An Open-Label, Phase 2, Pilot Study Investigating the Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics of Oral Treatment with the BTK Inhibitor PRN1008 in Patients with Newly Diagnosed or Relapsing Pemphigus Vulgaris

• Register: EUCTR
• Last refreshed on: 21 December 2021
• Main ID: EUCTR2015-003564-37-HR
• Date of registration: 06/07/2016
• Prospective Registration: No
• Primary sponsor: Principia Biopharma Australia Pty Ltd
• Public title: An Open-Label, Phase 2, Pilot Study Investigating the Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics of Oral Treatment with the BTK Inhibitor PRN1008 in Patients with Newly Diagnosed or Relapsing Pemphigus Vulgaris
• Scientific title: An Open-Label, Phase 2, Pilot Study Investigating the Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics of Oral Treatment with the BTK Inhibitor PRN1008 in Patients with Newly Diagnosed or Relapsing Pemphigus Vulgaris
• Date of first enrolment: 18/04/2016
• Target sample size: 50
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-003564-37
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Croatia, France, Greece, Israel

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 biopsy proven (positive direct immunofluorescence and appearance on H&E microscopy), mild-moderate PV in Part A (PDAI 8 to 45) and mild-severe PV in Part B (PDAI 8 to 60)
2.Newly diagnosed or relapsing patients for whom an initial period of PRN1008 monotherapy or combination therapy with low-dose corticosteroids (=0.5 mg/kg of prednis[ol]one or equivalent), is judged clinically acceptable, provided tapering of the corticosteroid treatment regimen is anticipated with good clinical response to PRN1008
3.BMI > 17.5 and < 40 kg/m2 Part A only
4.Adequate hematologic, hepatic, and renal function (absolute neutrophil count = 1.5 X 109/L, Hgb > 9 g/dL, platelet count = 100 X 109/L, AST/ALT = 1.5 x ULN, albumin = 3 g/dL, creatinine = ULN (Part A) and creatinine = 1.5 x ULN (Part B)
5.Female patients who are of reproductive potential must agree for the duration of active treatment in the study to use an effective means of contraception (hormonal contraception methods that inhibits ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized partner, condoms, or sexual abstinence). Unless surgically sterile, postmenopausal females should have menopause confirmed by FSH testing.
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 40
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 10

Exclusion criteria:
1.Previous use of a BTK inhibitor. Patients enrolled in a previous version of this protocol who are still in their 12-week active treatment period with PRN1008 are eligible to continue treatment, initially with their current dose level, under this amended protocol for an additional 12 weeks, i.e. 24 weeks total, following review and signature of the EC approved patient’s consent.Patients who completed Part A and did not discontinue the study due to a medical condition that might compromise safety assessments or for a PRN1008 related adverse event may be screened for entry under Part B.
2.Pregnant or lactating women
3.ECG findings of 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
4.A history of malignancy of any type, other than surgically excised non-melanoma skin cancers or in situ cervical cancer within 5 years before the day of dosing
5.Use of immunologic response modifiers with the following periods prior to Day 1: as concomitant therapy, other immunologic response modifiers not detailed in this exclusion apart from corticosteroids; 1 week: cyclophosphamide; 4 weeks: IVIG, Kinaret (anakinra) and Enbrel (etanercept); 12 weeks: Remicade (infliximab), Humira (adalimumab), Simponi (golimumab), Orencia (abatercept), Actemra (tocilizumab), Cimzia (certolizumab), Cosentyx (secukinumab), plasmapheresis; 6 months: Rituxan/MabThera (rituximab), ofatumumab, any other anti-CD20 antibody, other long-acting biologics
6.More than 0.5 mg/kg of prednis(ol)one per day (“low-dose corticosteroids”) within the two weeks prior to Day 1
7.Use of proton pump inhibitor drugs such as omeprazole and esomeprazole (it is acceptable to change patient to H2 receptor blocking drugs prior to the first dose of PRN1008)
8.Concomitant use of known strong-to-moderate inducers or inhibitors of CYP3A (Appendix 2) within 3 days or 5 half-lives (whichever is longer) of study drug dosing
9.Use of CYP3A-sensitive substrate drugs (Appendix 3) with a narrow therapeutic index within 3 days or 5 half-lives (whichever is longer) of study drug dosing 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 receiving the first dose of study medication, 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 study drug absorption
14.History of anorexia nervosa or periods of three months or more of low body weight (BMI < 17.5) in the past 5 years
15.Donation of a unit or more of blood or blood products within 4 weeks prior to Day 1
16.History of solid organ transplant
17.History of epilepsy or other forms of seizure in the last 5 years
18.Positive for screening for HIV, hepatitis B (surface and core antibodies unrelated to vaccination), or hepatitis C (anti-HCV antibody confirmed with Hep C RNA)
19.Positive interferon-gamma release ass

