A Phase 3 interventional study of Everolimus (RAD001) and Everolimus Placebo in Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM), sponsored by Novartis Pharmaceuticals. Completed at 25 sites in 11 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-02-17.
Sponsored by Novartis Pharmaceuticals · Phase 3, Interventional, and Treatment
This study will evaluate the safety and efficacy of RAD001 in treating patients with Angiomyolipoma associated with Tuberous Sclerosis Complex or Sporadic Lymphangioleiomyomatosis.
109 studies on the registry are indexed under Tuberous Sclerosis; 27 are open to participants now.
This study's enrollment of 118 is above the median of 50 across 70 interventional studies indexed under Tuberous Sclerosis.
Browse Tuberous Sclerosis studies →Novartis Pharmaceuticals is the lead sponsor of 2,673 studies on the registry; 228 are open to participants now.
Of its 576 completed or terminated interventional studies of FDA-regulated products, 431 (75%) have results posted.
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Exclusion Criteria:
Study drug was given by continuous oral daily dosing of two 5 mg tablets.
Drug: Everolimus (RAD001)
Placebo was given by continuous oral daily dosing of two 5 mg tablets.
Drug: Everolimus Placebo
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.
Also known as: RAD001
Matching placebo was provided as a matching tablet and was also blister-packed under aluminum foil in units of ten.
Angiomyolipoma Response Rate as Per Central Radiology Review
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.
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 Progression as Per Central Radiology Review
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.
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
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). 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.
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
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. Severe renal impairment was defined as a GFR of \<30ml/min/1.73m2.
Time frame: Day 1 up to 28 days after end of treatment
Change From Baseline in Plasma Angiogenic Molecules - Vascular Endothelial Growth Factor (VEGF) Marker
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.
Time frame: 4 weeks, 12 weeks, 24 weeks, 36 weeks 48 weeks, 60 weeks, 72 weeks
Everolimus Trough Concentrations (Cmin)
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.
Time frame: Prior to dosing at weeks 2, 4, 12, 24, 48
Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose
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 frame: 2 hours post-dose administration at Weeks 2, 4, 12, 24, 48
Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response
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.
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
Duration of Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response
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.
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
Duration of Skin Lesion Response - Only Everolimus Patients With Best Overall Skin Lesion Response of Complete Clinical Response (CCR) or Partial Response (PR)
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.
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
A multicenter trial conducted at 24 sites in 11 countries. As the primary analysis of the core phase of the study favored everolimus over placebo, an open-label extension phase started: patients randomized in placebo were offered to switch on everolimus and those still receiving everolimus at the end of the core phase could continue the treatment.
| Milestone | Everolimus | Placebo |
|---|---|---|
| Started | 79 | 39 |
| Completed | 72 | 26 |
| Not completed | 7 | 13 |
| Withdrew: Protocol violation | 1 | 0 |
| Withdrew: Progressive disease | 0 | 9 |
| Withdrew: Adverse event | 2 | 4 |
| Withdrew: Abnormal lab value (s) | 1 | 0 |
| Withdrew: Withdrawal by subject | 1 | 0 |
| Withdrew: Administrative problems | 1 | 0 |
| Withdrew: Death | 1 | 0 |
| Milestone | Everolimus | Placebo |
|---|---|---|
| Started | 112 | 0 |
| Completed | 83 | 0 |
| Not completed | 29 | 0 |
| Withdrew: Adverse event | 9 | 0 |
| Withdrew: Abnormal lab value (s) | 1 | 0 |
| Withdrew: Withdrawal by subject | 7 | 0 |
| Withdrew: Lost to follow-up | 1 | 0 |
| Withdrew: Administrative problems | 2 | 0 |
| Withdrew: Death | 1 | 0 |
| Withdrew: Disease progression | 5 | 0 |
| Withdrew: Protocol violation | 1 | 0 |
| Withdrew: New treatment | 2 | 0 |
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.
| Percentage of Participants | Everolimus Randomized (Core Period) | Placebo Randomized (Core Period) | Everolimus (Core and/or Extension Period) |
|---|---|---|---|
| Angiomyolipoma Response Rate as Per Central Radiology Review | 41.8 (30.8 to 53.4) | 0 (0.0 to 9.0) | 58.0 (48.3 to 67.3) |
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.
| months | Everolimus Randomized (Core Period) | Placebo Randomized (Core Period) | Everolimus (Core and/or Extension Period) |
|---|---|---|---|
| Time to Angiomyolipoma Progression as Per Central Radiology Review | NA (NA to NA) | 11.37 (11.07 to NA) | NA (NA to NA) |
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 | Everolimus Randomized (Core Period) | Placebo Randomized (Core Period) | Everolimus (Core and/or Extension Period) |
|---|---|---|---|
| Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline) | 26 (16.6 to 37.2) | 0 (0.0 to 9.5) | 68.2 (58.5 to 76.9) |
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.
| Percentage of Participants | Everolimus Randomized (Core Period) | Placebo Randomized (Core Period) | Everolimus (Core and/or Extension Period) |
|---|---|---|---|
| Glomerular filtration rate <30 ml/min/1.73m^2 | 2.5 | 7.7 | 7.1 |
| Glomerular filtration rate≥ 30 ml/min/1.73m^2 | 97.5 | 92.3 | 92.9 |
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.
| pg/mL | Everolimus Randomized (Core Period) | Placebo Randomized (Core Period) |
|---|---|---|
| Week 4 (n:56, 28) | 38.7 ± 141.89 | 17.6 ± 57.51 |
| Week 12 (n:56, 29) | 43.4 ± 60.62 | -6.1 ± 46.28 |
| Week 24 (n:53, 29) | 31.1 ± 75.83 | -4.3 ± 44.76 |
| Week 36 (n:26, 18) | 18.0 ± 45.07 | 5.4 ± 24.01 |
| Week 48 (n:16, 8) | 55.3 ± 80.31 | 3.1 ± 34.55 |
| Week 60 (n:0, 1) | NA ± NA | -4.12 ± NA |
| Week 72 (n:0, 1) | NA ± NA | -6.1 ± NA |
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.
| ng/mL | Everolimus Randomized (Core Period) |
|---|---|
| Prior to dosing at Week 2 (n:43) | 7.63 ± 4.32 |
| Prior to dosing Week 4 (n:44) | 7.72 ± 4.35 |
| Prior to dosing Week 12 (n:49) | 8.79 ± 6.75 |
| Prior to dosing Week 24 (n:46) | 9.37 ± 8.83 |
| Prior to dosing Week 48 (n:15) | 11.49 ± 12.01 |
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.
| ng/mL | Everolimus Randomized (Core Period) |
|---|---|
| 2 hours post dose administration at Week 2 (n:55) | 33.38 ± 15.66 |
| 2 hours post dose administration at Week 4 (n:49) | 30.89 ± 14.96 |
| 2 hours post dose administration at Week 12 (n:56) | 34.48 ± 15.10 |
| 2 hours post dose administration at Week 24 (n:50) | 39.27 ± 22.25 |
| 2 hours post dose administration at Week 48 (n:14) | 33.20 ± 18.45 |
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.
| months | Everolimus Randomized (Core Period) | Everolimus (Core and/or Extension Period) |
|---|---|---|
| Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response | 2.86 (2.79 to 3.02) | 2.89 (2.79 to 3.19) |
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.
| months | Everolimus Randomized (Core Period) | Everolimus (Core and/or Extension Period) |
|---|---|---|
| Duration of Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response | NA (NA to NA) | NA (NA to NA) |
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.
| months | Everolimus Randomized (Core Period) | Everolimus (Core and/or Extension Period) |
|---|---|---|
| Duration of Skin Lesion Response - Only Everolimus Patients With Best Overall Skin Lesion Response of Complete Clinical Response (CCR) or Partial Response (PR) | NA (NA to NA) | NA (NA to NA) |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Everolimus Randomized (Core & Ext) | — | 28/79 (35.4%) | 79/79 (100%) |
| Placebo Randomized/Crossed Over to Everolimus | — | 17/33 (51.5%) | 33/33 (100%) |
| Placebo Randomized/Never Crossed-over | — | 3/6 (50%) | 5/6 (83.3%) |
| Event | Everolimus Randomized (Core & Ext) | Placebo Randomized/Crossed Over to Everolimus | Placebo Randomized/Never Crossed-over |
|---|---|---|---|
| VolvulusGastrointestinal disorders | 0/79 | 0/33 | 1/6 |
| Incision site infectionInfections and infestations | 0/79 | 0/33 | 1/6 |
| AngiomyolipomaNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/79 | 0/33 | 1/6 |
| HallucinationPsychiatric disorders | 1/79 | 0/33 | 1/6 |
| PneumoniaInfections and infestations | 1/79 | 3/33 | 0/6 |
| EpilepsyNervous system disorders | 3/79 | 3/33 | 0/6 |
| Cardiac failure congestiveCardiac disorders | 0/79 | 1/33 | 0/6 |
| Vertigo positionalEar and labyrinth disorders | 0/79 | 1/33 | 0/6 |
| Abdominal adhesionsGastrointestinal disorders | 0/79 | 1/33 | 0/6 |
| Abdominal compartment syndromeGastrointestinal disorders | 0/79 | 1/33 | 0/6 |
| Event | Everolimus Randomized (Core & Ext) | Placebo Randomized/Crossed Over to Everolimus | Placebo Randomized/Never Crossed-over |
|---|---|---|---|
| NasopharyngitisInfections and infestations | 36/79 | 19/33 | 1/6 |
| StomatitisGastrointestinal disorders | 41/79 | 10/33 | 0/6 |
| HeadacheNervous system disorders | 26/79 | 15/33 | 0/6 |
| Back painMusculoskeletal and connective tissue disorders | 12/79 | 14/33 | 0/6 |
| FatigueGeneral disorders | 17/79 | 13/33 | 1/6 |
| HypercholesterolaemiaMetabolism and nutrition disorders | 29/79 | 11/33 | 0/6 |
| Aphthous stomatitisGastrointestinal disorders | 19/79 | 12/33 | 1/6 |
| Urinary tract infectionInfections and infestations | 25/79 | 12/33 | 1/6 |
| HypertensionVascular disorders | 22/79 | 12/33 | 0/6 |
| Abdominal painGastrointestinal disorders | 13/79 | 5/33 | 2/6 |
| Age, Continuous(years) | Everolimus | Placebo | Total |
|---|---|---|---|
| Mean | 32.5 ± 10.37 | 31.0 ± 9.64 | 32.0 ± 10.12 |
| Age, Customized(Participants) | Everolimus | Placebo | Total |
|---|---|---|---|
| <30 years | 35 | 20 | 55 |
| ≥ 30 years | 44 | 19 | 63 |
| Gender(Participants) | Everolimus | Placebo | Total |
|---|---|---|---|
| Female | 52 | 26 | 78 |
| Male | 27 | 13 | 40 |
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