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Comparing and Combining Bortezomib and Mycophenolate in SSc Pulmonary Fibrosis

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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

Tracking Information
First Submitted Date  ICMJE February 11, 2015
First Posted Date  ICMJE February 25, 2015
Results First Submitted Date  ICMJE June 14, 2021
Results First Posted Date  ICMJE August 25, 2021
Last Update Posted Date August 25, 2021
Study Start Date  ICMJE March 2016
Actual Primary Completion Date December 16, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 2, 2021)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 18, 2015)
Safety and Tolerability of bortezomib with mycophenolate mofetil assessed by the incidence of serious adverse events [ Time Frame: 48 weeks ]
Assess the safety and tolerability of bortezomib
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 2, 2021)
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 18, 2015)
  • Effect of bortezomib with mycophenolate mofetil on quality of life measured by Promis-29 SF-36, and St. George Respiratory Dyspnea Score questionnaires [ Time Frame: 48 weeks ]
    Assess the effect of bortezomib with mycophenolate on the quality of life and respiratory symptoms in SSc patients at high risk of progression of pulmonary disease
  • Effect of bortezomib with mycophenolate mofetil on skin fibrosis measured by the Modified Rodnan Skin Score [ Time Frame: 48 weeks ]
    Assess the effect of bortezomib with mycophenolate on skin fibrosis in SSc patients at risk of progression of pulmonary disease
  • Effect of bortezomib with mycophenolate mofetil on lung function measured by change in Forced Vital Capacity during pulmonary function tests [ Time Frame: 48 weeks ]
    Assess the effect of bortezomib with mycophenolate on lung function in SSc patients at risk of progression of pulmonary disease
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: February 18, 2015)
Effect of bortezomib with mycophenolate mofetil on serum biomarkers measured by a change in blood tests measuring serum biomarkers [ Time Frame: 48 weeks ]
Effect of bortezomib with mycophenolate mofetil on serum biomarkers
 
Descriptive Information
Brief Title  ICMJE Comparing and Combining Bortezomib and Mycophenolate in SSc Pulmonary Fibrosis
Official Title  ICMJE Comparing and Combining Bortezomib and Mycophenolate in SSc Pulmonary Fibrosis Grant Number: R34HL122558
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Lung Diseases, Interstitial
  • Systemic Sclerosis
  • Scleroderma
Intervention  ICMJE
  • 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: 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
Study Arms  ICMJE
  • 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
    Interventions:
    • Drug: Bortezomib
    • Drug: Mycophenolate mofetil
  • 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
    Interventions:
    • Drug: Placebo
    • Drug: Mycophenolate mofetil
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 2, 2021)
9
Original Estimated Enrollment  ICMJE
 (submitted: February 18, 2015)
30
Actual Study Completion Date  ICMJE January 1, 2020
Actual Primary Completion Date December 16, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02370693
Other Study ID Numbers  ICMJE R34
1R34HL122558-01A1 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Manu Jain, Northwestern University
Study Sponsor  ICMJE Northwestern University
Collaborators  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Principal Investigator: Manu Jain, MD, MSc Northwestern University
PRS Account Northwestern University
Verification Date August 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP