Rituximab in Patients With Acute Rheumatic Fever (AGRAF-2)

Open-label, Randomized Controlled Trial to Assess Efficacy and Safety of Rituximab in Patients With Acute Rheumatic Fever in Africa

Acute Rheumatic Fever is an autoimmune inflammatory post-infectious syndrome, mainly caused by type A streptococcus. It is characterized as an inadequate immune response. It may provoke carditis, combined with articular, skin and neurologic signs. Only carditis, prevalent in 60% of acute rheumatic diseases, may provoke valvular sequels, which define rheumatic cardiopathy. Antibiotherapy based on penicillin is the standard treatment of both acute rheumatic fever and its prevention. Although no anti-inflammatory treatment has proved its efficacy, with or without steroids anti-inflammatory treatments are administered in acute episode of ARF. Up to date, only prevention strategies have shown efficacy.

Study Overview

• Status: Suspended
• Conditions: Rheumatic Heart Disease in Children
• Intervention / Treatment: Drug: Rituximab added to standard of care treatment; Drug: standard of care treatment alone

Detailed Description

Acute Rheumatic Fever is an autoimmune inflammatory post-infectious syndrome, mainly caused by type A streptococcus. It is characterized as an inadequate immune response. It may provoke carditis (which associates valvular leakages, cardiac conduction system troubles, and pericardial signs), combined with articular, skin and neurologic signs. Only carditis, prevalent in 60% of acute rheumatic diseases, may provoke valvular sequels, which define rheumatic cardiopathy. Prevalence of acute rheumatic disease (ARD) in pproximately 6 cases per 1000 children in Sub-Saharan Africa countries, whereas prevalence in developed countries is less than a case per 100 000 children, with an annual incidence of 470 000 cases and almost 230 000 deaths annually worldwide. Carditis affect between 15 and 20 million people worldwide, mostly children and young adults from low and middle-income countries. This prevalence may be underestimated. In 2007, our team conducted a study in Mozambique and Cambodia that highlighted that, through a screening based on systematic echocardiography in children from several schools, approximately 2/3 of them had asymptomatic and unknown cardiac lesions, which cannot be screened only with a clinical examination. Role of B-type lymphocytes (B cells) in auto-immune diseases physiopathology is nowadays largely accepted and justifies, in certain auto-immune diseases, the use of therapeutics that target and destroy B cells. Rituximab is a CD-20-specific monoclonal chimeric antibody, indicated to treat B lymphomas, where its efficacy and safety have changed the management of these diseases. Recently, it is thought to use Rituximab in auto-immune diseases. Antibiotherapy based on penicillin is the standard treatment of both acute rheumatic fever and its prevention. Although no anti-inflammatory treatment has proved its efficacy, with or without steroids anti-inflammatory treatments are administered in acute episode of ARF. Up to date, only prevention strategies have shown efficacy.

• Study Type: Interventional
• Enrollment (Estimated): 234
• Phase: Phase 2

Contacts and Locations

Study Locations

• Senegal
  • Dakar, Senegal
    • Fann Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Children aged between >= 5 and < 17 years old;
• Diagnosed acute rheumatic fever with at least one progressive rheumatic valvular lesion confirmed through a cardiac echography.
• Informed consent, signed and dated by both parents or legal guardians of the patient

Exclusion Criteria:

• Simultaneous active infection, such as HIV, hepatitis B, C, tuberculosis, Epstein-Barr virus (EBV), or history of frequent, unusual or serious infections ;
• Pathologies likely to affect immunity (cancer, multiple sclerosis, diabetes, other auto-immune diseases)
• Recent history of drug administration that may affect the immune system, for the past 4 weeks (immunosuppressive drugs, corticosteroids, anticancer drugs);
• Hypersensitivity reaction to rituximab or one of its components. Hypersensitivity to penicillin
• History of monoclonal antibodies administration
• Recent vaccination (less than a month) or planned within the 12 months after randomization;
• History of heart failure
• Renal failure with a creatinine clearance <45 ml/min/1,73m²
• Pregnancy (a negative urinary test is necessary for women who had their first menstruations or aged 14 years old and more)
• Patients diagnosed with Guillain-Barré syndrome
• Patient with at least one of the following biological features : Hemoglobin < 8,5 g/dL, Platelets < 100 G/L, Neutrophils < 1,5 G/L, Leucocytes < 3 G/L, AST or ALT increased > 2,5 the normal superior limit)
• Any acute or chronic infection clinically significant which would limitate the patient's capacity to follow up the study protocol, which remains under appreciation of the investigator.
• Any participation in another clinical trial in the 6 months before the pre-randomization visit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rituximab plus standard of care (RTX); Rituximab i.v of two perfusions (375 mg/m²) administered in a 14 day-interval added to a standard of care treatment	Drug: Rituximab added to standard of care treatment; Rituximab with standard of care treatment; Other Names: Rituximab with standard of care treatment
Active Comparator: Standard of care treatment (Control); Standard of care treatment	Drug: standard of care treatment alone; Standard of care treatment alone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rheumatic valvular lesions rate	Rheumatic valvular lesions rate, measured by echocardiography	6 months post randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of rheumatic valvular lesions	Rate of rheumatic valvular lesions will be compared between groups	14 days, 3, 6 and 12 months post-randomization
Serious adverse events rates	Serious adverse events rate will be compared between groups	at 14 days, 3, 6, and 12 months after randomization

Collaborators and Investigators

• Sponsor: African Academy of Methodology and Statistics

Study record dates

Study Major Dates

• Study Start (Actual): January 5, 2023
• Primary Completion (Estimated): September 30, 2024
• Study Completion (Estimated): February 1, 2025

Study Registration Dates

• First Submitted: December 15, 2022
• First Submitted That Met QC Criteria: January 3, 2023
• First Posted (Actual): January 12, 2023

Study Record Updates

• Last Update Posted (Actual): June 11, 2024
• Last Update Submitted That Met QC Criteria: June 9, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Infections; Joint Diseases; Musculoskeletal Diseases; Connective Tissue Diseases; Arthritis; Bacterial Infections; Bacterial Infections and Mycoses; Streptococcal Infections; Gram-Positive Bacterial Infections; Heart Diseases; Rheumatic Diseases; Rheumatic Fever; Rheumatic Heart Disease; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: AGRAF-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No