Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Comparing and Combining Bortezomib and Mycophenolate in SSc Pulmonary Fibrosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02370693
Recruitment Status : Completed
First Posted : February 25, 2015
Results First Posted : August 25, 2021
Last Update Posted : August 25, 2021
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Manu Jain, Northwestern University

Brief 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.

Condition or disease Intervention/treatment Phase
Lung Diseases, Interstitial Systemic Sclerosis Scleroderma Drug: Bortezomib Drug: Placebo Drug: Mycophenolate mofetil Phase 2

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 transforming growth factor (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 chronic graft-versus-host disease in patients after allogeneic hematopoietic stem cell transplant 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 forced vital capacity (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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Comparing and Combining Bortezomib and Mycophenolate in SSc Pulmonary Fibrosis Grant Number: R34HL122558
Study Start Date : March 2016
Actual Primary Completion Date : December 16, 2019
Actual Study Completion Date : January 1, 2020


Arm Intervention/treatment
Active Comparator: bortezomib plus mycophenolate mofetil
Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks
Drug: Bortezomib
Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks
Other Name: Velcade

Drug: Mycophenolate mofetil
Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks
Other Name: CellCept

Placebo Comparator: Placebo plus mycophenolate mofetil
Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks
Drug: Placebo
Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks
Other Name: normal saline

Drug: Mycophenolate mofetil
Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks
Other Name: CellCept




Primary Outcome Measures :
  1. Number of Participants With Serious Adverse Events [ Time Frame: First dosing day to last study visit day: Mean duration 8 months. ]
    To assess the safety and tolerability of bortezomib with mycophenolate mofetil assessed by the incidence of serious adverse events.


Secondary Outcome Measures :
  1. Change of Skin Fibrosis Measured by the Rodnan Skin Score Between Baseline and 24 Weeks [ Time Frame: 24 weeks ]
    The Modified Rodnan Skin Score (mRSS) is a measure of skin thickness that sums individual scores of skin thickness (0 - No Thickening, 1 - Mild Thickening, 2 - Moderate Thickening, 3 - Severe Thickening) measured at 17 body sites to reach a total score (Range: 0 to 51, higher value representing thicker skin). The Score is used as a surrogate for disease activity and severity, and a worsening score over time is associated with worse outcomes.

  2. Change of Lung Function Measured by Forced Vital Capacity (FVC) Between Baseline and 24 Weeks [ Time Frame: 24 weeks ]
    Forced vital capacity, or FVC, is the amount in liters of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. It measures the effect that lung disease has on a person's ability to inhale and exhale. Higher values are better, and decreases over time can indicate disease progression.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Meet established criteria for diffuse or limited systemic sclerosis (SSc) and evidence of pulmonary at high risk of progression with or without progressive skin disease.
  • Definition includes subjects who meet the American College of Rheumatology 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 high-resolution computed tomography (HRCT) maximum fibrosis score >3 or FVC < 85% and modified Rodnan skin score (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
  • Absolute neutrophil count >1000
  • Platelets >75,000
  • Stable mycophenolate mofetil dose for 16 weeks

Exclusion Criteria:

  • Inability to give informed consent or comply with protocol procedures
  • FVC < 40% or diffusing capacity of carbon monoxide (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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02370693


Locations
Layout table for location information
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
Sponsors and Collaborators
Northwestern University
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Layout table for investigator information
Principal Investigator: Manu Jain, MD, MSc Northwestern University
  Study Documents (Full-Text)

Documents provided by Manu Jain, Northwestern University:
Layout table for additonal information
Responsible Party: Manu Jain, Professor in Medicine-Pulmonary and Pediatrics, Northwestern University
ClinicalTrials.gov Identifier: NCT02370693    
Other Study ID Numbers: R34
1R34HL122558-01A1 ( U.S. NIH Grant/Contract )
First Posted: February 25, 2015    Key Record Dates
Results First Posted: August 25, 2021
Last Update Posted: August 25, 2021
Last Verified: August 2021
Keywords provided by Manu Jain, Northwestern University:
mycophenolate
lung scarring
Additional relevant MeSH terms:
Layout table for MeSH terms
Lung Diseases
Pulmonary Fibrosis
Lung Diseases, Interstitial
Scleroderma, Systemic
Scleroderma, Diffuse
Respiratory Tract Diseases
Connective Tissue Diseases
Skin Diseases
Mycophenolic Acid
Bortezomib
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action