Safety of Simvastatin in LAM and TSC

NCT02061397 | Completed Phase 1 Results DMC

• 1 other identifier: The SOS Trial
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this research study is to see if simvastatin can be taken safely in patients with either LAM or TSC, who are already being treated with everolimus or sirolimus. This is the first step in looking at simvastatin as a drug that may help patients, by impacting the growth and survival of cells that make up the lung lesions that cause problems in LAM and TSC patients. The study also seeks to learn more about how simvastatin works, when given to patients being treated with everolimus or sirolimus, and to evaluate the safety and any potential benefit to patients taking this 2-drug combination. The primary objective of this study is to determine the safety of simvastatin in the treatment of LAM-S or LAM-TS in patients on a stable (for at least 3 months) dose of sirolimus or everolimus. Secondary objectives include:

• To assess the effect of simvastatin on forced expiratory volume in 1 second (FEV1).
• To assess the effect of simvastatin on forced vital capacity (FVC).
• To assess the effect of simvastatin on diffusing lung capacity (DLCO).
• To assess the effect of simvastatin on vascular endothelial growth factor -D (VEGF-D) serum levels.
• To assess the effect of simvastatin with questionnaire- based assessments of dyspnea, fatigue, and quality of life (QOL).
• Assess signs of clinical benefit.

Conditions

Lymphangioleiomyomatosis; Tuberous Sclerosis Complex

Keywords

lymphangioleiomyomatosis (LAM); tuberous sclerosis complex (TSC); simvastatin; sirolimus; everolimus

Outcome Measures

Primary Outcomes (1)

• Safety of Simvastatin in the Treatment of LAM-S and LAM-TS Patients

  Safety is a primary outcome measure which will be assessed by any major changes or deterioration in patient health.

  5 months

Secondary Outcomes (1)

• Percent Predicted FEV1

  5 months

Study Arms (1)

simvastatin treatment arm

EXPERIMENTAL

Eligible patients on sirolimus or everolimus will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4.

Drug: Simvastatin; Drug: Sirolimus Oral Product; Drug: Everolimus Oral Product

Interventions

Simvastatin DRUG

Eligible patients on sirolimus or everolimus will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4.

Also known as: trade name Zocor

simvastatin treatment arm

Sirolimus Oral Product DRUG

Eligible patients on sirolimus will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4.

Also known as: Rapamune

simvastatin treatment arm

Everolimus Oral Product DRUG

Eligible patients on everolimus will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4.

Also known as: Afinitor

simvastatin treatment arm

Eligibility Criteria

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

You may qualify if:

• Female, age 18 and older with clinically definitive diagnosis (biopsy proven or compatible chest CT/MRI scan) of sporadic LAM (LAM-S) or LAM associated with TS (LAM-TS).
• Treated with a stable (at least 3 months) dose of sirolimus or everolimus
• Negative pregnancy test (women of child bearing potential) at screening.
• Women of childbearing potential must be using barrier, medically acceptable contraceptive precautions.
• Signed and dated informed consent.

You may not qualify if:

• Age \< 18 years
• Known allergy to simvastatin or currently taking simvastatin, or therapy with a medication in the same class as simvastatin within the past 30 days.
• Allergy to sirolimus or everolimus.
• Current use of other than sirolimus or everolimus investigational drug for TSC or LAM within the past 30 days.
• Use of estrogen containing medications, including birth control pills, within the 30 days prior to enrollment.
• Treatment with drugs having known metabolic interactions with statin drugs (e.g. cytochrome P450 3A4 metabolism), including ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, azithromycin, niacin (nicotinic acid), digoxin, warfarin, sildenafil or use of strong CYP3A4 inhibitors including gemfibrozil, cyclosporine, danazol, verapamil, diltiazem, and dronedarone. amiodarone, amlodipine, and ranolazine.
• Participation in another clinical study(ies) of an investigational treatment or drug within 30 days prior to the screening visit.
• Amiodarone; within the past 30 days.
• Significant dysfunction of liver (ALT \> 2 times upper limit of normal-ULN), kidney (serum creatinine \> 1.5 times ULN), or blood (leucopenia (ANC\<2000), anemia, Hgb \< 11 gm/dl).
• History of inflammatory muscle disease or myopathy.
• Bleeding diathesis or anticoagulant therapy.
• Uncontrolled hyperlipidemia or diabetes.
• Pregnant, breast feeding, or plan to become pregnant within the next 6 months
• Inadequate contraception (must agree to barrier method)
• History of organ transplant.

Sponsors & Collaborators

• University of Pennsylvania: lead
• The LAM Foundation: collaborator

Study Sites (1)

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (4)

• Krymskaya VP. Treatment option(s) for pulmonary lymphangioleiomyomatosis: progress and current challenges. Am J Respir Cell Mol Biol. 2012 May;46(5):563-5. doi: 10.1165/rcmb.2011-0381ED. No abstract available.

  PMID: 22550272 BACKGROUND

• Goncharova EA, Goncharov DA, Fehrenbach M, Khavin I, Ducka B, Hino O, Colby TV, Merrilees MJ, Haczku A, Albelda SM, Krymskaya VP. Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM). Sci Transl Med. 2012 Oct 3;4(154):154ra134. doi: 10.1126/scitranslmed.3003840.

  PMID: 23035046 BACKGROUND

• Atochina-Vasserman EN, Goncharov DA, Volgina AV, Milavec M, James ML, Krymskaya VP. Statins in lymphangioleiomyomatosis. Simvastatin and atorvastatin induce differential effects on tuberous sclerosis complex 2-null cell growth and signaling. Am J Respir Cell Mol Biol. 2013 Nov;49(5):704-9. doi: 10.1165/rcmb.2013-0203RC.

  PMID: 23947572 BACKGROUND

• Goncharova EA, Goncharov DA, Li H, Pimtong W, Lu S, Khavin I, Krymskaya VP. mTORC2 is required for proliferation and survival of TSC2-null cells. Mol Cell Biol. 2011 Jun;31(12):2484-98. doi: 10.1128/MCB.01061-10. Epub 2011 Apr 11.

  PMID: 21482669 RESULT

MeSH Terms

Conditions

Lymphangioleiomyomatosis; Tuberous Sclerosis

Interventions

Simvastatin; Sirolimus; 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; Hamartoma; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Nervous System Diseases; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Macrolides; Lactones

Results Point of Contact

• Title: Dr. Vera Krymskaya
• Organization: University of Pennsylvania

krymskay@pennmedicine.upenn.edu

215-573-9861

Study Officials

• Vera P Krymskaya, PhD, MBA

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

• Maryl Kreider, MD, MSCE

  University of Pennsylvania

  STUDY DIRECTOR

• Frank McCormack, MD

  University of Cincinnati

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 23, 2014
• First Posted: February 12, 2014
• Study Start: March 1, 2014
• Primary Completion: December 13, 2019
• Study Completion: December 13, 2019
• Last Updated: August 25, 2020
• Results First Posted: August 25, 2020

Record last verified: 2020-08

Locations

US (1)