Cutaneous Lupus, Systemic Lupus Erythematosus
Conditions
Brief summary
This 76-week, 3-part Phase 1b/2 study is intended to evaluate the pharmacological properties (pharmacokinetics and pharmacodynamics), safety, tolerability and preliminary effectiveness of TOFA administrated to young adults (18-45 years) with moderately to severely active SLE-CL. Subjects will be studied at the Cincinnati Children's Hospital Medical Center (CCHMC) and in Cleveland at MetroHealth Medical Center.
Detailed description
Cohort 1 (n=10, weight \> 40kg and age \> 18 years and ≤ 45 years ) will undergo intense PK-sampling to determine exposures following TOFA dosed at 5 mg BID. TOFA dose escalation will not be considered for inadequate response of SLE-CL. Cohort 2 (n=10, weight \> 40kg and age \> 18 years and ≤ 45 years) will be treated with the same dose as Cohort 1. No PK sampling will occur for Cohort 2. Enrollment of Cohort 2 will only start once Cohort 1 has completed 8 weeks of TOFA and results of PK analyses from Cohort 1 are available. * Part A (up to week 8) requires stable background medications; * Part B (up to week 24) allows for tapering of corticosteroids (CS) in the setting of significant clinical improvement of SLE-CL as defined by a decrease in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score by \>50% from baseline , and * Part C (until week 76) permits tapering of other background medications in subjects with clinical remission of SLE-CL (CLASI activity score=0). TOFA dosing is kept stable during Part C.
Interventions
DRUGTofacitinib
Tofacitinib 5 mg twice daily
Sponsors
Children's Hospital Medical Center, Cincinnati
Pfizer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female \> 18 years of age and \< 45 years of age and \> 40 kg body weight. 2. Fulfilled at least 4 out of the 11 Classification Criteria for SLE by the time of screening. 3. Willing to give written informed consent, must fully understand the requirements of the trial, and must be willing to comply with all trial visits and assessments. 4. CLASI activity score of 8 or higher at screening and baseline despite standard of care therapy. 5. Stable dose of prednisone of ≤ 20 mg/day within 2 weeks of enrollment. 6. Female subjects of childbearing potential must use a highly effective method of contraception to prevent pregnancy (abstinence is considered highly effective) and must agree to continue to practice adequate contraception for the duration of their participation in the trial and for 28 days after their last dose of TOFA. 7. Female subjects of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at Trial Day 1 before dosing. 8. For subjects receiving leflunomide treatment, total daily dose does not exceed 20 mg. 9. A negative QuantiFERON-TB Gold In-Tube test performed within the 3 months prior to screening, or within the screening period prior to baseline. A negative PPD test can be substituted for the QuantiFERON-TB. 10. Subjects either have protective varicella titers or evidence of having been vaccinated against varicella.
Exclusion criteria
1. Mild SLE-CL defined as a CLASI activity score of 7 or lower at screening and baseline. 2. Increase in CS dosing within 2 weeks prior to Trial Day 1, or expected to require an increase in CS dosing during the first 4 weeks of the study. 3. Use of i.v. corticosteroids within 4 weeks prior to Trial Day 1. 4. Increase in dosing of methotrexate, leflunomide, within 4 weeks before Trial Day 1 or expected to require an increase during the first 8-weeks of the study. 5. Increase in dosing of hydroxychloroquine, or chloroquine within 4 weeks before Trial Day 1 or expected to require an increase during the first 8-weeks of the study. 6. Rituximab within 1 year of Trial Day 1. 7. Increase in dosing of any medication or herbal treatment considered to have immunosuppressive properties with 4 weeks before Trial Day 1. 8. Prior treatment with or known intolerability of TOFA. 9. Use of cyclophosphamide (i.v. or oral), cyclosporine, or tacrolimus within 12 weeks prior to Trial Day 1. 10. Treatment with other investigational agents within the last 6 months or 5 half-lives, or as per washout requirement from the previous protocol, whichever is longer. 11. Estimated glomerular filtration rate less than or equal to 60 mL/min /1.73 m2. 12. Known positive Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), or Hepatitis B surface antigen (HBsAg) serology. 13. Any condition, including findings in the laboratory tests, medical history, or other screening assessments, that, in the opinion of the Investigator, constitutes an inappropriate risk or a contraindication for participation in the trial or that could interfere with the trial's objectives, conduct, or evaluation. 14. Active central nervous system SLE deemed to be severe or progressive and/or associated with significant cognitive impairment leading to inability to provide informed consent and/or comply with the protocol. 15. Significant renal disease due to a reason(s) other than Lupus Nephritis (e.g. diabetes mellitus, renovascular disease, or antiphospholipid syndrome). 16. Severely active Lupus Nephritis defined as a renal BILAG A score. 17. History of dialysis within 3 months prior to Trial Day 1 or expected to need during the trial. 18. History of or planned renal or other organ transplantation. 19. Known active clinically significant viral, bacterial or fungal infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 8 weeks of screening, or completion of oral anti-infectives within 2 weeks of Trial Day 1. 20. Breastfeeding or currently pregnant. 21. Legal incapacity or limited legal capacity to provide informed consent or assent. 22. Blood dyscrasias, including: * Hgb \<10 g/dL or Hct \<33%. * WBC \<3.0 x 109/L. * Neutrophil count \<1.2 x 109/L. * Platelet count \<100 x 109/L. * Lymphocyte count of \<0.5 x 109/L. 23. AST or ALT \> 1.5 times the upper limit of normal or any other clinically significant laboratory abnormality. 24. History of any other rheumatic autoimmune disease. 25. Infections: * Latent or active TB or any history of previous TB. * Chronic infections. * Any infection requiring hospitalization, parenteral antimicrobial therapy or judged to be opportunistic by the investigator within the 6 months prior to the first dose of study drug. * Any treated infections within 2 weeks. * History of recurrent (more than one episode) herpes zoster or disseminated (a single episode) herpes zoster or disseminated (a single episode) herpes simplex. * History or current symptoms suggestive of any lymphoproliferative disorder, including Cytomegaly Virus (CMV) or Epstein Barr Virus (EBV) related lymphoproliferative disorder, history of lymphoma, leukemia, or signs and symptoms suggestive of current lymphatic disease. 26. Subjects taking potent and moderate cytochrome P450 3A4 (CYP3A4) inhibitors (see Appendix 2). 27. Subjects taking potent and moderate CYP3A4 inducers (see Appendix 2). 28. Subjects who have been vaccinated with live or attenuated vaccines within the 6 weeks prior to the first dose of study medication. All subjects should be up-to-date with respect to standard of care vaccinations (as defined by their country health ministry) as permitted by past immunosuppressive therapy for SLE. 29. Subjects with a malignancy or with a history of malignancy with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ. 30. Subjects with a history or current diagnosis of diverticulitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Oral Clearance (CL/F) (Cohort 1 Only) | Day 5 | Apparent total clearance of the drug from plasma after oral administration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score | weeks 4, 8 and 24 compared to baseline. | Proportion of subjects who achieve a skin response per the validated CLASI The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score consists of two scores. The first summarizes the activity of the disease while the second is a measure of the damage done by the disease. The Activity Score range is 0-70 with the maximum score (70) indicating the worst outcome. The Damage Score range is 0-80 with the maximum score (80) indicating the worst outcome. |
| AUCt (Cohort 1 Only) | Day 5 | Area under the plasma concentration-time curve linear scale Median Concentration (ng/mL) per nominal time 0-8 hours. |
| Cmax (Cohort 1 Only) | Day 5 | Maximum (or peak) plasma concentration of Tofacitinib |
| Tmax (Cohort 1 Only) | Day 5 | Time to reach maximum (peak) plasma concentration following administration of Tofacitinib |
| Vz/F (Cohort 1 Only) | Day 5 | Apparent volume of distribution during terminal phase after non-intravenous administration |
| Half-life of Tofacitinib (Cohort 1 Only) | Day 5 | half-life of Tofacitinib |
| Safety of Tofacitinib: Total Number of Adverse Events is Reported (Cohorts 1 and 2) | 76 weeks | Rate and severity of adverse events and lab abnormalities experienced by participants in both cohorts of the research study. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORHermine Brunner, MD
Cincinnati Childrens Hospital Medical Center
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 & Cohort 2 Tofacitinib: Tofacitinib 5 mg twice daily
Comparison was not planned for Cohort 1 vs Cohort 2. Cohort 1 received pk analysis. Since only 1 subject was enrolled in cohort 2 the study team is completing analysis with the cohorts combined except for those indicated cohort 1 only in the protocol | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | Cohort 1 & Cohort 2 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Age, Continuous | 21.04 years STANDARD_DEVIATION 5.89 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 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 | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment United States | 11 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 11 |
| other Total, other adverse events | 9 / 11 |
| serious Total, serious adverse events | 1 / 11 |
Outcome results
Primary
Oral Clearance (CL/F) (Cohort 1 Only)
Apparent total clearance of the drug from plasma after oral administration
Time frame: Day 5
Population: Tofacitinib PK was collected from in total of 8 patients, PK parameters were generated for N=7 patients. The PK data for one patient was not used when generating the PK parameters and descriptive summaries due to a dosing event error.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Oral Clearance (CL/F) (Cohort 1 Only) | 28.4 (L/hr) | Geometric Coefficient of Variation 23.5 |
Secondary
AUCt (Cohort 1 Only)
Area under the plasma concentration-time curve linear scale Median Concentration (ng/mL) per nominal time 0-8 hours.
Time frame: Day 5
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | AUCt (Cohort 1 Only) | 176 (ng.hr/mL) | Geometric Coefficient of Variation 23.5 |
Secondary
Cmax (Cohort 1 Only)
Maximum (or peak) plasma concentration of Tofacitinib
Time frame: Day 5
Population: Tofacitinib PK was collected from in total of 8 patients, PK parameters were generated for N=7 patients. The PK data for one patient was not used when generating the PK parameters and descriptive summaries due to a dosing event error.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Cmax (Cohort 1 Only) | 51.7 (ng/mL) | Geometric Coefficient of Variation 21.6 |
Secondary
Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score
Proportion of subjects who achieve a skin response per the validated CLASI The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score consists of two scores. The first summarizes the activity of the disease while the second is a measure of the damage done by the disease. The Activity Score range is 0-70 with the maximum score (70) indicating the worst outcome. The Damage Score range is 0-80 with the maximum score (80) indicating the worst outcome.
Time frame: weeks 4, 8 and 24 compared to baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score | Baseline | 16.55 score on a scale | Standard Deviation 8.03 |
| Cohort 1 | Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score | Week 4 | 10.91 score on a scale | Standard Deviation 8.4 |
| Cohort 1 | Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score | Week 8 | 8.64 score on a scale | Standard Deviation 7.8 |
| Cohort 1 | Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score | Week 24 | 8.82 score on a scale | Standard Deviation 7.9 |
Secondary
Half-life of Tofacitinib (Cohort 1 Only)
half-life of Tofacitinib
Time frame: Day 5
Population: Tofacitinib PK was collected from in total of 8 patients, PK parameters were generated for N=7 patients. The PK data for one patient was not used when generating the PK parameters and descriptive summaries due to a dosing event error.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Half-life of Tofacitinib (Cohort 1 Only) | 2.1 hr | Standard Deviation 0.321 |
Secondary
Safety of Tofacitinib: Nature, Severity, and Frequency of Adverse Events (Cohorts 1 and 2)
Rate and severity of adverse events and lab abnormalities
Time frame: 76 weeks
Secondary
Tmax (Cohort 1 Only)
Time to reach maximum (peak) plasma concentration following administration of Tofacitinib
Time frame: Day 5
Population: Tofacitinib PK was collected from in total of 8 patients, PK parameters were generated for N=7 patients. The PK data for one patient was not used when generating the PK parameters and descriptive summaries due to a dosing event error.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Tmax (Cohort 1 Only) | 1 hr |
Secondary
Vz/F (Cohort 1 Only)
Apparent volume of distribution during terminal phase after non-intravenous administration
Time frame: Day 5
Population: Tofacitinib PK was collected from in total of 8 patients, PK parameters were generated for N=7 patients. The PK data for one patient was not used when generating the PK parameters and descriptive summaries due to a dosing event error.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Vz/F (Cohort 1 Only) | 85.2 L | Geometric Coefficient of Variation 25.6 |
Other Pre-specified
Change in British Isles Lupus Activity Group (BILAG) Score
Measure Tofacitinib impact on disease activity
Time frame: 76 weeks
Other Pre-specified
Change in Patients Global Assessment Score
Quality-of-life measure for patients
Time frame: Baseline, week 24 and week 76
Other Pre-specified
Change in SKINDEX Score
Quality-of-life measure for patients with skin disease
Time frame: Baseline, week 24 and week 76
Other Pre-specified
Change in SLE Disease Activity Index (SLEDAI) Score
Measure Tofacitinib impact on disease activity
Time frame: 76 weeks
Other Pre-specified
Steroid Dose Comparison
Assess steroid sparing properties of Tofacitinib by comparing doses to baseline and rate of steroid discontinuation
Time frame: 76 weeks