| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| pemphigus vulgaris [PV] or pemphigus foliaceus [PF] |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057054 |
| E.1.2 | Term | Pemphigus foliaceous |
| E.1.2 | System Organ Class | 100000004858 |
|
| 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 rilzabrutinib 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 rilzabrutinib 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 rilzabrutinib
• To evaluate differences in potentially CS-related adverse events
|
|
| E.2.2 | Secondary objectives of the trial |
PK/PD Objectives
• To evaluate the population pharmacokinetics (PK) of rilzabrutinib
• To evaluate pharmacodynamic (PD) effects of rilzabrutinib on anti-desmoglein (anti-dsg) autoantibody titers (anti-dsg1 and anti-dsg3)
Exploratory Objectives
• To evaluate the PK of rilzabrutinib metabolites
• To examine the effects of rilzabrutinib, if any, of the baseline covariates on PK and/or PD, and the relationship between PK, PD, and efficacy
• To explore association of vaccine response with rilzabrutinib
• To examine the effect of rilzabrutinib 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
Long Term Extension Objective
• To evaluate the long-term safety and efficacy of rilzabrutinib |
|
| 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 (see Section 7.7.3).
2. Positive circulating anti-dsg1 or 3 autoantibody titer
3. At Screening, 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. Adequate hematologic, hepatic, and renal function (including but not
limited to 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).
5. Female patients who are of childbearing potential must agree for the duration of the study to use a highly effective means of contraception (e.g., combined estrogen-progresterone containing hormonal contraception methods that inhibit ovulation (oral, intravaginal, transdermal), progesterone-only hormonal contraception methods that inhibit ovulation (oral, injectable, implantable intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized partner or sexual abstinence (only if it is the preferred and usual lifestyle of the patient). A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
6. Has been informed and has given written informed consent and agreeable to the schedule of assessments
7. Male patients should use condoms during study treatment and until 90-days after the last dose of Rilzabrutinib/placebo, and should not donate sperm during this same time period. For a non-pregnant female partner of childbearing potential, contraception recommendations for the female partner should also be considered. |
|
| 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 BTK inhibitor
3. Pregnant or lactating women
4. 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 con med 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): anti-CD20 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 and 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 prev 12 months
12. Alcoholism or excessive alcohol use, defined as regular consumption of more than appr 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 HIV, hepatitis B (surface antigen and core antibodies), 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 (QFT Plus) at Screening. Unless, the patient has latent tuberculosis (TB) and all of the following 3 conditions are true
a. Chest X-ray does not show evidence suggestive of active TB disease
b. here are no clinical signs and symptoms of pulmonary and/or extra-pulmonary TB disease
c. Documented receipt of one of the following prophylactic treatment regimens
i. Oral daily Isoniazid for 6 months or
ii. Oral daily Rifampin (RIF) for 4 months or
iii. Isoniazid and Rifapentine weekly for 3 months (3HP)
On a case by case basis, after discussion and approval by the Sponsor, a local TB test that is negative and is considered equivalent to 1 of the above tests may be used for eligibility. For example, if a QuantiFERON®-TB Gold, or QuantiFERON-TB Gold Plus (QFT Plus) is indeterminate for any reason and a local blood test or T-Spot TB test is negative, the patient may be enrolled using the local result upon approval of the Sponsor.
18. History of serious infections requiring intravenous therapy with the potential for recurrence or currently active moderate to severe infection at Screening (Grade 2 or higher)
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. In areas endemic for Chagas disease, screening is recommended prior to enrollment
21. Patients who have a known contraindication to Sponsor-provided corticosteroid and/or inability to follow corticosteroid dosing as outlined in the protocol (see Table 1 for more details) or with a known sensitivity to Rilzabrutinib or its excipients
22. institutionalized patients
23. patients unduly influenced
24. Patients who have a positive test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection per local testing standards. |
|
| 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)
|
|
| 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 |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoints
• Cumulative CS dose from Baseline to Week 37
• Cumulative duration of CR with a CS dose ≤10 mg/day, from Baseline
to Week 37
• Time to first CR with a CS dose ≤10 mg/day, from Baseline to Week 37
• Proportion of patients with at least one disease relapse/flare from
initial control of disease activity (CDA) to Week 37
• Cumulative duration of CR with a CS dose ≤10 mg/day, from Week 37
to Week 61
• Cumulative duration of CR with a CS dose = 0 mg/day, from Week 37
to Week 61
Other Secondary Endpoints
• The proportion of patients who are in CR from Week 29 to Week 37
with a CS dose of ≤10 mg/day
• The proportion of patients who have a PDAI score <3 from Week 29 to
Week 37 with a CS dose ≤10 mg/day
• Cumulative duration of CR with a CS dose ≤10 mg/day from Baseline
to Weeks 61 and 109
• Cumulative duration of CR with a CS dose = 0 mg/day from Baseline to
Weeks 61 and 109
• GTI score at Week 37
• Change in PDAI score from baseline to Weeks 5, 13, 25, 37, 61 and 109
• Change in Autoimmune Bullous Disease Quality of Life (ABQOL) score
from baseline to Weeks 5, 13, 25, 37, 61 and 109
• Proportion of patients with ABQOL Score of zero at Weeks 5, 13, 25,
37, 61 and 109
• Change in EuroQOL-5 Dimension 5 Level (EQ-5D-5L) results (visual
analog scale [VAS] results and individual dimension) scores from
Baseline to Weeks 5, 13, 25, 37, 61 and 109
• Time to first CR with a CS dose ≤10 mg/day, from Baseline to Weeks
61 and 109
• Total number of disease flares/relapses from initial CDA to Week 37
• Time to initial flare/relapse from initial CDA to Week 37
• Proportion of patients with 3 or more new lesions within 1 month that
do not heal spontaneously within 1 week, or with extension of established lesions, from Baseline to Week 37. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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, LTE for 48 Weeks, 4 week FU |
|
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| Brazil |
| Canada |
| Israel |
| Taiwan |
| Turkey |
| Ukraine |
| United States |
| Bulgaria |
| France |
| Germany |
| Greece |
| Italy |
| Poland |
| United Kingdom |
| Argentina |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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