A Pilot Study Investigating the Safety, Clinical Activity, Drug Levels, and Effects on PRN 1008 in Patients with Newly Diagnosed or Relapsing Pemphigus Vulgaris

• Register: EUCTR
• Last refreshed on: 30 March 2020
• Main ID: EUCTR2015-003564-37-GR
• Date of registration: 13/01/2016
• Prospective Registration: Yes
• Primary sponsor: Principia Biopharma Australia Pty Ltd
• Public title: A Pilot Study Investigating the Safety, Clinical Activity, Drug Levels, and Effects on PRN 1008 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: 21/04/2016
• Target sample size: 25
• 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: Project management
• Affiliation: PPD Global Limited

• Name: Project management
• Affiliation: PPD Global Limited

Key inclusion & exclusion criteria

Inclusion criteria:
1 Male or female patients, aged 18 to 80 years old, with biopsy-proven, mild-moderate PV (PDAI 15 to 45) that are either newly diagnosed patients (i.e. naïve to an effective induction treatment regimen) for whom an initial period of PRN1008 monotherapy is judged clinically acceptable, or relapsing patients, for whom an initial period of PRN1008 monotherapy or combination therapy with any of low dose corticosteroid (= 10 mg/day), azathioprine, mycophenylate mofetil, sulfasalazine and dapsone, is judged clinically acceptable, provided cessation of azathioprine, mycophenylate mofetil, sulfasalazine, and dapsone within two to four weeks is anticipated
2. BMI >17.5 and <40 kg/m2
3. Adequate hematologic, hepatic, and renal function (absolute neutrophil count =1.5 X 10^9/L, Hgb > 9 g/dL, platelet count =100 X 10^9/L, AST/ALT = 1.5 x ULN, albumin =3 g/dL, creatinine = ULN
4. Female patients or female partners of a male patient who are of reproductive potential must agree for the duration of the study to use an effective means of contraception (e.g., diaphragm plus spermicide, condoms, or oral contraceptive). Unless surgically sterile, postmenopausal females should have menopause confirmed by FSH testing.
5. Male patients must agree to use a condom during sexual intercourse with female partners who are of reproductive potential for the duration of PRN1008 treatment and for 12 weeks thereafter (i.e. during the entire period of follow up)
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
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Previous use of a BTK inhibitor
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: 1 week: cyclophosphamide; 4 weeks: Kinaret (anakinra) and Enbrel (etanercept); 12 weeks: Remicade (infliximab), Humira (adalimumab), Simponi (golimumab), Orencia (abatercept), Actemra (tocilizumab), Cimzia (certolizumab), Cosentyx (secukinumab), IVIG, plasmapheresis; 6 months: Rituxan/MabThera (rituximab), ofatumumab, any other anti-CD20 antibody
6. Use of >10 mg per day of oral prednisolone for more than 1 week within 4 weeks prior to Day 1 (inhaled and mucosal [for symptomatic treatment of oral lesions] corticosteroids are allowed)
7. Use of proton pump inhibitor drugs such as omeprazole, 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 within 7 days or 5 half-lives (whichever is longer) of study drug dosing
9. Use of CYP3A-sensitive substrate drugs with a narrow therapeutic index within 7 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 14 standard drinks per week
13. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate study drug 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 for screening for HIV, hepatitis B (surface and core antibodies unrelated to vaccination), or hepatitis C (anti-HCV antibody confirmed with Hep C RNA)
17. History of active or latent tuberculosis (TB) infection (subjects must also test negative using the QuantiFERON® test to be eligible for the study)
18. Any other clinically significant disease, condition, or medical history that, in the opinion of the Investigator, would interfere with subject safety, study evaluations, and/or study procedures


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

Health Condition(s) or Problem(s) studied

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

Pemphigus: Pemphigus Vulgaris
MedDRA version: 18.1 Level: LLT Classification code 10052802 Term: Pemphigus vulgaris System Organ Class: 100000004858

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)

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.

Clinical activity*:
? 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 and the relationship of PK and PD to each other, and to efficacy and safety

Main Objective: To evaluate the clinical activity and safety of PRN1008 in patients with PV over a 12 week treatment period

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.

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
? 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
? 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
? 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)

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
? 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
? 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
? 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)

PRN1008-005

Source(s) of Monetary Support

Principia Biopharma Australia Pty Ltd

Ethics review

Status: Approved
Approval date: 21/04/2016
Contact: