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Comparing and Combining Bortezomib and Mycophenolate in SSc Pulmonary Fibrosis

Information source: Northwestern University
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Interstitial Lung Disease; ILD; Systemic Sclerosis; Scleroderma

Intervention: Bortezomib (Drug); Placebo (Drug); Mycophenolate mofetil (Drug)

Phase: Phase 2

Status: Not yet recruiting

Sponsored by: Northwestern University

Official(s) and/or principal investigator(s):
Manu Jain, MD, Principal Investigator, Affiliation: Northwestern University

Overall contact:
Margaret Travis, RN, BSN, Phone: 312-695-2269, Email: margaret.travis@northwestern.edu

Summary

The purpose of this study is to look at whether bortezomib, mycophenolate or the combination of both is better to treat scarring of the lung caused by Systemic Sclerosis.

Clinical Details

Official title: Comparing and Combining Bortezomib and Mycophenolate in SSc Pulmonary Fibrosis Grant Number: R34HL122558

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Primary outcome: Safety and Tolerability of bortezomib with mycophenolate mofetil assessed by the incidence of serious adverse events

Secondary outcome:

Effect of bortezomib with mycophenolate mofetil on quality of life measured by Promis-29 SF-36, and St. George Respiratory Dyspnea Score questionnaires

Effect of bortezomib with mycophenolate mofetil on skin fibrosis measured by the Modified Rodnan Skin Score

Effect of bortezomib with mycophenolate mofetil on lung function measured by change in Forced Vital Capacity during pulmonary function tests

Detailed description: Systemic sclerosis (SSc) is a chronic multisystem autoimmune connective tissue disease for which the etiology remains unknown. The prevalence for SSc is between 19-75 cases per 100,000 and it is more frequent in women, with a peak occurrence in the 4th or 5th decade of life. Morbidity and Mortality in SSc are substantial and pulmonary complications are now the leading cause of death among patients with SSc. Bortezomib is an FDA approved therapy for the treatment of multiple myeloma and other malignancies. The investigators have data that bortezomib inhibits TGF- signaling in vitro and promotes normal repair and prevents against lung fibrosis in the TGF-mediated intratracheal bleomycin mouse model as well as in a mouse model for skin fibrosis. This is consistent with other data in the literature that proteasomal inhibition can prevent the development of fibrosis. Further there are multiple reports on the efficacy of bortezomib in ameliorating cGVHD in patients after allogeneic HSCT for multiple myeloma. Bortezomib was also well tolerated in the large clinical trials of multiple myeloma patients with neuropathy and thrombocytopenia the primary adverse events. No pulmonary toxicities were reported in these studies. Mycophenolate mofetil (CellCept or Myfortic) belongs to a class of medications known as immunosuppressives. This medication was used originally in the management of patients with organ transplants, but is now recommended in the treatment of some autoimmune diseases such as SSc. Mycophenolate mofetil targets an enzyme in the body called inosine monophosphate dehydrogenase that is important for the formation of deoxyribonucleic acid (DNA) in cells. By interfering with DNA, the medication impairs function of immune system cells that become overactive in autoimmune diseases. Mycophenolate mofetil is currently approved in the treatment of patients with SSc. This study is being conducted to establish the safety and tolerability of bortezomib in SSc patients at high risk for pulmonary disease progression. In addition, the study will examine the effect of bortezomib on the rate of FVC decline (a physiologic parameter closely associated with disease outcome) and other clinical parameters. In addition the investigators will also measure the effect of bortezomib on biomarkers associated with fibroblast activation. If successful, the study will provide the rationale for a multi-center placebo controlled trial to test the efficacy of bortezomib in SSc patients at high risk for progressive pulmonary disease.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Meet established criteria for diffuse or limited SSc and evidence of pulmonary at

high risk of progression with or without progressive skin disease.

- Definition includes subjects who meet the ACR criteria for scleroderma

- High Risk of disease progression (see rationale) will be defined as follows

- If first non-Raynaud's manifestation of SSc < 36 months, then if any of the following

are true: FVC <70% predicted or HRCT Fibmax >3 or FVC < 85% and MRSS increase > 5 over 6 months Regardless of disease duration

- Fall in FVC > 10% over the preceding 12 months or less in the absence of prior

therapy or another identified causative process as assessed by the primary scleroderma physician

- Fall in FVC > 10% over 6 months on at least 12 months of prior therapy

- Age > 18 years

- Ability to give informed consent.

- Willingness to discontinue present therapy for the duration of the study

- Female subject is either post-menopausal or surgically sterilized or willing to use

an acceptable method of birth control (i. e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.

- Male subject agrees to use an acceptable method for contraception for the duration of

the study.

- No evidence of acute infection

- ANC >1000

- Platelets >75,000

- Stable MMF dose for 16 weeks

Exclusion Criteria:

- Inability to give informed consent or comply with protocol procedures

- FVC < 40% or DLCO <30% predicted

- Patient has a platelet count of less than 50,000 within 14 days before enrollment.

- Patient has an absolute neutrophil count of less 1000 within 14 days before

enrollment.

- Patient has a calculated or measured creatinine clearance of < 20 ml/minute within 14

days before enrollment.

- Patient has Grade 2 peripheral neuropathy by history within 14 days before

enrollment.

- Myocardial infarction within 6 months prior to enrollment or has New York Heart

Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.

- Patient has hypersensitivity to bortezomib, boron or mannitol.

- Female subject is pregnant or breast-feeding. Confirmation that the subject is not

pregnant must be established by a negative serum - human chorionic gonadotropin (-

hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.

- Patient has received other investigational drugs within 4 weeks before enrollment

- Serious medical co-morbidity which in the opinion of the investigator makes

participation in the study too high risk

- Psychiatric illness likely to interfere with participation in this clinical study.

Locations and Contacts

Margaret Travis, RN, BSN, Phone: 312-695-2269, Email: margaret.travis@northwestern.edu

Northwestern University, Chicago, Illinois 60611, United States; Not yet recruiting
Margaret Travis, RN, BSN, Phone: 312-695-2269, Email: margaret.travis@northwestern.edu
Manu Jain, MD, Principal Investigator
Jane Dematte-D'Amico, MD, Sub-Investigator
John Varga, MD, Sub-Investigator
Rishi Raj, MD, Sub-Investigator
Additional Information

Starting date: April 2015
Last updated: February 18, 2015

Page last updated: August 23, 2015

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