Resveratrol and Sirolimus in Lymphangioleiomyomatosis Trial

NCT ID: NCT03253913

Last Updated: 2023-02-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-31
• Study Completion Date: 2022-10-15

Brief Summary

RESULT is a phase II dose-escalating, open-label, safety and efficacy study to determine if there is a potential benefit of resveratrol in combination with sirolimus in patients with lymphangioleiomyomatosis (LAM). The primary study objective is to assess the change in serum vascular endothelial growth factor-D (VEGF-D) level after 24 weeks of treatment with a combination of resveratrol and sirolimus as compared to the VEGF-D level in patients on a stable dose of sirolimus alone. The secondary objectives of this study include an assessment of the safety and adverse effect profile of combined resveratrol and sirolimus in adult patients with LAM, and to determine the effect of treatment with a combination of resveratrol and sirolimus on changes in lung function and quality of life.

Detailed Description

Study Design RESULT was an open label, dose-escalation, phase 2 study with longitudinal repeated measures. In order to be eligible for trial inclusion, patients had to satisfy all of the following criteria: 1) confirmed diagnosis of LAM per the American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines14, 2) age ≥18 years with signed informed consent, 3) on sirolimus for at least 20 weeks, and 4) VEGF-D stabilization as demonstrated by two stable values post initiation of sirolimus and drawn at least 12 weeks apart from each other. Key exclusion criteria included inability to provide consent, active listing for lung transplantation, enrolled in another interventional clinical trial, known allergy or hypersensitivity to resveratrol, and current or planned pregnancy in the next six months.

RESULT was a single site study conducted at the University of Cincinnati (UC). Study enrollment was open to LAM patients throughout the United States with travel reimbursement provided through the study. The study was reviewed and approved by UC's Institutional Review Board (IRB 2016-4904). An independent Data and Safety Monitoring Board (DSMB) was convened and met every six months to ensure the safety of study participants. All subjects provided written informed consent prior to the conduct of any study related activity.

Outcome Measures The primary objective of this study was to assess the change in serum VEGF-D value after 24 weeks of treatment with a combination of resveratrol and sirolimus, as compared to the historical VEGF-D values of patients prior to the study on sirolimus alone. Serial assessments of serum VEGF-D, pulmonary function tests (PFTs), treatment related adverse effects (AEs), complete blood count, liver and renal function tests, and HRQOL were performed at baseline and at 8, 16, and 24 weeks. In addition, sirolimus trough levels, measured 24 +/- 4 hours following the last dose, were assessed at baseline and at weeks 2, 4, 8, 12, 16, 18, 20 and 24. VEGF-D quantification was performed at the Translational Trial Development and Support Laboratory based at Cincinnati Children's Hospital Medical Center in a College of American Pathologists (CAP)/Clinical Laboratory Improvement Amendments (CLIA) approved manner. All other laboratory assessments were performed via Quest Diagnostics. HRQOL was measured by using four validated scales: St. George's Respiratory Questionnaire (SGRQ), University of California San Diego Shortness of Breath score (SDSOB), EuroQol visual analogue scale (EQVAS), and A Tool to Assess Quality of Life in LAM (ATAQ-LAM).

Study Drug Resveratrol used in this study was obtained from Evolva and manufactured by fermentation using genetically modified yeast in a process that results in trans-resveratrol with a purity of at least 98%, and packaged into capsules with each capsule containing 125mg resveratrol. The capsules were independently verified for content by mass spectrometry performed at UC and for sterility by microbial testing at Q Laboratories Inc., Cincinnati. Investigational new drug (IND) designation for studying Resveratrol in this trial was obtained from the United States Food and Drug Administration (FDA): IND 131722; IND Sponsor: N. Gupta.

Resveratrol was administered in a stepwise dose escalating fashion at 8-week intervals with assessment of VEGF-D, PFTs, AEs, and HRQOL prior to each dose escalation. The starting dose of resveratrol was 250mg once daily for the first 8 weeks, followed by 500mg daily from Weeks 8 - 16, and 500mg twice daily for the last 8 weeks (Weeks 16 - 24), with provisions for dose reduction if necessitated by AEs. Treatment related AEs were tabulated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.

Conditions

Lymphangioleiomyomatosis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment Arm

Resveratrol 250mg daily for the first 8 weeks, followed by 250mg twice daily for the next 8 weeks, and then 500mg twice daily for the last 8 weeks.

Patients will be on a stable background therapy of sirolimus prior to enrolling and will continue on that regimen throughout the study.

Group Type: EXPERIMENTAL

Sirolimus

Intervention Type: DRUG

Patients will have been on a stable dose of sirolimus prior to enrolling and will continue that throughout the study.

Resveratrol

Intervention Type: DRUG

Escalating doses of resveratrol will be given throughout the study. Patients will start at 250mg daily for 8 weeks, followed by 500mg daily for 8 weeks, and 500mg BID for the last 8 weeks.

Interventions

Sirolimus

Patients will have been on a stable dose of sirolimus prior to enrolling and will continue that throughout the study.

Intervention Type: DRUG

Resveratrol

Escalating doses of resveratrol will be given throughout the study. Patients will start at 250mg daily for 8 weeks, followed by 500mg daily for 8 weeks, and 500mg BID for the last 8 weeks.

Intervention Type: DRUG

Other Intervention Names

Rapamycin

Eligibility Criteria

Inclusion Criteria

Subjects enrolled in the trial must meet all of the following criteria.

1. Definitive diagnosis LAM based on the presence of characteristic cystic change on high-resolution computed tomography (HRCT) of the chest. The diagnosis must be confirmed by one of the following:

A) Histopathological confirmation by biopsy (lung, abdominal mass, lymph node or kidney or cytology from thoracic or abdominal sources revealing human melanoma black-45 (HMB45)+ staining of spindled/epithelioid cells) B) Compatible chest CT scan findings in the setting of tuberous sclerosis, angiomyolipomas (diagnosed by CT, magnetic resonance imaging (MRI) by the site radiologist or biopsy) or chylous pleural effusion (verified by tap) C) Chest CT scan findings compatible with LAM and a VEGF-D level ≥ 800pg/ml.

2. Age 18 years or greater.

3. Signed and dated informed consent

4. Currently on sirolimus for treatment of LAM for at least 20 weeks

5. Evidence of disease stabilization on sirolimus as demonstrated by two stable values of serum VEGF-D post initiation of sirolimus drawn at least 12 weeks apart from each other. For the purpose of this study, a variation in serum VEGF-D of less than or equal to 15% is considered stable.

Exclusion Criteria

• Subjects who meet any of the following criteria are not eligible for enrollment as study participants:

1. Known allergy or hypersensitivity to Resveratrol

2. Inability to provide informed consent

3. Active enrollment in other clinical drug trials for LAM

4. Pregnant or plan to become pregnant in the next 6 months

5. Breast feeding

6. Inability to comply with pulmonary function tests or follow up visits

7. Inadequate contraception

8. Use of estrogen containing medications within the 30 days prior to randomization

9. History of organ transplant

10. Actively listed for lung transplantation

11. Inability to comply with study procedures or attend scheduled study visits

12. Any clinically significant medical disease (other than LAM) that is associated with an expected survival of less than 2 years, or likely to impact the ability of the patient to participate in the study in the opinion of the investigator, or impact the study efficacy or safety assessments.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Cincinnati

OTHER

Sponsor Role: lead

Responsible Party

Nishant Gupta, MD, MS

Adjunct Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nishant Gupta, MD

Role: PRINCIPAL_INVESTIGATOR

University of Cincinnati

Locations

University of Cincinnati

Cincinnati, Ohio, United States

Countries

United States

References

Gupta N, Zhang B, Zhou Y, McCormack FX, Ingledue R, Robbins N, Kopras EJ, McMahan S, Singla A, Swigris J, Cole AG, Holz MK. Safety and Efficacy of Combined Resveratrol and Sirolimus in Lymphangioleiomyomatosis. Chest. 2023 May;163(5):1144-1155. doi: 10.1016/j.chest.2023.01.007. Epub 2023 Jan 13.

Reference Type: DERIVED

PMID: 36642366 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

1R34HL138235-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2016-4904

Identifier Type: -

Identifier Source: org_study_id