Single-cell deep phenotyping of B lymphocytes to personalize immunotherapy in patients with Myasthenia Gravis: clinical trial to evaluate the efficacy and safety of Rituximab in generalized AChR-antibody positive Myasthenia Gravis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

28 Feb 2022 → ongoing

Decision date (initial)

2024-11-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Ministero della salute (project code: GR-2019-12368727)

External identifiers

EU CT number

2024-518939-12-00

EudraCT number

2020-005619-35

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess whether rituximab can reduce patients’ functional impairment caused by MG

Secondary objectives 6

1. To evaluate the effect of rituximab on corticosteroid usage.
2. To evaluate the effect of rituximab on MG-related disability
3. To evaluate whether rituximab can improve MG-related quality of life
4. To evaluate the safety and tolerability of rituximab in MG
5. To evaluate if rituximab reduces MG exacerbations
6. Exploratory objectives: To evaluate the effect of rituximab on disease biomarkers

Conditions and MedDRA coding

Generalized Myasthenia Gravis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Male or female subjects ≥ 18 years old
2. Written informed consent and European Union Data Privacy Directive obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
3. Diagnosis of MG defined as: a. Positive serologic test for anti-AChR or anti-MuSK antibody titers as confirmed at screening (one retest allowed), and b. At least one of the following:  History of abnormal neuromuscular transmission test results demonstrated by single-fiber electromyography or repetitive nerve stimulation; or  History of positive anticholinesterase test (eg, edrophonium chloride test); or  Patient demonstrated improvement in MG signs on oral cholinesterase inhibitors, as assessed by the treating physician; or  Clinical syndrome consistent with a diagnosis of MG, and not otherwise explained by another condition
4. MGFA Clinical Classification Class II, III, or IV at the time of screening and randomization
5. MG-ADL score of 5 or greater at screening and at randomization with > 50% of this score attributed to non-ocular items
6. QMG score of 11 or greater at screening and at randomization
7. Subjects must be on corticosteroids only, with no dose increase within 4 weeks prior to randomization and at least 20 mg prednisone per day (or equivalent dose on alternate day regimen)
8. Willing and able to comply with the protocol, complete study assessments, and return for follow-up visits.
9. Females of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective contraception method (Table 1) from the time of screening and for 12 months after the final dose of IP. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or those who are not postmenopausal (defined as 12 months with no menses without an alternative medical cause).
10. Non-sterilized males who are sexually active with a female partner of childbearing potential must use a condom from Day 1 for the duration of the study and for 3 months after the last dose of IP. Because male condom is not a highly effective contraception method, it is strongly recommended that female partners of a male study subject also use a highly effective method of contraception throughout this period (table 1 of the protocol)
11. Vital signs, electrocardiogram (ECG), and laboratory parameters within the normal ranges at screening, or, if outside normal ranges, deemed not clinically significant by the Investigator

