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Trial record 4 of 1177 for:    MYCOPHENOLIC ACID

Comparing and Combining Bortezomib and Mycophenolate in SSc Pulmonary Fibrosis

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ClinicalTrials.gov Identifier: NCT02370693
Recruitment Status : Recruiting
First Posted : February 25, 2015
Last Update Posted : September 4, 2019
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
Interstitial Lung Disease ILD 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 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 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
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 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 Names:
  • MMF
  • 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 Names:
  • MMF
  • CellCept




Primary Outcome Measures :
  1. Safety and Tolerability of bortezomib with mycophenolate mofetil assessed by the incidence of serious adverse events [ Time Frame: 24 weeks ]
    Assess the safety and tolerability of bortezomib


Secondary Outcome Measures :
  1. 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: 24 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

  2. Effect of bortezomib with mycophenolate mofetil on skin fibrosis measured by the Modified Rodnan Skin Score [ Time Frame: 24 weeks ]
    Assess the effect of bortezomib with mycophenolate on skin fibrosis in SSc patients at risk of progression of pulmonary disease

  3. Effect of bortezomib with mycophenolate mofetil on lung function measured by change in Forced Vital Capacity during pulmonary function tests [ Time Frame: 24 weeks ]
    Assess the effect of bortezomib with mycophenolate on lung function in SSc patients at risk of progression of pulmonary disease


Other Outcome Measures:
  1. Effect of bortezomib with mycophenolate mofetil on serum biomarkers measured by a change in blood tests measuring serum biomarkers [ Time Frame: 24 weeks ]
    Effect of bortezomib with mycophenolate mofetil on serum biomarkers



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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 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.

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


Contacts
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Contact: Mary Carns, MS 312-503-1137 m-carns@northwestern.edu
Contact: Abbas Arastu, BS 312-695-2269 abbas.arastu@northwestern.edu

Locations
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United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Mary Carns, MS    312-503-1137    m-carns@northwestern.edu   
Contact: Abbas Arastu, BS    312-695-2269    abbas.arastu@northwestern.edu   
Principal Investigator: Manu Jain, MD         
Sub-Investigator: Jane Dematte-D'Amico, MD         
Sub-Investigator: John Varga, MD         
Sponsors and Collaborators
Northwestern University
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Manu Jain, MD, MSc Northwestern University

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Responsible Party: Manu Jain, Professor in Medicine-Pulmonary and Pediatrics, Northwestern University
ClinicalTrials.gov Identifier: NCT02370693     History of Changes
Other Study ID Numbers: R34
1R34HL122558-01A1 ( U.S. NIH Grant/Contract )
First Posted: February 25, 2015    Key Record Dates
Last Update Posted: September 4, 2019
Last Verified: September 2019
Keywords provided by Manu Jain, Northwestern University:
mycophenolate
lung scarring
Additional relevant MeSH terms:
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Mycophenolic Acid
Lung Diseases
Pulmonary Fibrosis
Lung Diseases, Interstitial
Scleroderma, Systemic
Scleroderma, Diffuse
Respiratory Tract Diseases
Connective Tissue Diseases
Skin Diseases
Bortezomib
Antineoplastic Agents
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action