pemphigus vulgaris [PV] or pemphigus foliaceus [PF] MedDRA version: 20.0 Level: LLT Classification code 10052802 Term: Pemphigus vulgaris System Organ Class: 100000004858 MedDRA version: 21.0 Level: LLT Classification code 10057054 Term: Pemphigus foliaceous System Organ Class: 100000004858
Conditions
Sponsors
Principia Biopharma
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female patients, aged 18 to 80 years old with moderate to severe, newly diagnosed or relapsing PV or PF, with a clinical presentation and histopathology consistent with PV or PF. 2. Positive circulating anti-dsg1 or 3 autoantibody titer 3. At screening PDAI score of at least 9 points for relapsing patients (> 6 months since diagnosis) or at least 15 points for newly diagnosed patients (diagnosed = 6 months prior to Screening) 4. Adequate hematologic, hepatic, and renal function (absolute neutrophil count = 1.5 × 109/L, hemoglobin (Hgb) > 9 g/dL, platelet count = 100 × 109/L, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) = 1.5 × upper limit of normal (ULN), albumin = 3 g/dL, creatinine = 1.5 × ULN 5. Female patients who are of reproductive potential must agree for the duration of the study to use an effective means of contraception (e.g., hormonal contraception methods that inhibit ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized partner or condoms). Unless surgically sterile, postmenopausal females should have menopause confirmed by follicle-stimulating hormone (FSH) testing. For females considered not to have reproductive potential: any woman of age =55 years with amenorrhea for > than 1 year, will be considered as having confirmed menopause and FSH or pregnancy testing will not be needed. Postmenopausal females 1 year) must have menopause confirmed by lelvated FSH levels at screening. Surgically sterile females do not require any further confirmation of menopause and will not be considered to have reproductive potential. 6. Able to provide written informed consent and agreeable to the schedule of assessments Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 100 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 20
Exclusion criteria
Exclusion criteria: 1. Suspected paraneoplastic pemphigus and other forms of pemphigus that are not pemphigus vulgaris or pemphigus foliaceus 2. Previous use of a Bruton’s tyrosine kinase (BTK) inhibitor 3. Pregnant or lactating women 4. Electrocardiogram (ECG) findings of QT corrected for heart rate (QTc) > 450 msec (males) or > 470 msec (females), poorly controlled atrial fibrillation (i.e., symptomatic patients or a ventricular rate above 100 beats/min on ECG), or other clinically significant abnormalities 5. A history of malignancy of any type within 5 years before Day 1, other than surgically excised non-melanoma skin cancers or in situ cervical cancer 6. Use of immunologic response modifiers as concomitant medication and with the following washout periods: A) stop at least 2 weeks prior to Screening: mycophenolate mofetil, azathioprine, methotrexate, cyclosporine, dapsone, intravenous immunoglobulin (IVIG), Kinaret (anakinra), Enbrel (etanercept) or any other immunosuppressant not mentioned in this exclusion criterion; B) 12 weeks prior to Screening: Remicade (infliximab), Humira (adalimumab), Simponi (golimumab), Orencia (abatercept), Actemra (tocilizumab), Cimzia (certolizumab), Cosentyx (secukinumab), plasmapheresis; C) 6 months prior to Screening (or shorter if there is documented B cell reconstitution for anti-CD20 drugs): antiCD20 drugs such as rituximab, ofatumumab, other long-acting biologics 7. Use of proton pump inhibitor drugs such as omeprazole and esomeprazole within 3 days of Day 1(It is acceptable to change patient to H2 receptor blocking drugs prior to Day 1.) 8. Concomitant use of known strong-to-moderate inducers or inhibitors of CYP3A within 3 days or 5 half-lives (whichever is longer) of Day 1 (Appendix 8) 9. Use of CYP3A-sensitive substrate drugs with a narrow therapeutic index within 3 days or 5 half-lives (whichever is longer) of Day 1 and for the remainder of the trial including, but not limited to alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus (topical or oral), or terfenadine 10. Has received any investigational drug (or is currently using an investigational device) within the 30 days before Day 1, or at least 5 times the respective elimination half-life time (whichever is longer) 11. History of drug abuse within the previous 12 months 12. Alcoholism or excessive alcohol use, defined as regular consumption of more than approximately 3 standard drinks per day 13. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate PRN1008/placebo absorption 14. Donation of a unit or more of blood or blood products within 4 weeks prior to Day 1 15. History of solid organ transplant 16. Positive at Screening for human immunodeficiency virus (HIV), hepatitis B (surface and core antibodies unrelated to vaccination, surface antigen), or hepatitis C (anti-HCV antibody confirmed with Hep C RNA) 17. Positive interferon-gamma release assay (IGRA) (e.g., T-spot TB test, QuantiFERON®-TB Gold or QuantiFERON®-TB Gold Plus (QFTPlus)) at Screening. Unless the patient has latent TB and all of the following 3 conditions are true: a. Chest X-ray does not show evidence suggestive of active tuberculosis (TB) disease b. There are no clinical signs and symptoms of pulmonary and/or extrapulmonary TB disease c. Documented receipt of one of the following prophylactic treatment regimens: - oral daily
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Efficacy objectives • To evaluate the efficacy of PRN1008 in achieving durable CR on low to zero doses of oral corticosteroid (CS) and on the timecourse of quantitative disease activity scores • To assess the ability of PRN1008 to reduce CS exposure and the adverse effects of CS • To evaluate the time to specified clinical endpoints • To assesss the longer term durability of CR Safety Objectives • To evaluate the safety of PRN1008 • To evaluate differences in potentially CS-related adverse events ;Secondary Objective: PK/PD Objectives • To evaluate the population pharmacokinetics (PK) of PRN1008 • To evaluate pharmacodynamic (PD) effects of PRN1008 on anti-desmoglein (anti-dsg) autoantibody titers (anti-dsg1 and anti-dsg3) Exploratory Objectives • To examine the effects of PRN1008, if any, of the baseline covariates on PK and/or PD, and the relationship between PK, PD, and efficacy • To examine the effect of PRN1008 on the costs of hospitalizations, outpatient medical visits, adverse events, concomitant medication use and other relevant health economic outcomes • To examine the temporal relationship of change from baseline in Pemphigus Disease Area Index (PDAI) total activity score and quality of life and health economic measures ;Primary end point(s): Efficacy endpoint: The proportion of patients who are in CR from Week = 29 to Week 37 with a daily prednisone dose of = 5 mg/day Safety Endpoints • Nature, frequency, and severity of adverse events, including serious adverse events, adverse events leading to discontinuation and possible corticosteroid-related adverse effects • Change from baseline in vital signs and clinical laboratory test results (including complete blood count and blood chemistry) ;Timepoint(s) of evaluation of this end point: Efficacy endpoints: at every visit between week 29 and Week 37 Safety endpoints: at every visit | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key Secondary Efficacy Endpoints • Cumulative CS dose over first 36 weeks (to Week 37) • Time to the beginning of the CR event used to define success for patients reaching the primary endpoint • Proportion of patients with CR from Week = 29 to Week 37 with a daily CS dose of = 10 mg/day Other Secondary Endpoints • GTI score at Week 37 • Change in EuroQOL-5 Dimension 5 Level (EQ-5D-5L) score from baseline to Week 37 • Change in EQ-5D-5L score from baseline to Weeks 5, 13, 25, and 61 • Change in Autoimmune Bullous Disease Quality of Life (ABQOL) score from baseline to Weeks 5, 13, 25, 37 and 61 • Change in PDAI score from baseline to Weeks 5, 13, 25, 37 and 61 • Change in Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL) score from baseline to Weeks 5, 13, 25, 37, and 61 • Proportion of patients in CR for = 8 weeks on zero CS at Week 61 by original PRN1008/placebo group assignment and overall • Proportion of patients in CR at Week 37 to maintain CR continuously to Week 61 • Proportion of patients not in CR at Week 37 to achieve CR at Week 61 • Proportion of patients to achieve CR of any duration at any time up to Week 37 • Duration of CR ;Timepoint(s) of evaluation of this end point: at every visit | — |
Countries
Argentina, Australia, Brazil, Bulgaria, Canada, Croatia, France, Germany, Greece, Israel, Italy, Poland, Serbia, Spain, Taiwan, Turkey, Ukraine, United Arab Emirates, United Kingdom, United States
Contacts
Public ContactChief Medical Officer
Principia Biopharma, Inc.
Outcome results
None listed