Comparison of a personalized maintenance therapy based on the evolution of anti-desmoglein antibodies as biomarkers of pemphigus subclinical activity, with the standard treatment (rituximab + corticosteroids) in pemphigus - (RITUX 4)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire Rouen

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

Trial duration

6 Nov 2024 → ongoing

Decision date (initial)

2024-08-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-514886-21-00

EudraCT number

2022-000060-22

ClinicalTrials.gov

NCT05898308

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Diagnosis

To assess the superiority of a personalized treatment strategy (based on maintenance infusions of rituximab proposed only in pemphigus patients with a high relapse risk who are identified using the initial disease severity (assessed by the PDAI score), and the evolution of serum antidesmoglein (Dsg) Abs as biomarkers of disease activity), in reducing the 4-year relapse rate as compared with the current treatment regimen proposed in the French guidelines.

Secondary objectives 11

1. To demonstrate that this personalized treatment strategy increases the time before first flare/relapse
2. To demonstrate that this personalized treatment strategy increases the time in remission
3. To demonstrate that this personalized treatment strategy permits the use of 1 g of rituximab for maintenance infusions instead of a 2 g dose (which is recommended in patients with a clinical relapse to achieve disease control)
4. To demonstrate that this personalized treatment strategy reduces the total quantity of rituximab prescribed
5. To demonstrate that this personalized treatment strategy is clinically well-tolerated
6. To demonstrate that this personalized treatment strategy is biologically well-tolerated
7. To demonstrate that this personalized treatment strategy avoid corticosteroids-related adverse events
8. To demonstrate that this personalized treatment strategy improves patients’ quality of life
9. To describe and compare the evolution of anti-Dsg1 and anti-Dsg3 autoantibodies according to treatment strategies
10. To assess the number of patient-years and number needed to treat (NNT) with the personalized treatment strategy to avoid one clinical relapse/flares by patient-year.
11. To assess the cost-effectiveness of this new strategy, expressed as the cost to avoid one relapse/flare and estimate the global budgetary impact of this new strategy.

Conditions and MedDRA coding

Pemphigus diseases (Pemphigus Vulgaris - PV and Pemphigus Foliaceus (PF).

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Age ≥ 18 and ≤ 80 years
2. Signed Informed Consent Form (or from the family in case of impossibility of patient’s consent).
3. Confirmed newly diagnosed PV or PF, based on the presence of the following: histological features of acantholysis on skin or mucosal biopsy, and deposition of IgG, complement component 3, or both on the keratinocyte membrane detected by direct immunofluorescence on affected skin or mucosa
4. Presence of moderate-to-severely active disease, defined by an overall PDAI score> 15
5. Patient able to receive the standard-of-care consisting of corticosteroids (prednisone 1 mg/kg/day PO) and rituximab
6. Patients must be vaccinated against Covid-19 before study entry. It is recommended that patients are vaccinated against influenza and pneumococcus and have their first injection (Prevenar 13 or 20) before study entry.
7. For women who are not postmenopausal (menopausal: ≥ 12 months of non−therapy-induced amenorrhoea) or not sterile: agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of <1% per year, during the treatment period and for at least 12 months after the last dose of study treatment. They must have a negative result from a blood beta-HCG test within 1 week prior to randomization Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Barrier methods must always be supplemented with the use of a spermicide.
8. For men: Surgical sterility or agreement to remain abstinent or use a condom during the treatment period and for at least 12 months after the last dose of study treatment and agreement to refrain from donating sperm during this same period. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
9. Able to comply with the study protocol, in the investigator’s judgment
10. Patient affiliated with, or beneficiary of a social security (national health insurance) plan

