

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outcome · POSTED

Everolimus Trough Concentrations (Cmin)

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outcome · POSTED

Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose

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outcome · POSTED

Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response

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outcome · POSTED

Duration of Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response

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outcome · POSTED

Duration of Skin Lesion Response - Only Everolimus Patients With Best Overall Skin Lesion Response of Complete Clinical Response (CCR) or Partial Response (PR)

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

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
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
Study drug was given by continuous oral daily dosing of two 5 mg tablets.
intervention Names
Drug: Everolimus (RAD001)
label
Everolimus
type
EXPERIMENTAL
description
Placebo was given by continuous oral daily dosing of two 5 mg tablets.
intervention Names
Drug: Everolimus Placebo
label
Placebo
type
PLACEBO_COMPARATOR

interventions

arm Group Labels
Everolimus
description
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.
name
Everolimus (RAD001)
other Names
RAD001
type
DRUG
arm Group Labels
Placebo
description
Matching placebo was provided as a matching tablet and was also blister-packed under aluminum foil in units of ten.
name
Everolimus Placebo
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: QUADRUPLE
who Masked: PARTICIPANT
CARE_PROVIDER
INVESTIGATOR
OUTCOMES_ASSESSOR

primary Purpose

TREATMENT

Enrollment

count: 118
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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. For the everolimus (core/extension periods) treatment group, the baseline means the latest value on or before starting everolimus.
measure
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

secondary Outcomes

description
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.
measure
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
description
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.
measure
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
description
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.
measure
Percentage of Participants With Renal Impairment
time Frame
Day 1 up to 28 days after end of treatment
description
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.
measure
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
description
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.
measure
Everolimus Trough Concentrations (Cmin)
time Frame
Prior to dosing at weeks 2, 4, 12, 24, 48
description
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.
measure
Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose
time Frame
2 hours post-dose administration at Weeks 2, 4, 12, 24, 48
description
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.
measure
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
description
Duration of angiomyolipoma response was defined as the time from the date of the first documented angiomyolipoma response until the date of the first documented angiomyolipoma progression . Angiomyolipoma response was 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.
measure
Duration of 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 about 5.7 years
description
Duration of skin lesion response is defined as the time from the date of the first skin lesion response until the date of the first skin lesion progression, according to the PGA (physician's global assessment of clinical condition). A progression is when the disease is worse than at baseline evaluation by \>=25% or more.
measure
Duration of Skin Lesion Response - Only Everolimus Patients With Best Overall Skin Lesion Response of Complete Clinical Response (CCR) or Partial Response (PR)
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

Full study description

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.

Source references

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.
pmid
23312829
type
BACKGROUND
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.
pmid
30192751
type
DERIVED
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.
pmid
30053159
type
DERIVED
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.
pmid
29023494
type
DERIVED
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.
pmid
26156073
type
DERIVED