E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
pemphigus vulgaris [PV] or pemphigus foliaceus [PF] |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052802 |
E.1.2 | Term | Pemphigus vulgaris |
E.1.2 | System Organ Class | 100000004858 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057054 |
E.1.2 | Term | Pemphigus foliaceous |
E.1.2 | System Organ Class | 100000004858 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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
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E.2.2 | Secondary objectives of the trial |
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
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. PDAI score of at least 9 points for relapsing patients (diagnosed > 6 months prior to Screening) or at least 15 points for newly diagnosed patients (diagnosed ≤ 6 months prior to Screening) 4. Body mass index (BMI) > 17.5 5. 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) and/or alanine aminotransferase (ALT) ≤ 1.5 × upper limit of normal (ULN), albumin ≥ 3 g/dL, creatinine ≤ 1.5 × ULN 6. 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 7. Able to provide written informed consent and agreeable to the schedule of assessments
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E.4 | Principal 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, other than surgically excised non-melanoma skin cancers or in situ cervical cancer within 5 years before Day 1 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 (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, 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., QuantiFERON®-TB Gold or T spot TB® Test) at Screening. Unless, 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 extra-pulmonary TB disease c. Documented receipt of a course of prophylactic TB treatment of at least 6 months 18. History of serious infections requiring intravenous therapy with the potential for recurrence 19. Live vaccine within 28 days prior to Day 1 or plan to receive one during the trial 20. Any other clinically significant disease, condition, or medical history that, in the opinion of the Investigator, would interfere with patient safety, trial evaluations, and/or trial procedures
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy endpoint: The proportion of patients who are in CR from Week ≤ 29 to Week 37 with a daily corticosteroid 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)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy endpoints: at every visit between week 29 and Week 37 Safety endpoints: at every visit |
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E.5.2 | 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
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
double-blind for the first 36 weeks, then open label from week 37 to 61 |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 49 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Bulgaria |
Canada |
Croatia |
France |
Germany |
Greece |
Israel |
Italy |
Serbia |
Spain |
Taiwan |
Turkey |
Ukraine |
United Arab Emirates |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 4 |