A Study to Determine the Safety and Effectiveness of RAD001 (Everolimus) in Patients With Lymphangioleiomyomatosis

NCT01059318 | Completed Phase 2 Results

• 2 other identifiers: CRAD001X22012010-019825-32
• Study Type: interventional
• Target: 24
• Locations: 3 countries
• Sites: 4

Brief Summary

This was an exploratory study to determine whether escalating doses of RAD001 (everolimus) were safe and effective in patients with Lymphangioleiomyomatosis

Conditions

Lymphangioleiomyomatosis

Keywords

Lymphangioleiomyomatosis,; High Resolution CT scan,; chest x-ray,; 6 minute walk test,; pulse oximetry,; renal MRI,; Pikometer

Outcome Measures

Primary Outcomes (2)

• Change From Baseline in Vascular Endothelial Growth Factor-D (VEGF-D) Concentrations

  Blood samples (1 mL) for determination of VEGF-D were collected from a forearm vein (direct venipuncture or from an indwelling cannula) and 2 aliquots of serum were collected. VEGF-D levels were determined from only 1 of the 2 serum aliquots, with the second acting as a back-up. A serum VEGF-D \>800 pg/mL level supports a diagnosis of Lymphangioleiomyomatosis (LAM)

  Baseline, 26 weeks

• Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State

  Venous blood samples (2 mL) for pharmacokinetic evaluation were collected pre dose and 2 hours post dose at preselected visits.

  pre-dose and at 2 hour post dose at week 26

Secondary Outcomes (6)

• Change From Baseline in Forced Vital Capacity (FVC)

  Baseline, 26 weeks

• Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)

  Baseline, 26 weeks

• Change From Baseline in Extended Pulmonary Function Testing

  Baseline, 26 weeks

• Change From Baseline in Carbon Monoxide Diffusing Capacity (DLCO)

  Baseline, 26 weeks

• Change From Baseline in 6-minute Walk Test Score to Measure Exercise Capacity

  Baseline, 26 weeks

Study Arms (1)

Everolimus

EXPERIMENTAL

All patients received a starting dose of everolimus 2.5mg/day for 4 weeks, followed by a dose of 5 mg/day for 4 weeks and finally a dose of 10mg/day for 18 weeks. The 26 week treatment period was followed by an optional extension period wherein patients continued therapy until the last patient had completed 26-weeks of treatment. The longest period a patient participated in the study was 62 weeks.

Drug: Everolimus

Interventions

Everolimus DRUG

Everolimus was formulated as tablets in strengths of 2.5mg, 5mg and 10mg.

Also known as: RAD001

Everolimus

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female aged \>/= 18 years with a diagnosis of LAM
• Pulmonary function abnormalities as follows:
• FEV1 of ≤ 80% of the predicted value following administration of a standard dose of a short acting β2-agonist (\*200 µg Salbutamol, measured between 10 and 15 minutes of inhalation) OR
• FEV1 \< 90% of the predicted value of bronchodilator following administration of a standard dose of a short acting β2-agonist (\*200 µg Salbutamol, measured between 10 and 15 minutes of inhalation) and DLco (uncorrected) \<80% predicted.
• Female patients including those of childbearing potential will be included in this study.
• Negative pregnancy test at screening and baseline

You may not qualify if:

• FEV1\<50% of predicted post-bronchodilator.
• Change in FVC (ml) \> ± 15% of screening value at baseline visit (not less than 14d after screening visit).
• Use of any medicine containing estrogen in the 4 months prior to the screening visit and for the duration of the study
• Significant hematologic, renal, hepatic laboratory abnormality or amylase \> 1.5x the upper limit of the normal range at the screening or baseline visits
• Fasting blood glucose \> 126mg/dl or random blood glucose \>200mg/dl at screening and/or baseline
• Recent surgery (involving entry into a body cavity or requiring sutures) within 2 months of the screening visit or any evidence of unhealed surgical wound.
• Uncontrolled hyperlipidemia (defined as persistent elevation of total cholesterol or triglycerides \>6.5nM/L) or a history of clinical atherosclerotic disease including heart attack, angina, peripheral vascular disease or stroke.
• Previous organ transplantation
• Inability to give informed consent
• Inability to perform pulmonary function or 6 minute walk tests and imaging assessments

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (4)

Center for LAM Research and Clinical Care

Boston, Massachusetts, 02115, United States

Location

University of Cincinnati, Department of Internal Medicine, Pulmonary, Critical Care & Sleep Medicine,

Cincinnati, Ohio, 45267, United States

Location

Novartis Investigative Site

Lyon, France

Location

Novartis Investigative Site

Milan, Italy

Location

Related Publications (2)

• McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011 Apr 28;364(17):1595-606. doi: 10.1056/NEJMoa1100391. Epub 2011 Mar 16.

  PMID: 21410393 RESULT

• Goldberg HJ, Harari S, Cottin V, Rosas IO, Peters E, Biswal S, Cheng Y, Khindri S, Kovarik JM, Ma S, McCormack FX, Henske EP. Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study. Eur Respir J. 2015 Sep;46(3):783-94. doi: 10.1183/09031936.00210714. Epub 2015 Jun 25.

  PMID: 26113676 DERIVED

MeSH Terms

Conditions

Lymphangioleiomyomatosis

Interventions

Everolimus

Condition Hierarchy (Ancestors)

Lymphangiomyoma; Neoplasm, Lymphatic Tissue; Neoplasms by Histologic Type; Neoplasms; Perivascular Epithelioid Cell Neoplasms; Neoplasms, Connective and Soft Tissue; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

trialandresults.registries@novartis.com

862-778-8300

Study Officials

• Novartis

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 28, 2010
• First Posted: January 29, 2010
• Study Start: January 1, 2010
• Primary Completion: June 1, 2012
• Study Completion: June 1, 2012
• Last Updated: November 19, 2020
• Results First Posted: November 19, 2020

Record last verified: 2020-10

Locations

US (2); IT (1); FR (1)