NISLE: Nelfinavir in Systemic Lupus Erythematosus

• Sponsor: Northwell Health (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02066311
• Collaborator: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (NIH)
• Enrollment: 15
• Locations: 8
• Arm: 1
• Duration (Months): 45
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Systemic Lupus Erythematosus	Drug: Nelfinavir	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Nelfinavir in Systemic Lupus Erythematosus: A Pilot Phase IIa Clinical Trial
• Study Start Date: Sep 1, 2014
• Actual Primary Completion Date: Jun 1, 2018
• Actual Study Completion Date: Jun 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: nelfinavir Nelfinavir tablets will be taken by oral administration, 750mg (three 250 mg tablets) three times a day	Drug: Nelfinavir; Other Names: Viracept

Outcome Measures

Primary Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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

1. 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).

2. 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).

3. If on glucocorticoids, the dose must be ≤10 mg daily and stable for the 4 weeks prior to screening and baseline

4. 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.

5. 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

1. Dialysis or serum creatinine >1.5mg/dL

2. Hypercholesterolemia: total cholesterol >230 mg/dL or LDL >150 mg/dl or hypertriglyceridemia (triglyceride >200mg/dL) at screening

3. Laboratory/clinical evidence of: pancreatitis: amylase/lipase >3x upper limit of normal at screening

4. Known current/active infections including HIV, Hepatitis B, Hepatitis C

5. History of cancer, excluding skin cancers (squamous cell or basal cell that have been treated)

6. Known active tuberculosis or untreated tuberculosis

7. Hemoglobin < 8 g/dL

8. Expectation by the investigator to increase corticosteroid or immunosuppressive, or immunomodulatory medication dose at screening, baseline, or over the course of the study

9. Pregnancy or lactation

10. Consumption of > 2 cups of grapefruit juice per day

11. Treatment with medications metabolized using the cytochrome P3A4 pathway, such as cyclosporine, tacrolimus, gemfibrozil, niacin, itraconazole, ketoconazole, erythromycin, azithromycin, clarithromycin, bosentan, nefazodone, tricyclic antidepressants

12. Any condition that, in the opinion of the Investigator, would jeopardize the subject's safety following exposure to the study drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
2	UCLA David Geffen School of Medicine	Los Angeles	California	United States	90095
3	Rush University Medical Center	Chicago	Illinois	United States	60612
4	Bronx Lebanon Hospital	Bronx	New York	United States	10457
5	The Feinstein Institute for Medical Research	Manhasset	New York	United States	11030
6	New York University School of Medicine	New York	New York	United States	10016
7	Columbia University Medical Center	New York	New York	United States	10032
8	Hospital for Special Surgery	New York	New York	United States	20021

Sponsors and Collaborators

• Northwell Health
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Investigators

• Principal Investigator: Meggan Mackay, MD, Northwell Health

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 17, 2017

More Information

Publications

None provided.

• Responsible Party: Meggan Mackay, Associate Investigator, MD, Northwell Health
• ClinicalTrials.gov Identifier: NCT02066311
• Other Study ID Numbers: NISLE
• First Posted: Feb 19, 2014
• Last Update Posted: Feb 24, 2020
• Last Verified: Feb 1, 2020

• Keywords provided by Meggan Mackay, Associate Investigator, MD, Northwell Health: lupus; SLE
• Additional relevant MeSH terms: Lupus Erythematosus, Systemic; Nelfinavir

Study Results

Participant Flow

Arm/Group Title	Open-label Study With the Simon Two-Stage Trial Design
Arm/Group Description	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.
Period Title: Overall Study
STARTED	15
COMPLETED	10
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Open-label Study With the Simon Two-Stage Trial Design
Arm/Group Description	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.
Overall Participants	15
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	15 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	13 86.7%
Male	2 13.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 60%
Not Hispanic or Latino	6 40%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 6.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 20%
White	9 60%
More than one race	0 0%
Unknown or Not Reported	2 13.3%
Region of Enrollment (participants) [Number]
United States	15 100%
Serum anti-dsDNA antibody titer (IU/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [IU/mL]	313.8 (299.7)

Outcome Measures

1. Primary Outcome

Title	Inhibition of Anti-dsDNA Binding
Description	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

Outcome Measure Data

Analysis Population Description

The number of participants whose anti-dsDNA antibody titer decreased by ≥ 35% from baseline to Day 56

Arm/Group Title	Open-label Study With the Simon Two-Stage Trial Design
Arm/Group Description	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.
Measure Participants	10
Count of Participants [Participants]	1 6.7%

Adverse Events

Time Frame	Day 1 to Day 84- 84 days
Adverse Event Reporting Description	Adverse events were assessed systematically by regular investigator assessments and regular laboratory testing.
Arm/Group Title	Open-label Study With the Simon Two-Stage Trial Design
Arm/Group Description	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.
All Cause Mortality
	Open-label Study With the Simon Two-Stage Trial Design
	Affected / at Risk (%)	# Events
Total	0/15 (0%)
Serious Adverse Events
	Open-label Study With the Simon Two-Stage Trial Design
	Affected / at Risk (%)	# Events
Total	2/15 (13.3%)
Immune system disorders
Pyrexia	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorders
Abscess	1/15 (6.7%)	1
Other (Not Including Serious) Adverse Events
	Open-label Study With the Simon Two-Stage Trial Design
	Affected / at Risk (%)	# Events
Total	15/15 (100%)
Blood and lymphatic system disorders
Anemia	1/15 (6.7%)	1
Eosinophilia	1/15 (6.7%)	1
Cardiac disorders
Chest Pain	1/15 (6.7%)	1
Hypotension	1/15 (6.7%)	1
Gastrointestinal disorders
Abdominal tenderness	1/15 (6.7%)	1
Dehydration	1/15 (6.7%)	1
Diarrhea	9/15 (60%)	9
Gastroenteritis	1/15 (6.7%)	1
Pancreatitis	1/15 (6.7%)	1
vomiting	1/15 (6.7%)	1
Hepatobiliary disorders
Hepatic Enzyme increased	1/15 (6.7%)	1
Immune system disorders
Alopecia	1/15 (6.7%)	1
Lupus Flare	1/15 (6.7%)	1
Pyrexia	1/15 (6.7%)	1
Infections and infestations
Abscess	2/15 (13.3%)	2
Lymphadentiis	1/15 (6.7%)	1
Oropharyngeal pain	1/15 (6.7%)	1
Sinusitis	1/15 (6.7%)	1
Upper Respiratory tract infection	3/15 (20%)	3
Viral Infection	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorders
arthralgia	1/15 (6.7%)	1
Arthritis	3/15 (20%)	3
Bursitis	1/15 (6.7%)	1
Joint Pain	1/15 (6.7%)	1
Muscle spasm	1/15 (6.7%)	1
Tendonitis	1/15 (6.7%)	1
Nervous system disorders
Headache	2/15 (13.3%)	2
Renal and urinary disorders
Nephrolithiasis	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Rash	4/15 (26.7%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.