A study to evaluate the efficacy and safety of PRN1008 in patients with pemphigus

• Register: EUCTR
• Last refreshed on: 28 February 2019
• Main ID: EUCTR2018-002261-19-ES
• Date of registration: 18/01/2019
• Prospective Registration: Yes
• Primary sponsor: Principia Biopharma
• Public title: A study to evaluate the efficacy and safety of PRN1008 in patients with pemphigus
• Scientific title: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial to Evaluate the Efficacy and Safety of Oral BTK Inhibitor PRN1008 in Moderate to Severe Pemphigus
• Date of first enrolment: 08/02/2019
• Target sample size: 120
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-002261-19
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: double-blind for the first 36 weeks, then open label from week 37 to 61 If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Bulgaria, Canada, Croatia, France, Germany, Greece, Israel, Italy, Poland, Serbia, Spain, Taiwan, Turkey, Ukraine, United Arab Emirates, United Kingdom, United States

Contacts

• Name: Chief Medical Officer
• Affiliation: Principia Biopharma, Inc.

• Name: Chief Medical Officer
• Affiliation: Principia Biopharma, Inc.

Key inclusion & exclusion 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. 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
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:
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 s

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

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: 20.0 Level: LLT Classification code 10057054 Term: Pemphigus foliaceous System Organ Class: 100000004858

Therapeutic area: Diseases [C] - Skin and Connective Tissue Diseases [C17]

Intervention(s)

Product Name: PRN1008
Product Code: PRN1008
Pharmaceutical Form: Tablet
INN or Proposed INN: not available
CAS Number: 1575596
Current Sponsor code: PRN1008
Other descriptive name: PRN1008
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 400-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

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

Timepoint(s) of evaluation of this end point: Efficacy endpoints: at every visit between week 29 and Week 37
Safety endpoints: at every visit

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)

Secondary Outcome(s)

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

Secondary ID(s)

2018-002261-19-BG

PRN1008-012

134595

Source(s) of Monetary Support

Principia Biopharma

Ethics review

Status: Approved
Approval date:
Contact: