Systemic Lupus Erythematosus
Conditions
Keywords
lupus, SLE
Brief summary
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease in which the body's immune system attacks different parts of the body. SLE is characterized by inflammation that leads to tissue damage in different organ systems. Any organ system may be involved, including the skin, the joints, the kidneys, the nervous system, the heart, the lungs, and the blood. The exact cause of SLE is not known. Patients with SLE often have elevated levels of anti-double stranded DNA antibodies. These levels are often associated with disease flares and disease severity. These antibodies can bind to tissue leading to organ damage. Preventing these antibodies from binding to their targets may help decrease disease activity. Protease inhibitors are medications that have been approved by the Food and Drug Administration (FDA) for use in the treatment of HIV (human immunodeficiency virus). Nelfinavir (also called viracept) is one of these protease inhibitors. Separate from their anti-viral effects, protease inhibitors have been found to decrease inflammation. These medications have been shown to interfere with binding of anti-double stranded DNA antibodies to their targets and may decrease inflammation in SLE. This research study tests whether the protease inhibitor, nelfinavir, will decrease anti-double stranded DNA antibody binding and decrease disease activity.
Interventions
DRUGNelfinavir
Sponsors
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Northwell Health
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Subject is capable of providing written informed consent 2. Subject is ≥ 18 years old and ≤ 65 years old 3. Meets at least 4 of 11 modified American College of Rheumatology (ACR) (1997) Revised Criteria for the Classification of Systemic Lupus Erythematosus 4. Has mild to moderate disease activity defined as * A minimum SLEDAI score of 2 excluding points for serology (anti-dsDNA antibody and complement) * No active renal or nervous system disease * No BILAG A in any organ system * No expectation by the investigator that corticosteroids will need to be added or doses increased during the 8 week treatment period for any reason * No expectation by the investigator that immunosuppressive medication will need to be added or doses increased during the 8 week treatment period 5. Has elevated titers of anti-ds DNA antibody at the time of screening (defined as the titer that meets criteria for high in the Core Laboratory at the North Shore/LIJ Health Systems; unequivocal high titer as opposed to borderline, indeterminate or intermediate). 6. Has elevated titers of cross-reactive anti-DNA/DWEYS antibodies at the time of screening (the assays for anti-DNA/DWEYS antibodies will be performed in Dr. B. Diamond's laboratory; study sites will be notified of results within 3 days of receipt of the samples). 7. If on glucocorticoids, the dose must be ≤10 mg daily and stable for the 4 weeks prior to screening and baseline 8. If on immunosuppressive or immunomodulatory medication such as azathioprine, methotrexate, leflunomide, mycophenolate, or hydroxychloroquine, the dose must have been stable for the 3 months prior to screening, and expected to remain stable over the course of the study. 9. Males and females with potential for reproduction must agree to practice effective birth control measures (2 approved methods of contraception). Nelfinavir can decrease serum levels of oral contraceptives; the slightly increased risk of pregnancy due to an interaction between oral contraception and nelfinavir will be discussed when appropriate and the requirement for a second approved method of contraception will be addressed.
Exclusion criteria
1. Current or prior treatment with rituximab, belimumab or anti-CD22 monoclonal antibody in the 12 months prior to this study or any other biologic agent for 90 days prior to this study 2. Treatment with cyclophosphamide within the 6 months prior to screening 3. Increase in glucocorticoid dose within 4 weeks of screening or addition of a DMARD in the three months prior to study 4. A history of drug or alcohol abuse within the 6 months prior to screening 5. Elevated LFT's: * ALT or AST ≥ 2 x upper limit of normal at screening * serum unconjugated bilirubin \> 3mg/dL at screening 6. Dialysis or serum creatinine \>1.5mg/dL 7. Hypercholesterolemia: total cholesterol \>230 mg/dL or LDL \>150 mg/dl or hypertriglyceridemia (triglyceride \>200mg/dL) at screening 8. Laboratory/clinical evidence of: pancreatitis: amylase/lipase \>3x upper limit of normal at screening 9. Known current/active infections including HIV, Hepatitis B, Hepatitis C 10. History of cancer, excluding skin cancers (squamous cell or basal cell that have been treated) 11. Known active tuberculosis or untreated tuberculosis 12. Hemoglobin \< 8 g/dL 13. Expectation by the investigator to increase corticosteroid or immunosuppressive, or immunomodulatory medication dose at screening, baseline, or over the course of the study 14. Pregnancy or lactation 15. Consumption of \> 2 cups of grapefruit juice per day 16. Treatment with medications metabolized using the cytochrome P3A4 pathway, such as cyclosporine, tacrolimus, gemfibrozil, niacin, itraconazole, ketoconazole, erythromycin, azithromycin, clarithromycin, bosentan, nefazodone, tricyclic antidepressants 17. Any condition that, in the opinion of the Investigator, would jeopardize the subject's safety following exposure to the study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Inhibition of Anti-dsDNA Binding | baseline to Day 56 | Change in serum anti-dsDNA titer from baseline to Day 56; a decrease in titer ≥ 35% was considered a positive response |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Open-label Study With the Simon Two-Stage Trial Design All subjects will be dosed with nelfinavir 750 mg orally three times daily. This dose may be decreased to 750 mg twice daily if not tolerated. For both stages of the trial the dosing period is 8 weeks followed by a 4 week observation period.
A maximum of 13 subjects will be enrolled in Stage 1. From the 13 subjects enrolled in Stage 1; if 3 or fewer subjects achieve a Response (a ≥35% reduction in serum anti-dsDNA antibody titer), the trial will be terminated. If 4 or more subjects achieve a Response, the study will be expanded to enroll an additional maximum of 30 patients in Stage 2. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Open-label Study With the Simon Two-Stage Trial Design |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 15 participants |
| Serum anti-dsDNA antibody titer | 313.8 IU/mL STANDARD_DEVIATION 299.7 |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 15 |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 2 / 15 |
Outcome results
Primary
Inhibition of Anti-dsDNA Binding
Change in serum anti-dsDNA titer from baseline to Day 56; a decrease in titer ≥ 35% was considered a positive response
Time frame: baseline to Day 56
Population: The number of participants whose anti-dsDNA antibody titer decreased by ≥ 35% from baseline to Day 56
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Open-label Study With the Simon Two-Stage Trial Design | Inhibition of Anti-dsDNA Binding | 1 Participants |