Treatment of Bullous Pemphigoid With Avdoralimab (IPH5401), an Anti-C5aR1 Monoclonal Antibody

Study Overview
=================
Brief Summary
-----------------
The development of Auto Immune bullous Diseases (AIBD) results from a complex interaction between innate and adaptive immune systems. Bullous pemphigoid (BP), the most frequently encountered AIBD, predominantly affects elderly patients above 70 with an estimated incidence of 21.7 new cases/million/year in France.Interestingly, coversin, an anti-C5a and -leukotriene B4 small molecule, is currently used in a phase IIA clinical trial in BP patients (NCT04035733). However, although overall C5-blocking drugs are potentially interesting, they are likely to interfere with C5a-C5aR2-axis activation as well, a pathway that has recently proved protective in BP 12. The main objective is to investigate the clinical efficacy of an anti-C5aR1 antibody in addition to superpotent topical steroids compared to superpotent topical steroids alone in BP patients at 3 months.It is a case-controlled, randomized, open-labelled, and multicenter phase II clinical trial. Four Dermatologic French centers (Nice, Marseille Nord, Marseille Timone and Montpellier university hospitals) specialized in the in the care of BP patients will be participating in the study. It is expected that forty subjects will be included in this trial. Conversely, a more targeted inhibition of C5a-C5aR1 axis might be more effective in BP, sparing the potentially protective effect of C5a-C5aR2 interaction. Avdoralimab (IPH5401), a specific anti-C5aR1 monoclonal antibody, has already been credited of a good safety profile in the treatment of solid tumors and rheumatoid arthritis. The investigators hypothesize that avdoralimab might be a safe and effective treatment in BP patients

Official Title
-----------------
Treatment of Bullous Pemphigoid With Avdoralimab (IPH5401), an Anti-C5aR1 Monoclonal Antibody

Conditions
-----------------
Bullous Pemphigoid

Intervention / Treatment
-----------------
* Drug: Avdoralimab (IPH5401)
* Other: Control


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female ≥ 18 years of age at the time of signing the informed consent document Clinical diagnosis of BP confirmed by histology, immunohistochemistry and/or ELISA data Patient requiring a treatment by superpotent topical steroids Patients hospitalized for the treatment of their BP For female, only post-menopaused patients For male patients included in the study with partners of child bearing potential should agree to use highly effective contraception for the duration of the study and 6 months after the last dose of avdoralimab Signed informed consent document prior to any study related assessments/procedures being conducted Patient able to adhere to the study visit schedule and other protocol requirements Patient registered to the French Social Security Exclusion Criteria: Patients requiring systemic steroids according to the physician in charge Contra indication to topical steroid Use of systemic steroids or any immunosuppressive drugs in the past 4 weeks Use of doxycycline or minocycline in the past 4 weeks Use of systemic rituximab or omalizumab or dupilimumab in the past 12 weeks Use of intravenous immunoglobulmins (IVIG) in the past 4 weeks Impossibility to come every week to receive the injection Participants in other clinical therapeutic studies involving a drug that could interfere with the present evaluation Vulnerable people: pregnant or breast-feeding women, minors, adult under guardianship or deprived of freedom

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: It is a case-controlled, randomized, open-labelled, and multicenter phase II clinical trial. Four Dermatologic French centers (Nice, Marseille Nord, Marseille Timone and Montpellier university hospitals) specialized in the in the care of BP patients will be participating in the study. It is expected that forty subjects will be included in this trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drug<br>Patients in this group will additionally receive 3 s.c. injections of avdoralimab every week during 12 weeks They receive 0.05% Clobetasol propionate cream as follows: Patients of less than 45kg of body weight: 2 tubes of 10g/d Patients of 45kg and above of body weight: 3 tubes of 10g/d Topical steroids will be applied every day until 15 days after the healing of the last bullous lesions | Drug: Avdoralimab (IPH5401)<br>* Preparation of avdoralimab and preparation of the syringes are to be performed aseptically by site pharmacy qualified personnel.<br>|
| Other: Conventional therapy<br>Superpotent topical steroids are the gold standard treatment for BP. All patients will receive 0.05% Clobetasol propionate cream as follows: Patients of less than 45kg of body weight: 2 tubes of 10g/d Patients of 45kg and above of body weight: 3 tubes of 10g/d Topical steroids will be applied every day until 15 days after the healing of the last bullous lesions | Other: Control<br>* Superpotent topical steroids are the gold standard treatment for BP. All patients will receive 0.05% Clobetasol propionate cream as follows: Patients of less than 45kg of body weight: 2 tubes of 10g/d Patients of 45kg and above of body weight: 3 tubes of 10g/d Topical steroids will be applied every day until 15 days after the healing of the last bullous lesion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Clinical Remission | To investigate the clinical efficacy of an anti-C5aR1 antibody in addition to superpotent topical steroids compared to superpotent topical steroids alone in BP patients.The efficacy will be evaluated through the proportion of patients in complete clinical remission (CCR) at 3 months without any relapse during the study period. The CCR will be defined as the absence of new bullous and skin inflammatory lesions and absence of pruritus for at least 2 weeks. | At 3 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The delay | To compare between the treatment groups the delay to complete clinical remission (CCR) | At 3 months | 
| Initial Clinical Remission | To compare between the treatment groups the delay to initial clinical remission (ICR) | At 3 months |