Efficacy and Safety of Subcutaneous Belimumab in Adults with Connective Tissue Disease-Associated Interstitial Lung Disease
- Trial ID
- 2024-513018-36-00
- Protocol
- 221672
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of belimumab compared to placebo, in addition to standard therapy, on reducing the decline in lung volume in participants with interstitial lung disease (ILD) associated with connective tissue disease (CTD). This is clinically relevant as it addresses the progressive nature of ILD, which can lead to significant morbidity and mortality due to declining lung function.
Secondary objectives include:
- Evaluating the efficacy of belimumab on reducing the decline in % predicted lung volume and slowing ILD progression.
- Assessing the effect of belimumab on fatigue, symptom severity, and health-related quality of life.
- Evaluating the maintenance of pulmonary structure as assessed by quantitative HRCT and the reduction in pulmonary gas transfer decline.
- Assessing the ability of belimumab to support reduction of steroid use and improve progression-free survival.
- Evaluating the safety and tolerability of belimumab in the treatment of participants with CTD.
Participants
The clinical trial involves a total of **312 participants** diagnosed with **interstitial lung disease (ILD)** associated with connective tissue disease (CTD). The study population includes both male and female subjects, aged 18 years and older, who are not considered part of a vulnerable population. Participants were selected based on specific inclusion criteria, including a documented diagnosis of rheumatoid arthritis, systemic lupus erythematosus, idiopathic inflammatory myopathy, Sjogren's syndrome, or mixed connective tissue disease, along with evidence of ILD progression. All participants are required to be on stable standard therapy for ILD and/or underlying CTD. Lifestyle considerations such as diet and physical activity are not specified, but participants must be capable of self-administering the study medication or have a caregiver to do so. The trial does not include pregnant or breastfeeding women unless they meet specific contraceptive criteria. The selection process ensures that participants have a confirmed diagnosis and are receiving appropriate treatment, aligning with the study's objective to evaluate the efficacy of belimumab in reducing lung volume decline.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled, parallel group study designed to evaluate the efficacy and safety of **belimumab** administered subcutaneously in adults with interstitial lung disease (ILD) associated with connective tissue disease (CTD). The primary objective is to assess the efficacy of belimumab compared to placebo, in addition to standard therapy, on reducing the decline in lung volume in participants with ILD associated with CTD. The trial is expected to last until December 2028, with recruitment starting in October 2024. Participants will be involved for a maximum treatment period of 52 weeks.
The trial includes several key study visits. The inclusion (screening) visit will confirm eligibility based on criteria such as age, documented diagnosis of specific connective tissue diseases, and evidence of ILD progression. Participants must be on stable standard therapy for ILD and/or underlying CTD. The study medication, either belimumab or placebo, will be administered subcutaneously, and participants or their caregivers must be capable of administering the medication throughout the study. Follow-up visits will occur regularly to monitor the participants' health and the study's primary endpoint, which is the absolute change from baseline in forced vital capacity (FVC) at Week 52. Secondary endpoints include changes in FVC % predicted, time to ILD progression or death, and various quality of life measures.
The end-of-study visit will assess the overall outcomes and any adverse events experienced by the participants. Participants may be terminated early from the study if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial is not categorized as low intervention, and it is crucial that participants adhere to the study requirements to ensure the integrity of the data collected. The study aims to provide valuable insights into the potential benefits of belimumab for individuals with ILD associated with CTD.
Treatment
The clinical trial involves the administration of **Benlysta**, a **200 mg solution for injection** in a pre-filled syringe. The active substance in Benlysta is **belimumab**, a protein-based therapeutic agent. The pharmaceutical form is a solution for injection, specifically designed for **subcutaneous use**. Participants will receive a maximum daily dose of 200 mg, with the treatment period extending up to 52 weeks. The administration frequency is determined by the study protocol, ensuring consistent dosing throughout the trial duration. Compliance with the dosing schedule will be monitored to ensure adherence to the treatment regimen.
In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo is formulated to match the Benlysta solution for injection, provided as a sterile solution for subcutaneous injection in single-use prefilled syringes. The placebo is administered in the same manner and frequency as the active treatment to maintain the study's blinding integrity. This ensures that any observed effects can be attributed to the active substance, belimumab, rather than other variables. Participant compliance with the placebo administration will also be monitored to maintain the study's validity.
Efficacy
The efficacy of belimumab in the clinical trial will be assessed by evaluating its impact on reducing the decline in lung volume in participants with interstitial lung disease (ILD) associated with connective tissue disease (CTD). The primary endpoint for efficacy assessment is the absolute change from baseline in forced vital capacity (FVC) measured in milliliters at Week 52. Secondary endpoints include the absolute change from baseline in FVC % predicted at Week 52, time to ILD progression or death, and various patient-reported outcomes such as the FACIT-Fatigue score, L-PF total symptom score, and King's Brief Interstitial Lung Disease Questionnaire (K-BILD) score, all evaluated at Week 52.
Additional secondary endpoints involve achieving specific declines in FVC, cumulative corticosteroid dose over 52 weeks, and time to CTD progression. The incidence of adverse events (AEs), adverse events of special interest (AESIs), and serious adverse events (SAEs) will also be monitored up to Week 52. Efficacy parameters will be collected and analyzed using validated scales and laboratory tests at specified timepoints, primarily focusing on the 52-week mark. The trial is designed as a Phase 3, randomized, double-blind, placebo-controlled, parallel group study, ensuring rigorous assessment of belimumab's efficacy in the target population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant is 18 years of age inclusive, or older at the time of signing the informed consent
- Documented diagnosis of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), idiopathic inflammatory myopathy (IIM; including polymyositis, dermatomyositis, antisynthetase syndrome), Sjogren’s syndrome (pSS), or mixed connective tissue disease (MCTD) in accordance with internationally recognized classification criteria (see Section 10.9 [Appendix 9]). NOTE: patients with overlap syndrome (including SSc overlap) are permitted if their primary diagnosis is RA, SLE, IIM, pSS or MCTD
- Diagnosis of inflammatory and/or fibrotic ILD on HRCT with a total disease extent of ≥10% of the whole lung, as confirmed by central reader at screening. NOTE: the 10% extent of ILD includes assessment of all inflammatory and fibrotic radiological ILD features. INC#3
- Evidence of persistent active/worsening ILD defined as at least one of the following criteria
- Must be currently receiving stable standard therapy to manage ILD and/or underlying CTD, or to have failed or failed to tolerate Standard therapy. Standard therapy in accordance with current treatment guidelines and local labels.
- Participant is capable and willing to self-administer the study medication or has a caregiver who is capable and willing to administer the study medication throughout the study
- Female participants INC#7: A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: o Is a WONCBP as defined in Section 10.4 (Appendix 4: Contraceptive and Barrier Guidance). OR o Is a WOCBP and using a contraceptive method that is highly effective, with a failure rate of <1%, as described in Section 10.4 (Appendix 4: Contraceptive and Barrier Guidance) during the study intervention period and for at least 4 months after the last dose of study intervention. The investigator should evaluate potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention. A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 24 hours before the first dose of study intervention. See Section 8.3.5. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Additional requirements for pregnancy testing during and after study intervention are located in Section 8.3.5. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Exclusion Criteria
- Diagnosis of ILD other than CTD-ILD.
- Primary diagnosis of Systemic Sclerosis (SSc).
- Participants with rapidly progressive disease (absolute drop of 10% or more of FVC between screening and baseline visit and/or recent pulmonary hospitalisation).
- FVC ≤45% of predicted, or a DLco (corrected for hemoglobin) ≤40% of predicted at screening as confirmed by central reader.
- History or presence of diffuse alveolar haemorrhage (DAH) or other confounding pulmonary disease, signs, or symptoms
- Pulmonary arterial hypertension requiring therapy, as determined by the investigator at, or prior to first day of dosing (Day 1).
- Dependence on continuous oxygen supplementation
- History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention or interfering with the interpretation of data.
- Obstructive pulmonary disease (pre-bronchodilator FEV1/FVC <0.7) as confirmed by central reader.
- Significant emphysema on screening or historical HRCT (extent of emphysema exceeds extent of ILD) as confirmed by central reader.
- Confirmed PML or unexplained new-onset or deteriorating neurologic signs and symptoms.
- Significant allergies to human or murine proteins, humanized monoclonal antibodies, or contrast agents
- Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear IgA dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis).
- Participants with PHQ-9 score ≥10 that in the opinion of a mental healthcare professional pose a serious suicide risk, or have any history of suicidal behavior in the last 6 months and/or any suicidal ideation in the last 2 months, or who in the investigator's judgment, poses a significant suicide risk. Note: For participants with a PHQ-9 score ≥10, at the screening visit or at the Day 1 visit before the first administration of the study drug, it is required that they be referred for an assessment by a mental healthcare professional (e.g. locally licensed psychiatrist, psychologist, or master’s level therapist) before the investigator makes a final decision regarding suitability for enrollment.
- Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years
- Breast cancer within the past 10 years
- Major surgery (including joint surgery) within 3 months prior to screening or planned during the duration of the study.