Exclusion criteria 28

1. Non-consenting patient or patient who cannot be followed regularly.
2. Diagnosis of paraneoplastic pemphigus or other non-PV or PF autoimmune blistering disease
3. Contraindication to rituximab marketed as 500 mg concentrate for solution for infusion
4. Contraindication to prednisone marketed as 20 mg scored tablet pharmaceutical form
5. Contraindication to methylprednisolone marketed as 120 mg powder for injectable solution pharmaceutical form
6. Contraindication to paracetamol marketed as 10 mg/mL solution for infusion pharmaceutical form
7. Contraindication to dexchlorpheniramine maleate marketed as 5 mg/1mL injectable solution pharmaceutical form
8. Lack of peripheral venous access
9. Pregnant or lactating women
10. Significant cardiovascular or pulmonary disease (including o bstructive pulmonary disease)
11. Uncontrolled concomitant disease that, in the investigator’s judgment, would preclude patient participation, including but not limited to nervous system, renal, hepatic, endocrine, or gastrointestinal disorders
12. Any concomitant condition that required treatment with oral or systemic corticosteroids within 12 weeks prior to randomization- excluding transitory treatments (such as a corticosteroid therapy prescribed for a few days for an acute infection), and chronic corticosteroid treatments with a prednisone / prednisolone dose ≤20 mg/day, (these latter patients remain eligible for study entry)
13. Treatment with IV Ig, plasmapheresis, or other similar procedure (immunoadsorption) within 8 weeks prior to randomization
14. Patients having received immunosuppressive treatment (such as cyclosporine, mycophenolate mofetil, azathioprine given at an effective dose for any other condition than Pemphigus, or any other treatment that might potentially be active on Pemphigus lesions (anti-TNF) within 4 weeks prior to baseline
15. Treatment with cyclophosphamide within 12 weeks prior to randomization
16. Patients with positive blood test for HIV
17. Inherited or acquired severe immune deficiency
18. Severe active infection (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV anti-infectives within 4 weeks prior to screening. Entry into this study may be reconsidered once the infection has fully resolved
19. Patients with a currently treated cancer, including solid tumors, hematologic malignancies, and carcinoma (except basal cell of the skin and squamous cell carcinoma of the skin which are small and localized and can be easily cured with a standard excision )
20. Patients with a past history (< 5 years) of cancer, including solid tumors, hematologic malignancies, and carcinoma (except complete excision of basal cell carcinoma and squamous cell carcinoma of the skin that have been excised and cured) NB: Patients whose cancer is cured and do not have anti-cancer treatment anymore must be referred to an oncologist before entry in the study
21. Currently active alcohol or drug abuse, or history of alcohol or drug abuse within 24 weeks prior to screening
22. Major surgery within 4 weeks prior to randomization, excluding diagnostic surgery
23. Treatment with rituximab or a B cell−targeted therapy (e.g., anti-CD20, anti-CD22, or anti-BLyS) within 12 months prior to randomization
24. Treatment with a live or attenuated vaccine within 28 days prior to randomization. It is recommended that a patient’s vaccination record and the need for immunization prior to study entry be carefully investigated.
25. Major biological abnormality which in the investigator’s judgment, would preclude patient participation
26. Positive test results for hepatitis B surface antigen (HBsAg),HBe antigen, positive hepatitis B DNA, or hepatitis C virus(HCV) serology at screening
27. Participation in another interventional clinical trial within 28 days prior to randomization and during the study
28. Person deprived of liberty by administrative or judicial decision or placed under judicial protection (guardianship or supervision)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Any concomitant condition that required treatment with oral or systemic corticosteroids within 12 weeks prior to randomization- excluding transitory treatments (such as a corticosteroid therapy prescribed for a few days for an acute infection), and chronic corticosteroid treatments with a prednisone / prednisolone dose ≤20 mg/day, (these latter patients remain eligible for study entry)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire Rouen

Sponsor organisation

Centre Hospitalier Universitaire Rouen

Address

1 Rue De Germont, Bp 96031 Bp 96031

City

Rouen Cedex

Postcode

76031

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire Rouen

Contact name

David MALLET

Public contact point

Organisation

Centre Hospitalier Universitaire Rouen

Contact name

David MALLET

Locations

1 EU/EEA country · 30 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications