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 questionnairesEffect 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
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