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The purpose of this study was to assess the safety and efficacy of everolimus (Afinitor®) in Chinese patients with renal angiomyolipoma (AML) associated with tuberous sclerosis complex (TSC).
This was an open label, single arm, multi-center, Phase IV Post-Approval Commitment (PAC) study with once daily oral dose of 10 mg everolimus in participants with renal AML associated with TSC. There were three separate phases in this study: a Screening phase, an Open-label treatment phase where participants received everolimus for 48 weeks or until disease progression, and a Treatment discontinuation follow-up phase for patients who discontinue study drug for reasons other than disease progression. Every participant had an End of Treatment visit within 28 days after last dose and a safety follow-up visit 30 days after last dose.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Everolimus | Experimental | Participants targeted to receive Everolimus tablets 10 mg orally once daily for 48 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Everolimus | Drug | Everolimus 2.5 mg and 5 mg tablets with dosage regimen of 10 mg orally once daily. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Percentage of participants with AEs and SAEs including significant changes from baseline in vital signs, electrocardiograms and laboratory parameters (laboratory assessments included hematology, biochemistry, coagulation and urinalysis) qualifying and reported as AEs. The percentage of participants in each category is reported in the table. | From the start of treatment to 30 days after end of treatment, assessed up to maximum duration of 52 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants With Best Overall Response (BOR) Status of Angiomyolipoma (AML) Response During Maximum Treatment Duration of 48 Weeks | BOR status is the best status recorded from start of treatment until disease progression. AML response status: reduction in AML volume of at least 50% relative to screening AML. In addition, AML response have to satisfy: no new AML ≥ 1 cm in longest diameter are identified, neither kidney increases in volume by more than 20% from nadir (where nadir is the lowest kidney volume at the screening), the participant does not have any angiomyolipoma-related bleeding of grade equal or over 2 (as defined by NCI CTCAE, version 4.03). Up to five of the largest measurable lesions (≥ 1 cm in longest diameter) in each kidney were measured at screening via Magnetic Resonance Imaging/Computed tomography (MRI/CT) and were defined as screening AML. The sum of the volumes of these individual lesions was defined as AML volume and it was measured at each assessment during the trial. Increases in the AML volume were evidence of worsening AML, decreases were evidence of clinical response. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Novartis Investigative Site | Wuhan | Hubei | 430030 | China | ||
| Novartis Investigative Site |
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on https://www.clinicalstudydatarequest.com/.
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Participants underwent a screening period of up to 28 days. All participants started the treatment at 10 mg orally once daily except one that started at 5 mg once daily due to a protocol deviation.
All participants were enrolled in 5 different sites in China.
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| ID | Title | Description |
|---|---|---|
| FG000 | Everolimus | Participants targeted to receive Everolimus tablets 10 mg once daily for 48 weeks. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Everolimus | Participants targeted to receive Everolimus tablets 10 mg once daily for 48 weeks. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Percentage of participants with AEs and SAEs including significant changes from baseline in vital signs, electrocardiograms and laboratory parameters (laboratory assessments included hematology, biochemistry, coagulation and urinalysis) qualifying and reported as AEs. The percentage of participants in each category is reported in the table. | All participants who received at least one dose of study treatment | Posted | Count of Participants | Participants | From the start of treatment to 30 days after end of treatment, assessed up to maximum duration of 52 weeks |
|
Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 52 weeks.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Everolimus | Participants targeted to receive Everolimus tablets 10 mg once daily for 48 weeks. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Haemorrhoids | Gastrointestinal disorders | MedDRA (23.1) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (23.1) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Novartis Pharmaceuticals | + 1 862 778 8300 | Novartis.email@Novartis.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Dec 6, 2019 | Jul 28, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 19, 2021 | Jul 28, 2021 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D018207 | Angiomyolipoma |
| D014402 | Tuberous Sclerosis |
| D018192 | Lymphangioleiomyomatosis |
| ID | Term |
|---|---|
| D018205 | Neoplasms, Adipose Tissue |
| D018204 | Neoplasms, Connective and Soft Tissue |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| D000068338 | Everolimus |
| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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Single arm, open label
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| Baseline, 48 weeks |
| Percentage of Participants With Best Overall Response Status of Angiomyolipoma (AML) Progression During Maximum Treatment Duration of 48 Weeks | AML progression status is defined as one or more of the following: an increase from nadir of 25% or more in AML volume to a value greater than screening AML (where nadir is the lowest AML volume obtained for the participant previously in the trial), the appearance of a new AML ≥ 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 screening (where nadir is the lowest kidney volume obtained for the participant previously in the trial), angiomyolipoma-related bleeding grade ≥2 (as defined by NCI CTCAE, version 4.03). Up to five of the largest measurable lesions (≥ 1 cm in longest diameter) in each kidney were measured at screening via Magnetic Resonance Imaging/Computed tomography (MRI/CT) and were defined as screening AML. The sum of the volumes of these individual lesions was defined as AML volume and it was measured at each assessment during the trial. Increases in the AML volume were evidence of worsening AML. | Baseline, 48 weeks |
| Percentage of Participants With Severe Renal Impairment | Renal impairment is defined as calculated Creatinine Clearance (CrCl) < 30 mL/min. CrCl was measured at baseline and at four other time points; only the baseline and the worst post-baseline value for every participant were counted (lowest value for CrCl). Creatinine clearance was estimated using the Cockcroft-Gault formula: creatinine clearance (mL/minute) = urine creatinine concentration (mL/dL) x volume of urine (mL/24 hour) / plasma creatinine concentration (mg/dL) x 1440 minute/24 hour | Baseline, 48 weeks |
| Percentage of Participants With NCI CTCA Grade 3/4 Serum Creatinine | NCI CTCAE grade 3/4 serum creatinine is defined as > 3.0 x upper limits of normal (ULN). Serum creatinine was measured at baseline and at four other time points; only the worst post-baseline value for every participant was counted (highest value for serum creatinine). | Baseline, 48 weeks |
| Shanghai |
| Shanghai Municipality |
| 200032 |
| China |
| Novartis Investigative Site | Chengdu | Sichuan | 610041 | China |
| Novartis Investigative Site | Beijing | 100028 | China |
| Novartis Investigative Site | Beijing | 100730 | China |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Secondary | Percentage of Participants With Best Overall Response (BOR) Status of Angiomyolipoma (AML) Response During Maximum Treatment Duration of 48 Weeks | BOR status is the best status recorded from start of treatment until disease progression. AML response status: reduction in AML volume of at least 50% relative to screening AML. In addition, AML response have to satisfy: no new AML ≥ 1 cm in longest diameter are identified, neither kidney increases in volume by more than 20% from nadir (where nadir is the lowest kidney volume at the screening), the participant does not have any angiomyolipoma-related bleeding of grade equal or over 2 (as defined by NCI CTCAE, version 4.03). Up to five of the largest measurable lesions (≥ 1 cm in longest diameter) in each kidney were measured at screening via Magnetic Resonance Imaging/Computed tomography (MRI/CT) and were defined as screening AML. The sum of the volumes of these individual lesions was defined as AML volume and it was measured at each assessment during the trial. Increases in the AML volume were evidence of worsening AML, decreases were evidence of clinical response. | All participants who received at least one dose of study treatment | Posted | Count of Participants | Participants | Baseline, 48 weeks |
|
|
|
| Secondary | Percentage of Participants With Best Overall Response Status of Angiomyolipoma (AML) Progression During Maximum Treatment Duration of 48 Weeks | AML progression status is defined as one or more of the following: an increase from nadir of 25% or more in AML volume to a value greater than screening AML (where nadir is the lowest AML volume obtained for the participant previously in the trial), the appearance of a new AML ≥ 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 screening (where nadir is the lowest kidney volume obtained for the participant previously in the trial), angiomyolipoma-related bleeding grade ≥2 (as defined by NCI CTCAE, version 4.03). Up to five of the largest measurable lesions (≥ 1 cm in longest diameter) in each kidney were measured at screening via Magnetic Resonance Imaging/Computed tomography (MRI/CT) and were defined as screening AML. The sum of the volumes of these individual lesions was defined as AML volume and it was measured at each assessment during the trial. Increases in the AML volume were evidence of worsening AML. | All participants who received at least one dose of study treatment | Posted | Count of Participants | Participants | Baseline, 48 weeks |
|
|
|
| Secondary | Percentage of Participants With Severe Renal Impairment | Renal impairment is defined as calculated Creatinine Clearance (CrCl) < 30 mL/min. CrCl was measured at baseline and at four other time points; only the baseline and the worst post-baseline value for every participant were counted (lowest value for CrCl). Creatinine clearance was estimated using the Cockcroft-Gault formula: creatinine clearance (mL/minute) = urine creatinine concentration (mL/dL) x volume of urine (mL/24 hour) / plasma creatinine concentration (mg/dL) x 1440 minute/24 hour | All participants who received at least one dose of study treatment | Posted | Count of Participants | Participants | Baseline, 48 weeks |
|
|
|
| Secondary | Percentage of Participants With NCI CTCA Grade 3/4 Serum Creatinine | NCI CTCAE grade 3/4 serum creatinine is defined as > 3.0 x upper limits of normal (ULN). Serum creatinine was measured at baseline and at four other time points; only the worst post-baseline value for every participant was counted (highest value for serum creatinine). | All participants who received at least one dose of study treatment | Posted | Count of Participants | Participants | Baseline, 48 weeks |
|
|
|
| 0 |
| 40 |
| 6 |
| 40 |
| 39 |
| 40 |
| Stomatitis | Gastrointestinal disorders | MedDRA (23.1) | Systematic Assessment |
|
| Gastroenteritis | Infections and infestations | MedDRA (23.1) | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (23.1) | Systematic Assessment |
|
| Uterine leiomyoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (23.1) | Systematic Assessment |
|
| Transient psychosis | Psychiatric disorders | MedDRA (23.1) | Systematic Assessment |
|
| Angular cheilitis | Gastrointestinal disorders | MedDRA (23.1) | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (23.1) | Systematic Assessment |
|
| Mouth ulceration | Gastrointestinal disorders | MedDRA (23.1) | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA (23.1) | Systematic Assessment |
|
| Toothache | Gastrointestinal disorders | MedDRA (23.1) | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA (23.1) | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (23.1) | Systematic Assessment |
|
| Folliculitis | Infections and infestations | MedDRA (23.1) | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA (23.1) | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (23.1) | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA (23.1) | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA (23.1) | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA (23.1) | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA (23.1) | Systematic Assessment |
|
| Blood alkaline phosphatase increased | Investigations | MedDRA (23.1) | Systematic Assessment |
|
| Blood cholesterol increased | Investigations | MedDRA (23.1) | Systematic Assessment |
|
| Blood creatinine increased | Investigations | MedDRA (23.1) | Systematic Assessment |
|
| Blood lactate dehydrogenase increased | Investigations | MedDRA (23.1) | Systematic Assessment |
|
| Blood triglycerides increased | Investigations | MedDRA (23.1) | Systematic Assessment |
|
| Creatinine renal clearance decreased | Investigations | MedDRA (23.1) | Systematic Assessment |
|
| Haemoglobin decreased | Investigations | MedDRA (23.1) | Systematic Assessment |
|
| Lymphocyte count decreased | Investigations | MedDRA (23.1) | Systematic Assessment |
|
| Neutrophil count decreased | Investigations | MedDRA (23.1) | Systematic Assessment |
|
| Platelet count decreased | Investigations | MedDRA (23.1) | Systematic Assessment |
|
| Protein urine present | Investigations | MedDRA (23.1) | Systematic Assessment |
|
| Weight decreased | Investigations | MedDRA (23.1) | Systematic Assessment |
|
| White blood cell count decreased | Investigations | MedDRA (23.1) | Systematic Assessment |
|
| Hypercholesterolaemia | Metabolism and nutrition disorders | MedDRA (23.1) | Systematic Assessment |
|
| Hypertriglyceridaemia | Metabolism and nutrition disorders | MedDRA (23.1) | Systematic Assessment |
|
| Epilepsy | Nervous system disorders | MedDRA (23.1) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (23.1) | Systematic Assessment |
|
| Proteinuria | Renal and urinary disorders | MedDRA (23.1) | Systematic Assessment |
|
| Menstrual disorder | Reproductive system and breast disorders | MedDRA (23.1) | Systematic Assessment |
|
| Menstruation delayed | Reproductive system and breast disorders | MedDRA (23.1) | Systematic Assessment |
|
| Menstruation irregular | Reproductive system and breast disorders | MedDRA (23.1) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (23.1) | Systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA (23.1) | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (23.1) | Systematic Assessment |
|
| Dermatitis acneiform | Skin and subcutaneous tissue disorders | MedDRA (23.1) | Systematic Assessment |
|
| Erythema | Skin and subcutaneous tissue disorders | MedDRA (23.1) | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA (23.1) | Systematic Assessment |
|
| Skin disorder | Skin and subcutaneous tissue disorders | MedDRA (23.1) | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA (23.1) | Systematic Assessment |
|
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
| D054973 | Perivascular Epithelioid Cell Neoplasms |
| D006222 | Hamartoma |
| D009378 | Neoplasms, Multiple Primary |
| D009386 | Neoplastic Syndromes, Hereditary |
| D065703 | Malformations of Cortical Development, Group I |
| D054220 | Malformations of Cortical Development |
| D009421 | Nervous System Malformations |
| D009422 | Nervous System Diseases |
| D020752 | Neurocutaneous Syndromes |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
| D008203 | Lymphangiomyoma |
| D018190 | Neoplasm, Lymphatic Tissue |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |