| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| moderate to severe bullous pemphigoid |
|
| E.1.1.1 | Medical condition in easily understood language |
| (moderate to severe) disease that causes an itch, red rash and blisters of the skin and sometimes the mouth and eyes |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006567 |
| E.1.2 | Term | Bullous pemphigoid |
| 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 |
Part A
Confirm the dose of nomacopan and sample size for Part B and evaluate the rank order of secondary endpoints |
|
| E.2.2 | Secondary objectives of the trial |
PartA
Compare nomacopan with adjunct OCS to placebo with adjunct OCS in achievement of Complete Remission of disease on minimal OCS (CRon)
Further objectives are listed in section 4.1.1.2 of the protocol based on different assessments inculding safety assessments (assess the safety and tolerability of nomacopan with adjunct OCS compared to placebo and adjunct OCS) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female between 18 and 89 years of age inclusive at the time of consent with Karnofsky score of 50% or more at screening.
2. Male or female ≥90 years of age at the time of consent with Karnofsky score of 70% or more at screening.
3. Diagnosis of Bullous Pemphigoid (either newly diagnosed or relapsing); if relapsing they may have previously been shown to satisfy these diagnostic criteria for BP:
a. blisters alone, or blisters and/or urticaria or papules or erythema with or without itch,
AND
b. direct immunofluorescence of perilesional skin collected near a fresh blister, erosion or papule showing linear deposition of immunoglobulin G (IgG) and/or C3 along the epidermal basement membrane zone.
AND
c. indirect immunofluorescence studies performed with patient serum on 1.0M NaCl human salt split skin, showing anti-basement membrane zone antibodies binding the epidermal side of the salt split skin OR anti-BP180 or anti-BP230 antibody positive by enzyme linked immunosorbent assay. Note, if the serum binds both the epidermal and dermal side of the salt split skin the serum must also be anti-BP180/BP230 antibody positive by ELISA for inclusion of the subject.
4. Patients with atypical Bullous Pemphigoid (ie without blisters) if they have positive direct immunofluorescence AND positive indirect immunofluorescence AND are anti-BP180 antibody positive.
5. Bullous Pemphigoid classified as either moderate or severe on the basis of the Investigator Global Assessment (IGA) at randomisation. Moderate BP classified as an IGA score of 3 and severe BP classified as an IGA score of 4.
6. Willing to receive immunisation against Neisseria meningitidis and/or antibiotic prophylaxis in accordance with applicable guidelines and local standard of care (SOC).
7. Ability to travel to site for scheduled clinic visits and be available for scheduled assessments to be performed in their place of residence by trained healthcare practitioners.
8. Provision of voluntary written informed consent. Note: Consent must be obtained prior to any study-related procedures.
9. Women of childbearing potential must agree to use two methods of contraception, one highly effective and one effective (barrier), consistently throughout the study and have a negative serum pregnancy test at screening and a negative urine pregnancy test per the schedule of events. Women are considered post-menopausal and not of childbearing potential if they have had 12 months of amenorrhea, without an alternative medical cause, or have had permanent sterilisation methods (including hysterectomy, bilateral salpingectomy and bilateral oophorectomy) at least six weeks before randomisation.
10. Males with a childbearing potential partner must agree to use two methods of contraception, one highly effective and one effective, consistently throughout the study including a barrier method.
11. Patients who have recovered from a proven SARS-CoV2 infection within the 6-months prior to screening or who have received SARS-CoV2 full vaccination according to local guidelines. |
|
| E.4 | Principal exclusion criteria |
1. Patients with recalcitrant BP that have never achieved CDA or who have never been in complete disease remission with persistent disease after a period of 12 months from the start of super potent steroid or OCS treatment.
2. Epidermolysis bullosa acquisita, mucous membrane pemphigoid, or anti p200 pemphigoid.
3. Mucosal lesion BPDAI score accounts for ≥30% of total BPDAI activity score at randomisation
4. BP considered to be drug induced, in particular diagnosis of BP made within two months of starting a drug well known to induce BP – notably including, but not limited to, dipeptidyl peptidase-4 (DDP-4) inhibitors (eg, sitagliptin, vildagliptin, linagliptin), anti-PD1 inhibitors (eg, pembrolizumab, nivolumab), and certain diuretics (eg, furosemide, spironolactone) and neuroleptics (eg, doxepin, risperidone).
5. Participation in a clinical trial of an investigational product within 6 weeks of screening.
6. Treatment with BP-directed biologics as follows:
a. Any cell-depleting agents including, but not limited to, rituximab within 12 months prior to baseline.
b. Other biologics within five half-lives (if known) or 16 weeks prior to the baseline, whichever is longer.
c. Intravenous immunoglobulin within 16 weeks prior to the baseline.
7. Taking > 0.3 mg/kg/day OCS at screening
8. Treatment with systemic immunomodulators such as dapsone or doxycycline within four half-lives of the drugs prior to baseline Day 1 (5 days for dapsone, 3 days for doxycycline).
9. Treatment with immunosuppressants (such as methotrexate, azathioprine, mycophenolate, calcineurin inhibitors) within the last two weeks prior to baseline (Day 1).
10. Treatment with an anti-complement therapy or with Zileuton (Zyflo) within the last three months prior to baseline (Day 1).
11. OCS dose no more than 0.3mg/kg/day in the 7 days before screening visit.
12. Taking super-potent topical corticosteroids (such as clobetasol propionate, augmented betamethasone dipropionate, diflucortolone valerate, fluocinonide, flurandrenolide and halobetasol propionate) and unable to discontinue them at or before the screening assessment.
13. Medical or surgical conditions at screening or Day 1, that in the Investigator's opinion would make the patient inappropriate for study entry; this might include severe medical conditions such as stroke, heart failure, or serious neoplasia with a very high risk of mortality. In patients considered at high risk (e.g., HIV, silicosis, organ transplantation, etc.) of reactivation of latent tuberculosis (TB) infection, a recent (within 6-months) negative TB investigation (e.g., chest X-ray (CXR), negative interferon gamma release assay) should be available or undertaken at screening.
14. Impaired neurological function which, in the Investigator’s opinion, will prevent participation in the study.
15. Active systemic or organ system bacterial or fungal infection or progressive severe infection (including unresolved or untreated N. meningitidis infection and Escherichia coli Shiga toxin).
16. Known congenital immunodeficiency or a history of acquired immunodeficiency including a positive human immunodeficiency virus (HIV) test.
17. Active infection with hepatitis B or C.
18. Positive nasal throat swab for Neisseria species.
19. Planned major surgical procedures during the conduct of the study.
20. Known hypersensitivity to nomacopan and any of its excipients.
21. Contraindication to OCS including uncontrolled diabetes mellitus, uncontrolled hypertension, cardiac insufficiency, recent serious infection and allergy to OCS.
22. Receipt of live attenuated vaccines for example yellow fever vaccine or some influenza vaccines within 2 weeks of Day 1 (Baseline).
23. Pregnant or breast feeding or planning to become pregnant during the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients in Complete Disease Remission on (CRon) minimal OCS therapy (0.1 mg/kg/day) for 8 weeks or more at week 24 [Time Frame: weeks 16 – 24]. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Other Endpoints (Exploratory for Part A, Secondary for Part B)
1. Cumulative OCS dose during treatment [Time Frame: randomization to 24 weeks].
2. Proportion of patients requiring rescue therapy during the 24 weeks of treatment [Time Frame: randomization to 24 weeks].
3. Proportion of patients in Partial Disease Remission on (PRon) minimal OCS therapy (0.1 mg/kg/day) for 8 weeks or more at week 24 [Time Frame: weeks 16 – 24].
4. Time (weeks) to onset of Complete Remission on (CRon) Minimal OCS and Partial Remission on (PRon) Minimal OCS [Time Frame: from week 6 to end of study].
5. Duration (weeks) of Complete Remission on (CRon) Minimal OCS and Partial Remission on (PRon) Minimal OCS [Time Frame: from week 6 to end of study].
6. Proportion of patients with Investigator Global Assessment (IGA) score of 0 or 1 (clear or almost clear) at 6 weeks, 12 weeks and end of treatment [Time Frame: weeks 6 – 24].
7. Frequency, type and relationship of AEs to treatment [Time Frame: randomisation to end of study].
8. Incidence of steroid-related AEs [Time frame randomisation to end of study].
9. Change from baseline in Dermatology Life Quality Index (DLQI) [Time Frame: randomisation to week 24].
10. Incidence of treatment-emergent anti-drug antibody (ADA) responses and titre and neutralising potential assessed in vitro at baseline and every 4 weeks [Time Frame: randomisation to end of study]. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| randomization to end of study or intermediate depending on the endpoint (details given in brackets "[]" with the respective 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 | No |
| 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 | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Partial-blind design: Blind for placebo/active but unblind for low/high dose |
|
| 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 | 4 |
| 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 | 17 |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
When the last subject completes their last follow-up visit.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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