A randomized, two-armed, single-blind, parallel, active controlled, and non-inferiority clinical trial to Compare Efficacy and Safety of anti TNF-alfa biosimilar molecules to the originators in children with active Juvenile Idiopathic Arthritis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

1 Oct 2022 → ongoing

Decision date (initial)

2024-08-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Italian Medicine Agency (AIFA) Independent clinical research

External identifiers

EU CT number

2024-515557-22-00

EudraCT number

2021-004031-86

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The study is aimed to evaluate, through a pragmatic trial, safety and efficacy of switching from the adalimumab and etanercept originator molecules versus their biosimilar competitors and vice-versa in children with JIA in clinical remission on anti-TNF medication.

Secondary objectives 8

1. Inactive disease The rate of patients who achieve the JADAS state of ID at any single point in time throughout the study period will be compared between the 2 arms. Rate of inactive disease will be evaluated also with American College of Rheumatology (ACR) criteria for inactive disease
2. Time to inactive disease as per JADAS or ACR criteria Time to achieve the state of inactive disease will be calculated as the time difference (in days) between the date of enrolment and the date of the visit at which the patient will be observed to be in ID
3. Time spent in inactive disease The cumulative time spent in the JADAS state of ID will be calculated as the time difference (in days) between the date of the first visit at which the patient will be observed to be in ID and the date at which he/she will be observed to be no longer in ID (flare, or completion of the 12-month observation period). We will assume that if a patient is found to be in ID at 2 consecutive visits, the patient had ID on all days between these visits. If a patient will be found to have CID at a particular visit, but lost the ID status at the subsequent visit, the patient will be considered to have been in ID until the recurrence of active disease. Patients found to be in ID only at the final visit of the study will contribute a single day of ID. The median time in inactive disease per patient will be recorded and compared between the study arms
4. Time to clinical remission Time to achieve the state of clinical remission will be calculated as the time difference (in days) between the date of enrolment and the date of the visit at which the patient will be observed to be in clinical remission (i.e. persistent inactive disease for at least 6 months)
5. Cumulative level of disease activity throughout the study period The area under the curve (AUC) of the clinical JADAS (cJADAS)-10 score assessed at every study visit will be recorded and compared between the study arms
6. Rate of flares The rate of patients who develop flare, defined as the recurrence of active disease after attaining inactive disease at last visit according JADAS scores, and the number of flares and the time to flare per patient will be recorded and compared
7. Rate of uveitis onset/flare The rate of patients who develop uveitis according to the Standardized Uveitis Nomenclature (SUN) will be recorded and compared between the study arms. The rate of patients requiring systemic medications for treatment of uveitis will be also recorded and compared between the study arms. However, these patients will be considered as treatment failure and will be given other therapeutic interventions, as deemed appropriate by the caring physician
8. Frequency of side effects of medications In case of patients enrolled in phase A treated with etanercept with a new onset of uveitis and candidate by the caring physician to adalimumab, they can be enrolled in the study for a second time, if inclusion criteria are met, and randomized to be included in the originator (Adalimumab - Humira ®) or biosimilar arm (see study design)

Conditions and MedDRA coding

Juvenile Idiopathic Arthritis

Study design 1 period

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Children with a diagnosis of JIA according to the ILAR criteria, candidate to treatment with anti-TNF alpha drugs (etanercept or adalimumab) as per the approved label indication and per treating physician/family decision, classified as per ILAR criteria in: Oligoarthritis; Rheumatoid factor negative polyarthritis; Rheumatoid factor positive polyarthritis; Psoriatic arthritis; Enthesitis-related arthritis.
2. Moderate to high disease activity despite methotrexate treatment for at least 3 months.
3. Age 2 to <18 years at time of enrolment
4. For Etanercept, only patients eligible for receiving authorized biosimilar formulations according to the Summary of Product Characteristics (SmPC), i.e. with the proper weight range, will be enrolled: since etanercept biosimilar formulations are available only with fix doses (25 mg and 50 mg), only patients, with age < 18 years old at the time of enrolment, weighted >30 and < 32 kg or subjects > 62 kg could be enrolled
5. Ability to comply with the entire study procedures, ability to communicate meaningfully with the investigational staff to be applied to the parents and/or patients, as appropriate
6. Duly executed, written, informed consent obtained from the patient’s parents
7. For sexually active participants, compliance in undertaking highly effective contraception methods throughout the study

