Lupus Nephritis
Conditions
Keywords
Lupus, Lupus Nephritis, ACTHar, Columbia, Rheumatology, CUMC, Autoimmune, SLE, Proliferative Lupus Nephritis
Brief summary
Systemic Lupus Erythematosus (SLE) is a disease in which the immune system attacks the healthy cells and tissues, causing inflammation that can damage organs in the body. About 50% of SLE patients experience inflammation in the kidneys. The purpose of this study is to determine the effectiveness and safety of two dosing arms of ACTHar gel in treating proliferative Lupus Nephritis (LN). This study hypothesizes that both dosing arms of ACTHar are safe and effective in treating proliferative LN (Class III and IV).
Detailed description
Systemic Lupus Erythematosus (SLE) is an autoimmune disease of unknown etiology that mainly affects females of childbearing age. The disease is characterized by immune activation and the development of autoantibodies. About 50% of SLE patients experience inflammation of the kidneys. Lupus Nephritis (LN) is a major cause of morbidity and mortality in patients with SLE. Mycophenolate Mofetil (MMF), accompanied by Prednisone, is considered the current standard of care for LN. However, long-term use of Prednisone has many serious side effects. ACTHar Gel is an FDA approved drug comprised of an active substance called adrenocorticotropic hormone (ACTH). ACTH belongs to an anti-inflammatory group called melanocortins and carries out its effects by binding to five different melanocortin receptors (MCRs). Specifically, ACTH binding to melanocortin 2 receptor subtype (MC2R) on the adrenal cortex stimulates the production of cortisol that reduces inflammation in the kidney. In addition to binding to melanocortin 1-5 receptor subtype (MC1-5R) and acting directly on kidney tissues, ACTH may bind to MCRs on various cell types, such as immune cells, and activate processes to protect the kidney. This study will evaluate the most effective dose of ACTHar gel in proliferative LN (Class III and IV) when given with MMF, the standard of care LN therapy. The intent of this study is to determine the effectiveness and safety of ACTHar gel in an attempt to change the clinical care requirements regarding steroid use in treating LN.
Interventions
DRUGCellCept
For both arms: CellCept 3 grams daily, oral, from Week 0-24 CellCept 2 grams daily, oral, from Week 25-144
DRUGACTHar gel
Arm 1: 80 U biw, subcutaneous, for 3 months. Optionally additional 3 months of 80 U biw if a patient has partial response. Arm 2: 80 U qod, subcutaneous, for 1 month, then 80 U biw, subcutaneous, for 2 months. Optionally additional 3 months of 80 U biw if a patient has partial response.
Sponsors
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of Systemic Lupus Erythematosus (SLE) by American College of Rheumatology (ACR)/SLICC criteria 2. Age ≥ 16 years 3. Active lupus nephritis defined by: a. Kidney biopsy documentation of International Society of Nephrology/Renal Pathology Society (ISN/RPS) Class III or Class IV proliferative nephritis (including Class V occurring in combination with Class III or IV) within 12 months and a urine protein/creatinine ratio \>1 at time of entry to study 4. Ability to provide informed consent
Exclusion criteria
1. Moderately severe anemia (Hgb \< 8 mg/dL) 2. Neutropenia (\< 1,000/mm3) 3. Thrombocytopenia (platelets \< 50,000/mm3) 4. Positive purified protein derivative (PPD) test confirmed by positive Quantiferon TB gold. 5. Pulmonary fibrotic changes on chest radiograph consistent with prior healed tuberculosis 6. Active infections that in the opinion of the investigator increase the risks to the subject. 7. Known human immunodeficiency virus (HIV) and hepatitis B or C 8. End-stage renal disease (estimated GFR clearance \< 20 mL/min/1.73 m2) 9. History of cancer, except carcinoma in situ and treated basal and squamous cell carcinomas 10. Pregnancy 11. Lactation 12. Unwillingness to use a medically acceptable form of birth control (including but not limited to a diaphragm, an intrauterine device, progesterone implants or injections, oral contraceptives, the double-barrier method, or a condom) 13. Previous failure to respond to MMF 14. Use of rituximab within the past year 15. Use of experimental therapeutic agents within the past 60 days 16. Greater than or equal to 5 times the upper limit of normal of liver function tests (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], or alkaline phosphatase) 17. Severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, or neurological disease (or, in the investigator's opinion, any other concomitant medical condition that places the participant at risk by participating in this study) with the exception of diseases or conditions related to active SLE 18. Current substance abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With a Complete Response (CR) | 6 Months | Complete response (CR) is defined as all of the following criteria having been achieved: 1. Stabilization of estimated glomerular filtration rate (eGFR) (i.e., a 6-month eGFR level ± 10% of baseline) or improvement if the screening value is changed from patient's baseline 2. Inactive urinary sediment (red blood cells per high-power field \[RBCs/HPF\] \< 5-10, not due to gyn bleeding) 3. Urine protein/creatinine ratio \< 0.5 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Extra-renal Flares | 6 Months | Frequency of extra-renal flares as defined by the SELENA-SLEDAI Flare Index. Extra-renal disease activity measured by SELENA-SLEDAI and BILAG |
| Number of Patients With Steroid -Like Side Effects | 6 Months | Steroid -like side effects: increase in blood pressure (BP) by 20 mmHg for both systolic blood pressure (SBP) and diastolic blood pressure (DBP), increased blood sugar with a fasting plasma glucose level ≥ 126 mg/dl, weight gain ≥ 10% of the initial weight, infections |