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

Health Condition(s) or Problem(s) studied

Pemphigus: Pemphigus Vulgaris
MedDRA version: 20.0 Level: LLT Classification code 10052802 Term: Pemphigus vulgaris System Organ Class: 100000004858

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Product Code: PRN1008
Pharmaceutical Form: Tablet
INN or Proposed INN: Not available
CAS Number: 1575596-29-0
Current Sponsor code: PRN1008
Other descriptive name: PRN1008 Freebase
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
INN or Proposed INN: Not available
CAS Number: 1575596-29-0
Current Sponsor code: PRN1008
Other descriptive name: PRN1008 Freebase
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 300-
INN or Proposed INN: Not available
CAS Number: 1575596-30-3
Current Sponsor code: PRN1008
Other descriptive name: PRN1008 Freebase
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
INN or Proposed INN: Not available
CAS Number: 1575596-30-3
Current Sponsor code: PRN1008
Other descriptive name: PRN1008 Freebase
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 300-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Patients will be screened within 28 days of dosing and will return for an end-of-study assessment 84 days after receiving their final dose of study drug. Patients will return at specified times on an outpatient basis for assessment of vital signs, physical examination,
assessment of adverse events, assessment of concomitant medication use, assessment of clinical benefit, and provision of blood samples for PK and PD, and other clinical laboratory tests.

Main Objective: To evaluate the clinical safety of PRN1008 in patients with PV over a 12-week (Part A) or 24-week (Part B) treatment period
To evaluate the clinical activity of PRN1008 in patients with PV, per criteria in the European Academy of Dermatology and Venereology (EADV) 2014 Pemphigus S2 Guideline

Primary end point(s): Safety:
? The incidence of treatment-emergent adverse events (AEs) including clinically significant changes in physical examination, laboratory safety tests, and vital signs.

Efficacy:
? Proportion of subjects who are able to achieve control of disease activity (CDA)* within 4 weeks of treatment, without the need for doses of prednis(ol)one >0.5mg/kg.

*Clinical activity endpoints as defined by the EADV 2014 pemphigus S2 guideline (Hertl et al. 2015;29:405-414)

Pharmacokinetics:
? Plasma concentrations of PRN1008
? Population PK analysis (data pooled with that from other studies)
? Exploratory PK/PD analysis

Pharmacodynamics:
? BTK occupancy in PBMCs
? Change in anti-dsg1-3 autoantibody levels by enzyme-linked immunosorbent assay (ELISA)

Secondary Objective: To evaluate the pharmacodynamics (PD) and pharmacokinetics (PK) of multiple doses of PRN1008 in patients with PV

Secondary Outcome(s)

Secondary end point(s): Secondary*:
? Proportion of subjects able to achieve CDA without corticosteroids within 4 weeks
? Proportion of subjects able to achieve a complete response (CR) without corticosteroids within 12 weeks (and 24 weeks in Part B)
? Proportion of subjects able to achieve CR without the need for doses of prednis(ol)one of greater than 0.5mg/kg within 12 weeks (and 24 weeks in Part B)
? Time to CDA
? Time to CR
? Time to end of consolidation phase
? Time to relapse after PRN1008 treatment discontinuation
? Cumulative corticosteroid usage over the first 12 weeks (and 24 weeks in Part B)
? Change from baseline in Pemphigus Disease Area Index (PDAI) and Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) scores at each follow up visit
? Change from baseline in Autoimmune Bullous Diseases Quality of Life (ABQOL) and Treatment of Autoimmune Bullous Diseases Quality of Life (TABQOL) scores at each follow up visit

*Clinical activity endpoints as defined by the EADV 2014 pemphigus S2 guideline (Hertl et al. 2015;29:405-414) with the exception that CR is defined as CR at a single point in time rather than present for =2 months

Timepoint(s) of evaluation of this end point: ? Proportion of subjects able to achieve CDA without corticosteroids within 4 weeks
?Proportion of subjects able to achieve a complete response (CR) without corticosteroids within 12 weeks (and 24 weeks in Part B)
? Proportion of subjects able to achieve CR without the need for doses of prednis(ol)one of greater than 0.5mg/kg within 12 weeks (and 24 weeks in Part B)
? Time to CDA
? Time to CR
? Time to end of consolidation phase
? Time to relapse after PRN1008 treatment discontinuation
? Cumulative corticosteroid usage over 12 weeks (and 24 weeks in Part B)
? Change from baseline in Pemphigus Disease Area Index (PDAI) and ABSIS scores at each follow up visit
? Change from baseline in ABQOL and Treatment of TABQOL scores at each follow up visit

Secondary ID(s)

2015-003564-37-GR

PRN1008-005

Source(s) of Monetary Support

Principia Biopharma Inc.

Ethics review

Status: Approved
Approval date: 24/02/2016
Contact:

Results

• Results available: Yes
• Date Posted: 24/01/2021
• Date Completed: 10/01/2020
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-003564-37/results