- An active infection, or a history of infections as follows: History of opportunistic infections that have not resolved by 6 months prior to the first day of dosing (Day 1) or recurrent infection as determined by the investigator. This does not include infections that may occur in immunocompetent individuals, such as fungal nail infections or vaginal candidiasis, unless it is of an unusual severity or frequency. o A serious infection requiring treatment with IV antibiotics and/or hospitalization, if the last dose of antibiotics or the hospital discharge date was within 60 days of the first day of dosing (Day 1). o An acute or chronic infection requiring treatment with oral antibiotics or antiviral medications, if the last dose was received within 30 days of the first day of dosing (Day 1). Prophylactic anti-infective treatment is allowed. o Any active or unresolved bacterial, viral, or fungal infection present on the first day of dosing (Day 1), whether requiring treatment or not. This does not include fungal nail infections. o Active or past osteomyelitis, unless fully resolved in the opinion of the investigator.
- Symptomatic herpes zoster within 3 months prior to Day 1
- Diagnosis of active TB confirmed by 1) evidence of active TB disease from chest imaging (posterior anterior and lateral x-rays or chest CT), 2) medical history and examination, and 3) positive microscopy smear or culture for mycobacteria /positive TB PCR i.e., Xpert. A positive TST or a positive (not indeterminate) interferon-gamma release assay (IGRA) TB test such as QuantiFERON-TB Gold Plus test is indicative, but not required for diagnosis of active TB. A positive TST is defined as a skin induration ≥5 mm at 48 to 72 hours (regardless of Bacillus Calmette-Guerin or other vaccination history). OR • Untreated latent TB infection confirmed by: 1) no evidence of active TB based on chest imaging, medical history and physical examination and laboratory evaluation of sputum; and 2) a positive TST, defined as a skin induration ≥5 mm at 48 to 72 hours (regardless of Bacillus Calmette-Guerin or other vaccination history); or a positive (not indeterminate) interferon-gamma release assay (IGRA) TB test such as QuantiFERON-TB Gold Plus test. Those with IGRA positive tests or positive TST who can document ongoing LTBI treatment for at least 4 weeks may be enrolled. Those with IGRA positive tests with documentation of the following may also be enrolled: o Successful completion of treatment for active TB o Completion of treatment for LTBI (with treatment as per local practice, for example: 3 months of isoniazid and rifampin or 4 months of rifampin or 3 months weekly isoniazid and rifapentine, or 9 months of isoniazid) o For those participants requiring Isoniazid (INH) therapy for latent TB, AST and ALT must be assessed following 3 weeks of INH treatment in screening. Participants will fail screening if ALT >2 × ULN is identified; these participants may be re-screened if ALT elevation resolves to ALT <2 × ULN during ongoing INH therapy following discussion with the medical monitor. • Those enrolled with positive IGRA or TST will be monitored during the study for new pulmonary symptoms (worsening cough, worse in intensity and productive) as well as fevers, night sweats or weight loss. Those reporting any of the above must be immediately evaluated by a physician for physical examination, imaging by chest x-ray or CT chest scan, laboratory evaluation of sputum (microscopy smear and culture for mycobacteria), and referral to TB specialist.
- Previous or planned major organ transplant (e.g., heart, lung, kidney, liver) or bone marrow transplant (e.g., autologous stem cell transplant).
- Plasmapheresis or extracorporeal photopheresis, or use of plasma filtering devices within 6 months prior to Day 1.
- Any prior treatment with anti-BlyS agents, including belimumab
- "Treatment with systemic biologic agents including the following biologic DMARDs anti IL6 therapies such as tocilizumab, sarilumab, anti CTLA4 such as abatacept or anti-TNF therapies (e.g., adalimumab, etanercept, infliximab, certolizumab) or other biologic DMARDs such as denosumab or anakinra, within 8 weeks (4 weeks for etanercept) or 5 half-lives (whichever is longer) prior to Day 1 and intravenous immunoglobulin (including anti-thymocyte globulin) or monoclonal antibodies, including marketed drugs, within 12 weeks or 5 half-lives (whichever is longer) prior to Day 1. "
- Treatment with rituximab or any other B-cell depleting therapies such as ofatumumab, ocrelizumab or inebilizumab within 6 months prior to Day 1.
- "Treatment with: o Janus kinase (JAK) inhibitors (tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib, others; either experimental or approved, within 4 weeks or 5 half-lives (whichever is longer) prior to Day 1 o Other non-biologic systemic immunosuppressive medication including targeted synthetic DMARDs within 3 months prior to Day 1 o Exception are the permitted medications listed under INC#5, when they are being continued during the study. "
- Treatment with cyclophosphamide (oral or intravenous) within 6 months prior to Day 1
- Use of anti-fibrotic agents including pirfenidone, tyrosine kinase inhibitors (e.g., nintedanib, nilotinib, imatinib, dasatinib) or phosphodiesterase 4B (PDE4B) inhibitors within 4 weeks prior to Day 1.
- Cytotoxic drugs such as, chlorambucil, nitrogen mustard, or other alkylating agents within 6 months of Day 1.
- Treatment with IM or IV corticosteroids within 4 weeks prior to Day 1.
- Live or live-attenuated vaccine(s) within 30 days prior to Day 1 or plans to receive such vaccines during the study.
- Participants who are expected to be non-compliant with restrictions on medications and vaccinations prior to the study, during the study or during the 8-week safety follow-up of the study. See Section 6.9.4 for details of prohibited medications/treatments and in Section 6.9.1 for details of permitted medications/treatments.
- Current enrolment or past participation in any other investigational study involving an investigational intervention (e.g., drug, vaccine, invasive device) within 3 months or 5 half-lives of the investigational drug (whichever is longer) before randomization or any other type of medical research within 3 months before randomization
- Positive human immunodeficiency virus (HIV) antibody test.
- Serologic evidence of Hepatitis B infection based on the results of testing for HBsAg, Anti-HBc and Anti-HBs as follows: EXC#35: • Patients positive for HBsAg are excluded. • Patients negative for HBsAg but positive for Anti-HBc, regardless of Anti-HBs antibody status, will require clarification of their status by testing for HBV DNA. o if HBV DNA is detectable, patients will be excluded from participation. o if HBV DNA is not detectable, patients will be eligible to enroll. NOTE: For those subjects included, additional ongoing assessment is required. Safety assessment for Hepatitis B during the trial will be as follows: • ALT, AST, HBsAg and HBV DNA will be tested approximately once a month for the first 6 months after initiation of study treatment, and approximately once every 3 months thereafter. • If HBsAg is positive or HBV DNA is detectable, study drug must be discontinued and the participant should be referred for a review by a liver specialist or hepatologist and consideration of hepatitis B treatment initiation. • If there is ALT/AST elevation greater than 2.5×ULN but repeat HBV DNA levels are nondetectable and HBsAg is negative, then investigate other causes for ALT/AST elevation. The suspected reason for ALT and/or AST elevation should be documented. • In case of Hepatitis B reactivation, follow local guidelines for treatment of Hepatitis B. "
- Positive Hepatitis C antibody test result at screening or within 3 months prior to starting study intervention. NOTE: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative hepatitis C RNA test is obtained.
- Positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study intervention. NOTE: Test is optional and participants with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing.
- History of a primary immunodeficiency, or hypogammaglobulinaemia (IgG <400 mg/dL), or IgA deficiency (IgA <10 mg/dL).
- Have a Grade 3 or greater neutropenia, defined as absolute neutrophil count <1000/mm3 (<1.0x10e9/L) based on the CTCAE v5.0.
- Have any other clinically significant abnormal laboratory value, that in the opinion of the investigator, is capable of significantly altering the absorption, metabolism, or elimination of drugs; constitutes a risk when taking the study intervention or interferes with the interpretation of data.
- Exposure to ionizing radiation in excess of 10 mSv above background over the three-year period before screening as a result of occupational exposure or previous participation in research studies.
- Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within a year prior to Day 1.
- Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator, contraindicates participation in the study.
- Use of any medicinal products intended to treat medical conditions that are not approved by the governing health authority in the participant’s country or region.
- Alanine transaminase (ALT) >2x upper limit of normal (ULN)
- Total bilirubin >1.5×ULN (isolated total bilirubin >1.5×ULN is acceptable if total bilirubin is fractionated and direct bilirubin <35%)
- Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice. NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome, asymptomatic gallstones, and chronic stable hepatitis B or C) is acceptable if the participant otherwise meets entry criteria
- QTc >450 msec or QTc >480 msec for patients with bundle branch block NOTE: The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machine-read or manually over-read. The specific formula used to determine eligibility and discontinuation for an individual participant should be determined prior to initiation of the study and used throughout the study for the individual participant. In other words, several different formulas cannot be used to calculate the QTc for an individual participant and then the lowest QTc value used to include or discontinue the participant from the trial.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 31 Oct 2024 | 8 |
 France | Recruiting | 31 Oct 2024 | 18 |
 Germany | Recruiting | 31 Oct 2024 | 20 |
 Greece | Recruiting | 31 Oct 2024 | 9 |
 Italy | Recruiting | 31 Oct 2024 | 31 |
 The Netherlands | Not Yet Recruiting | 31 Oct 2024 | — |
 Spain | Recruiting | 31 Oct 2024 | 30 |
| Netherlands | — | — | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo for Belimumab Solution for Injection, 200 mg/mL.
The placebo for Belimumab Solution for Injection, 200 mg/mL is provided as a sterile
solution for subcutaneous (SC) injection in single-use prefilled syringes. | Placebo | N/A | — | — | — | N/A |
Benlysta 200 mg solution for injection in pre-filled syringe. | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS USE | 200 | 52 | PRD5568803 |