| Number of Responders | 6 Months | Responders = Complete Responders (CR) + Partial Responders (PR). PR = improvement from baseline of at least ≥ 50% in all abnormal renal parameters (proteinuria and serum creatinine) without deterioration of any measurements at 6 months |
| Number of Patients With Side Effects | 6 Months | Number of participants who experienced side effects from taking ACTHar |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mean Cortisol Levels | Upon study completion, up to 30 months | Cortisol levels 8 hours after ACTHar dose in 2-3 patients per dosing arm |
| Mean Urinary Lymphocytes | Upon study completion, up to 30 months | Urinary markers of active inflammatory nephritis |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CellCept Daily & ACTHar Gel BIW (Two Times Per Week) Patients will be treated with CellCept 3 grams daily and ACTHar gel 80 U BIW for 3 months per Aim 1. After 3 months, patients with complete response will stop ACTHar gel but continue CellCept 3 grams daily for another 3 months whereas patients with partial response will continue CellCept 3 grams daily and be offered the option to continue ACTHar 80 U biw for another 3 months. After 6 months, all patients will continue CellCept at a dose of 2 grams daily for another 18 months. | 4 |
| CellCept Daily & ACTHar Gel TIW (Three Times Per Week) Patients will be treated with CellCept 3 grams daily for 3 months, and ACTHar gel 80 U TIW for the first month and ACTHar gel 80 U BIW for the following 2 months per Aim 2. After 3 months, patients with complete response will stop ACTHar gel but continue CellCept 3 grams daily for another 3 months whereas patients with partial response will continue CellCept 3 grams daily and be offered the option to continue ACTHar 80 U BIW for another 3 months. After 6 months, all patients will continue CellCept at a dose of 2 grams daily for another 18 months. | 4 |
| Total | 8 |
Baseline characteristics
| Characteristic | CellCept Daily & ACTHar Gel BIW (Two Times Per Week) | Total | CellCept Daily & ACTHar Gel TIW (Three Times Per Week) |
|---|---|---|---|
| Age, Continuous | 26.5 years | 26.5 years | 28.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment United States | 4 participants | 8 participants | 4 participants |
| Sex: Female, Male Female | 3 Participants | 7 Participants | 4 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 |
| other Total, other adverse events | 1 / 4 | 0 / 4 |
| serious Total, serious adverse events | 0 / 4 | 1 / 4 |
Outcome results
Primary
Number of Patients With a Complete Response (CR)
Complete response (CR) is defined as all of the following criteria having been achieved: 1. Stabilization of estimated glomerular filtration rate (eGFR) (i.e., a 6-month eGFR level ± 10% of baseline) or improvement if the screening value is changed from patient's baseline 2. Inactive urinary sediment (red blood cells per high-power field \[RBCs/HPF\] \< 5-10, not due to gyn bleeding) 3. Urine protein/creatinine ratio \< 0.5
Time frame: 6 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CellCept Daily & ACTHar Gel BIW (Two Times Per Week) | Number of Patients With a Complete Response (CR) | 2 Participants |
| CellCept Daily & ACTHar Gel TIW (Three Times Per Week) | Number of Patients With a Complete Response (CR) | 0 Participants |
Secondary
Number of Patients With Extra-renal Flares
Frequency of extra-renal flares as defined by the SELENA-SLEDAI Flare Index. Extra-renal disease activity measured by SELENA-SLEDAI and BILAG
Time frame: 6 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CellCept Daily & ACTHar Gel BIW (Two Times Per Week) | Number of Patients With Extra-renal Flares | 0 Participants |
| CellCept Daily & ACTHar Gel TIW (Three Times Per Week) | Number of Patients With Extra-renal Flares | 1 Participants |
Secondary
Number of Patients With Side Effects
Number of participants who experienced side effects from taking ACTHar
Time frame: 6 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CellCept Daily & ACTHar Gel BIW (Two Times Per Week) | Number of Patients With Side Effects | 0 Participants |
| CellCept Daily & ACTHar Gel TIW (Three Times Per Week) | Number of Patients With Side Effects | 0 Participants |
Secondary
Number of Patients With Steroid -Like Side Effects
Steroid -like side effects: increase in blood pressure (BP) by 20 mmHg for both systolic blood pressure (SBP) and diastolic blood pressure (DBP), increased blood sugar with a fasting plasma glucose level ≥ 126 mg/dl, weight gain ≥ 10% of the initial weight, infections
Time frame: 6 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CellCept Daily & ACTHar Gel BIW (Two Times Per Week) | Number of Patients With Steroid -Like Side Effects | 0 Participants |
| CellCept Daily & ACTHar Gel TIW (Three Times Per Week) | Number of Patients With Steroid -Like Side Effects | 0 Participants |
Secondary
Number of Responders
Responders = Complete Responders (CR) + Partial Responders (PR). PR = improvement from baseline of at least ≥ 50% in all abnormal renal parameters (proteinuria and serum creatinine) without deterioration of any measurements at 6 months
Time frame: 6 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CellCept Daily & ACTHar Gel BIW (Two Times Per Week) | Number of Responders | 2 Participants |
| CellCept Daily & ACTHar Gel TIW (Three Times Per Week) | Number of Responders | 1 Participants |
Other Pre-specified
Mean Cortisol Levels
Cortisol levels 8 hours after ACTHar dose in 2-3 patients per dosing arm
Time frame: Upon study completion, up to 30 months
Population: Data was not collected due to lack of funding leading to early termination of the study.
Other Pre-specified
Mean Urinary Lymphocytes
Urinary markers of active inflammatory nephritis
Time frame: Upon study completion, up to 30 months
Population: Data was not collected due to lack of funding leading to early termination of the study.