Exclusion criteria 27

1. Any condition that, in the opinion of the Investigator, would place the patient at unacceptable risk of complications, interfere with evaluation of the IP, or confound the interpretation of patient safety or study results
2. Lactating or pregnant females, or females who intend to become pregnant anytime from signing the informed consent form (ICF) throughout the RCP plus 6 months following last dose of IP
3. History of drug or alcohol abuse within < 1 year prior to screening, or any condition associated with poor compliance as judged by the Investigator
4. Site staff and their family members
5. Currently committed to an institution by way of official or judicial order
6. Subjects diagnosed with congenital myasthenic syndromes
7. Known immunodeficiency disorder, including human immunodeficiency virus (HIV) infection
8. Thymectomy within ≤ 12 months prior to baseline (Day 1) visit or planned thymectomy during the duration of the RCP.
9. Receipt of the following medications or treatments at any time prior to randomization: a. Alemtuzumab (Lemtrada®, Campath®) b. Total lymphoid irradiation c. Bone marrow transplant d. T-cell vaccination therapy e. Natalizumab (Tysabri®)
10. Receipt of ANY immunosuppressive treatment (excluding corticosteroids) at ANY time prior to randomization (such as Azathioprine, Mycophenolate mofetil or Mycophenolic acid, Cyclosporine (except eye drop), Tacrolimus (except topical), Methotrexate, Cyclophosphamide, Tocilizumab (Actemra®), Belimumab (Benlysta®), Eculizumab (Soliris®), rituximab (MabThera®, Rituxan®), ocrelizumab (Ocrevus®), ofatumumab (Arzerra®), obinutuzumab (Gazyva®), inebilizumab, or any experimental B-cell depleting agent)
11. Receipt within the 4 weeks prior to Day 1: a. Intravenous immunoglobulin (IVIg) b. Plasma exchange (PLEX) treatment
12. Current use of: a. Prednisone < 20 mg/day or < 40 mg over a 2-day period (or equivalent dose of other corticosteroids) b. Pyridostigmine > 480 mg/day or unstable dose in the 2 weeks prior to Day 1
13. Concurrent/previous enrollment in another clinical study involving an investigational treatment within 4 weeks or 5 half-lives of the investigational treatment, whichever is longer, prior to Day 1
14. Receipt of a live attenuated vaccine within 4 weeks prior to randomization. Administration of inactivated (killed) vaccines is acceptable
15. History of severe allergic or anaphylactic reactions to biologic agents or known allergy to any component of the IP formulation
16. History of recurrent significant infections (eg, requiring hospitalization or IV antibiotics).
17. Within 2 weeks prior to the screening visit: clinically significant active infection requiring antimicrobial medication but allowing chronic nail infections
18. Unresected thymoma (Note: subjects with a benign thymoma resected > 1 year prior to screening may enroll. Benign is defined as no known metastases and no extension into or beyond the capsule on pathological examination. Imaging to evaluate for thymoma must have been performed prior to randomization per standard of care)
19. History of cancer, except for the following: a. In situ carcinoma of the cervix treated with apparent success with curative therapy for > 12 months prior to screening b. Cutaneous basal cell or squamous cell carcinoma treated with apparent success with curative therapy for > 12 months prior to screening c. Prostate cancer treated with radical prostatectomy or radiation therapy with curative intent > 3 years prior to screening and without known recurrence or current treatment d. Malignant thymoma (i.e. Masaoka stage ≥ IIa) resected > 5 years prior to screening with no evidence of active disease and no therapy received over the previous 5 years. Imaging to evaluate for thymoma must have been performed prior to randomization per standard of care
20. Spontaneous or induced abortion, still or live birth, or pregnancy ≤ 4 weeks prior to screening
21. Any of the following laboratory abnormalities at screening (one repeat test may be conducted to confirm results prior to randomization within the same screening period): a. Elevated liver enzymes (aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN)). b. Total bilirubin > 1.5 × ULN (unless due to Gilbert’s syndrome) c. Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 d. CD19+ B-cell count < 40 cells/μL e. Absolute neutrophil count (ANC) < 1.2 × 103 cells/μl f. Platelet count < 75,000/μL (or < 75 × 109/L) g. Hemoglobin < 8.0 g/dL h. Total immunoglobulin < 600 mg/dL
22. Positive test for chronic hepatitis B infection at screening, defined as either (1) positive hepatitis B surface antigen (HBsAg) or (2) a positive hepatitis B core antibody (anti-HBc) PLUS negative hepatitis B surface antibody (anti-HBs). Note: Subjects with a positive anti-HBs only, or a positive anti-HBc plus positive anti-HBs and negative HBsAg, are eligible to enroll
23. Positive test for hepatitis C virus antibody
24. Positive HIV test
25. Blood transfusion within 4 weeks prior to screening or during the screening period
26. Inability to read.
27. History of active or latent tuberculosis (TB), or a positive QuantiFERON®-TB Gold test at screening, unless treatment for tuberculosis was completed per local guidelines. Subjects with latent TB or a positive QuantiFERON®-TB Gold test who are actively on anti-TB treatment can enroll if they have completed at least 1 month of anti-TB treatment and intend to complete the full course of anti-TB treatment. Subjects with an indeterminate QuantiFERON®-TB Gold test result can enroll if a repeat QuantiFERON®-TB Gold is negative or a tuberculin skin test is negative.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline in Quantitative Myasthenia Gravis Score (QMG) at week 12 (3 months) of the RCP

Secondary endpoints 12

1. Change in corticosteroid dosage from week 12 to the end of the RCP
2. Change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score at week 12
3. Change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score at the end of RCP
4. Change from baseline in Quantitative Myasthenia Gravis Score (QMG) score at the end of RCP
5. Proportion of subjects with both (1) ≥ 3-point improvement in MG-ADL at end of the RCP (2) no use of rescue therapy during RCP
6. Change from baseline in Myasthenia Gravis Quality of Life-15, revised (MGQOL-15r) score at the week 12 and at the end of the RCP
7. Proportion of patients achieving the status of minimal-manifestation or better at week 12 and the end of the RCP
8. Proportion of patients requiring rescue therapy during the RCP
9. Time to first exacerbation
10. Change in Myasthenia Gravis Composite (MGC) score from baseline to week 12 of the RCP
11. The safety and tolerability of rituximab as measured by the incidence of t adverse events (AEs), and serious adverse events (SAEs). Laboratory measurements will also be evaluated
12. Exploratory endpoints: 1. Change in anti-acetylcholine receptor (anti-AChR) antibody titers and correlation with clinical outcomes. 2. B- and T-cell subset flow-cytometry 3. B-cell repertoire profiling (substudy)

Investigational products

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

Test 1

Placebo 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Sponsor organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Address

Largo Francesco Vito 1

City

Rome

Postcode

00168

Country

Italy

Scientific contact point

Organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Contact name

Raffaele Iorio

Public contact point

Organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Contact name

Raffaele Iorio

Locations

1 EU/EEA country · 1 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 6 files

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

Application history

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