Lung Diseases, Interstitial, Scleroderma, Systemic Sclerosis
Conditions
Keywords
mycophenolate, lung scarring
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.
Interventions
DRUGBortezomib
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
DRUGPlacebo
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
DRUGMycophenolate mofetil
Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Northwestern University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Events | 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
| Measure | Time frame | Description |
|---|---|---|
| Change of Skin Fibrosis Measured by the Rodnan Skin Score Between Baseline and 24 Weeks | 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 | 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. |
Countries
United States
Participant flow
Pre-assignment details
2 subjects were enrolled (signed consent form) but did not continue through the screening process far enough to reach randomization.
Participants by arm
| Arm | Count |
|---|---|
| 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
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
Mycophenolate mofetil: Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks | 3 |
| 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
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
Mycophenolate mofetil: Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks | 4 |
| Enrolled But Not Randomized Subjects who were enrolled (signed consent form) but did not continue through the screening process far enough to reach randomization. | 2 |
| Total | 9 |
Baseline characteristics
| Characteristic | Enrolled But Not Randomized | Total | Placebo Plus Mycophenolate Mofetil | Bortezomib Plus Mycophenolate Mofetil |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 8 Participants | 4 Participants | 2 Participants |
| Age, Continuous | 42.6 years STANDARD_DEVIATION 10.4 | 52.6 years STANDARD_DEVIATION 8.9 | 52.3 years STANDARD_DEVIATION 4.6 | 59.4 years STANDARD_DEVIATION 8.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 8 Participants | 3 Participants | 3 Participants |
| Region of Enrollment United States | 2 participants | 9 participants | 4 participants | 3 participants |
| Sex: Female, Male Female | 0 Participants | 4 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 2 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 4 |
| other Total, other adverse events | 3 / 3 | 4 / 4 |
| serious Total, serious adverse events | 1 / 3 | 1 / 4 |
Outcome results
Primary
Number of Participants With Serious Adverse Events
To assess the safety and tolerability of bortezomib with mycophenolate mofetil assessed by the incidence of serious adverse events.
Time frame: First dosing day to last study visit day: Mean duration 8 months.
Population: All subjects who received at least one dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bortezomib Plus Mycophenolate Mofetil | Number of Participants With Serious Adverse Events | 0.33 Number of Participants with Serious Adve | Standard Deviation 0.58 |
| Placebo Plus Mycophenolate Mofetil | Number of Participants With Serious Adverse Events | 0.25 Number of Participants with Serious Adve | Standard Deviation 0.5 |
Secondary
Change of Lung Function Measured by Forced Vital Capacity (FVC) Between Baseline and 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.
Time frame: 24 weeks
Population: All subjects who had comparable forced vital capacity data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bortezomib Plus Mycophenolate Mofetil | Change of Lung Function Measured by Forced Vital Capacity (FVC) Between Baseline and 24 Weeks | 0.51 Percentage of change in FVC %predicted | Standard Deviation 0.55 |
| Placebo Plus Mycophenolate Mofetil | Change of Lung Function Measured by Forced Vital Capacity (FVC) Between Baseline and 24 Weeks | -0.69 Percentage of change in FVC %predicted | Standard Deviation 1.02 |
Secondary
Change of Skin Fibrosis Measured by the Rodnan Skin Score Between Baseline and 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.
Time frame: 24 weeks
Population: All subjects who had comparable skin score data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bortezomib Plus Mycophenolate Mofetil | Change of Skin Fibrosis Measured by the Rodnan Skin Score Between Baseline and 24 Weeks | -3.00 Score on a Scale | Standard Deviation 2.65 |
| Placebo Plus Mycophenolate Mofetil | Change of Skin Fibrosis Measured by the Rodnan Skin Score Between Baseline and 24 Weeks | -0.33 Score on a Scale | Standard Deviation 0.58 |