Exclusion criteria 16

1. Children with systemic JIA according to ILAR criteria
2. Ongoing treatment in the screening phase with any other second-line agents (except methotrexate) or intravenous immunoglobulin
3. Abnormalities in laboratory values: white blood cell count < 3,000/mm3, a platelet count < 50,000/mm3, levels of serum glutamic oxaloacetic transaminase/asparagine aminotransferase (SGOT/AST) or serum glutamic pyruvic transaminase/alanine aminotransferase (SGPT/ALT) above the upper limit of normal according to the local lab reference, creatinine levels above the upper limit of normal according to the local lab reference or eGFR < 60 ml/min/1.73 m2 calculated according with bedside Schwartz equation, chronic proteinuria or hematuria (2–4/4 on dipstick on 2 consecutive tests)
4. Positive serologic findings of hepatitis B or C
5. Active tuberculosis TB or a history of incompletely treated TB
6. Purified protein derivative (PPD) skin test or QuantiFERON-TB positive patients (with no active disease) are excluded from the study unless it is documented by a specialist that the patient has been adequately treated for TB and can start treatment with a biologic agent, based on the medical judgment of the study investigator and / or an infectious disease specialist
7. Suspected extrapulmonary TB infection
8. Patients at high risk of contracting TB, such as close contact with individual with active or latent TB
9. Any live attenuated vaccine within 4 weeks prior to the baseline visit, such as varicella-zoster, oral polio, measle, mumps or rubella vaccines and throughout the study. Killed or inactive vaccine may be permitted based on the investigator’s judgment
10. Prior or current history of malignancy, including lymphoproliferative diseases, other than adequately-treated carcinoma in-situ of the cervix, nonmetastatic squamous cell, or basal cell carcinoma of the skin, within 5 years prior to the baseline visit
11. Prior or current history of other significant concomitant illness(es) that, according to the Investigator’s judgment, would adversely affect the patient’s participation in the study. These include, but are not limited to, cardiovascular, renal, neurological disorder (including demyelinating disease), active infectious diseases, endocrinological, gastrointestinal, hepatobiliary, metabolic, pulmonary (e.g. severe asthma, cystic fibrosis), nonmalignant lymphoproliferative diseases, other lymphatic disease(s), autoimmune disease, psychiatric disorders, history of inflammatory bowel disease, severe diverticulitis, or previous gastrointestinal perforation, uncontrolled diabetes mellitus, defined as glycosylated hemoglobin (HbA1c) ≥ 9% at the screening visit
12. Sepsis or risk of sepsis, active infections including chronic or local infections
13. Moderate to severe heart failure (NYHA class III/IV)
14. A history of COVID-19 infection or vaccination does not exclude participation in the trial if real-time reverse transcription polymerase chain reaction (RT-PCR) confirm the absence of viral RNA in patient specimens
15. For Etanercept, patients with a weight range different from the indications reported in the Summary of Product Characteristics of the biosimilar formulations will not be enrolled. If, during the study, the weight falls outside the indicated ranges for taking biosimilars, the subject will be withdrawn from the study
16. Hypersensitivity to the active substance or to any of the excipients

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Clinical remission. Efficacy of therapeutic strategies will be compared by assessing the frequency of clinical remission (CR) at 18 months (6 months after randomization for entrance in Phase B). CR is defined as the persistence of the Juvenile Arthritis Disease Activity Score (JADAS) state of inactive disease (ID) for at least 6 months. Assessment of efficacy of the switch will be determined comparing the proportion of patients in CR at 18 months in the switched vs the non switched cohort

Investigational products

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

Test 2

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Sponsor organisation

Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Address

Via Francesco Sforza 28

City

Milan

Postcode

20122

Country

Italy

Scientific contact point

Organisation

Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Contact name

Giovanni Filocamo

Public contact point

Organisation

Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Contact name

Giovanni Filocamo

Locations

1 EU/EEA country · 17 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 8 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