Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Ianalumab in Patients with Active Sjögren’s Syndrome
- Trial ID
- 2024-511069-12-00
- Protocol
- CVAY736A2301
- Sponsor
- Novartis Pharma AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the **superiority** of ianalumab over placebo based on the change from baseline in the EULAR Sjögren's Syndrome Disease Activity Index (**ESSDAI**) score at Week 48. This objective is clinically relevant as it aims to establish the efficacy of ianalumab in reducing disease activity in patients with active Sjögren's Syndrome, a chronic autoimmune condition characterized by dry mouth and eyes, fatigue, and systemic manifestations.
Secondary objectives include:
- Demonstrating superiority of ianalumab over placebo based on the proportion of patients achieving ≥3 points reduction from baseline in ESSDAI score at Week 48.
- Demonstrating superiority based on the proportion of patients achieving low systemic disease activity defined as ESSDAI<5 at Week 48.
- Evaluating the proportion of patients achieving ≥1 point or 15% reduction from baseline in the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) at Week 48.
- Demonstrating superiority based on the proportion of patients achieving ≥3 points reduction from baseline in ESSDAI score at Week 24.
- Demonstrating superiority based on change from baseline in stimulated whole salivary flow (sSF) rate at Week 48.
- Demonstrating superiority based on change from baseline in Physician’s Global Assessment (PhGA) at Week 48.
- Demonstrating superiority based on change from baseline in Patient’s Global Assessment (PaGA) at Week 48.
- Demonstrating superiority based on change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score at Week 48.
- Evaluating the safety and tolerability of ianalumab.
- Evaluating the immunogenicity of ianalumab.
- Evaluating the pharmacokinetics (PK) of ianalumab.
- Demonstrating superiority based on the proportion of patients achieving meaningful improvement in Sjögren's measured by Sjögren's Syndrome Symptom Diary (SSSD) score at Week 48.
Participants
The clinical trial involves a total of **148 participants** diagnosed with **Sjögren’s Syndrome**. The study population includes both **male and female** subjects aged **18 years and older**. Participants were selected based on specific criteria, including a diagnosis of Sjögren's syndrome according to the ACR/EULAR 2016 criteria, and a time since diagnosis of 7.5 years or less at screening. The trial includes individuals with a positive anti-Ro/SSA antibody or a positive salivary gland biopsy confirmed by central expert review, with enrollment of anti-Ro/SSA-negative patients limited to 10% of the study population. Participants are required to have a screening ESSDAI score of 5 or higher within specified domains and a stimulated whole salivary flow rate of at least 0.05 mL/min at screening. The trial population is composed of individuals who are able to communicate effectively with the investigator and comply with study requirements. Lifestyle considerations include the continuation of certain medications such as hydroxychloroquine, methotrexate, or azathioprine, provided they have been on a stable dose for at least 30 days prior to randomization. The study does not specify any particular dietary or physical activity requirements for participants.
Plans and Procedures
The clinical trial is a **randomized, double-blind, placebo-controlled** study designed to evaluate the efficacy and safety of **ianalumab** in patients with active **Sjögren's syndrome**. The trial is structured as a two-arm, multicenter phase 3 study, with an estimated duration from July 2022 to March 2028. Participants will be randomly assigned to receive either ianalumab or a placebo, with the primary objective being to demonstrate the superiority of ianalumab over placebo based on changes from baseline in the **ESSDAI** score at Week 48.
The trial will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as a positive anti-Ro/SSA antibody or a positive salivary gland biopsy, and a screening ESSDAI score of ≥ 5. Following successful screening, participants will be randomized and begin the treatment phase, which spans 52 weeks. During this period, participants will attend regular follow-up visits to monitor safety, efficacy, and adherence to the study protocol. These visits will include assessments of ESSDAI response, systemic disease activity, and other secondary endpoints such as changes in stimulated whole salivary flow and patient-reported outcomes.
The end-of-study visit will occur at the conclusion of the 52-week treatment period, where final assessments will be conducted to evaluate the long-term effects of the treatment. Participants are expected to be involved in the study for approximately 56 weeks, including the screening and follow-up periods. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. The trial is designed to ensure rigorous monitoring and data collection to support the evaluation of ianalumab's clinical efficacy and safety in treating active Sjögren's syndrome.
Treatment
The clinical trial involves the administration of **ianalumab**, marketed under the name VAY736, which is a **solution for injection in a pre-filled syringe**. This investigational drug is administered via **subcutaneous use**. The maximum daily dose is 300 mg, with a total maximum dose of 3900 mg over a treatment period of 52 weeks. The active substance, ianalumab, is a protein-based therapeutic agent developed by Novartis Pharma AG. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.
The study also includes a **placebo** comparator, which is a solution for injection in a pre-filled syringe designed to match the appearance and administration route of VAY736. The placebo is administered in the same manner as the investigational drug, ensuring the study remains double-blind. The placebo is intended to serve as a control to evaluate the efficacy and safety of ianalumab in patients with active Sjögren’s syndrome.
An auxiliary treatment, classified under **glucocorticoids**, is also part of the trial. This treatment is administered **orally** with a maximum daily dose of 50 mg, and the treatment period is limited to 1 week. The glucocorticoid treatment is included to manage any potential inflammatory responses during the trial. The administration and dosage of this auxiliary treatment will be carefully monitored to maintain participant safety and study integrity.
Efficacy
The efficacy of ianalumab in patients with active Sjögren's syndrome will be assessed through a randomized, double-blind, placebo-controlled, multicenter phase 3 study. The primary efficacy endpoint is the change from baseline in the **ESSDAI** (EULAR Sjögren's Syndrome Disease Activity Index) score at Week 48. Secondary endpoints include the ESSDAI response at Week 48 and Week 24, low systemic disease activity (ESSDAI < 5), ESSPRI (EULAR Sjögren's Syndrome Patient Reported Index) response, changes from baseline in stimulated whole salivary flow (sSF), Physician's Global Assessment (PhGA), Patient's Global Assessment (PaGA), and FACIT-F (Functional Assessment of Chronic Illness Therapy-Fatigue) scores. Additionally, the proportion of patients achieving meaningful improvement in the SSSD (Sjögren's Syndrome Symptom Diary) score at Week 48 will be evaluated.
Measurements will be collected at specified timepoints, including baseline, Week 24, and Week 48, using validated scales and laboratory tests. The ESSDAI and ESSPRI scores will be used to quantify disease activity and patient-reported outcomes, respectively. The trial aims to demonstrate the superiority of ianalumab over placebo in improving these parameters, thereby providing evidence of its efficacy in treating active Sjögren's syndrome.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed informed consent must be obtained prior to participation in the study
- Women and men ≥ 18 years of age
- Classification of Sjögren's syndrome according to the ACR/EULAR 2016 criteria (Shiboski et al 2017)
- Time since diagnosis of Sjögren's of ≤ 7.5 years at screening
- Positive anti-Ro/SSA antibody at screening • Patients negative for anti-Ro/SSA antibody are eligible, if they have a positive salivary gland biopsy confirmed by central expert review • Enrollment of anti-Ro/SSA-negative patients will be limited up to ≤10% of the study population
- Screening ESSDAI score of ≥ 5 within the following 8 domains: constitutional, lymphadenopathy, glandular, articular, cutaneous, renal, hematological and biologic.
- Stimulated whole salivary flow (sSF) rate of ≥ 0.05 mL/min at screening
- Ability to communicate well with the Investigator, understand and agree to comply with the requirements of the study
- Patients taking hydroxychloroquine (≤ 400 mg/day), methotrexate (≤ 25 mg/week) or azathioprine (≤ 150 mg/day) alone or in combination, are allowed to continue their medication, and must have been on a stable dose for at least 30 days prior to randomization. Stable dose within the predefined dose limits should be maintained throughout the 52 weeks of the blinded treatment period of the study
- Patients taking systemic corticosteroids have to be on a stable dose of ≤ 10 mg/day predniso(lo)ne or equivalent for at least 30 days before randomization. Stable dose should be maintained throughout the 52 weeks of the blinded treatment period of the study, however limited increases of the corticosteroid dose for a limited time and tapering of background steroids are allowed during the course of the study as described in Section 6.2.1 of the Protocol.
- Patients taking: • disease-modifying antirheumatic drugs (DMARDs) other than specifically allowed in inclusion criterion #9 must or • the following Traditional Chinese Medicines: Total glucoside of peony (TGP) or Tripterium glycosides (TG) must discontinue these medications at least 30 days prior to randomization, except for leflunomide, which has to be discontinued for 8 weeks prior to randomization unless a cholestyramine wash-out has been performed.
Exclusion Criteria
- Presence of another autoimmune rheumatic disease that is active and constitutes the principal illness, specifically: • Moderate-to-severe active systemic lupus erythematosus (SLE) with anti-dsDNA positivity and renal involvement, or other organ involvement that impedes on ability to score ESSDAI domains • Active rheumatoid arthritis (RA) that impedes on the ability to score the ESSDAI articular domain • Systemic sclerosis • Any other concurrent connective tissue disease (e.g., lupus nephritis (LN), large vessel vasculitis (LVV), Sharp syndrome (mixed connective tissue disease) that is active and requires immunosuppressive treatment outside the scope of this trial and would impede on Sjögren's syndrome organ domain assessments.
- Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days or until the expected pharmacodynamic effect has returned to baseline, whichever is longer, or longer if required by local regulations
- Prior treatment with ianalumab
- Prior use of a B-cell depleting therapy other than ianalumab (e.g., rituximab, other anti-CD20 mAb, anti-CD22 mAb or anti-CD52 mAb) within 36 weeks prior to randomization or as long as B-cell count is less than the lower limit of normal or baseline value prior to receipt of previous B cell-depleting therapy (whichever is lower)
- Prior treatment with any of the following:: • within 24 weeks prior to randomization: iscalimab (anti CD-40 mAb), belimumab (anti-BAFF mAb), abatacept (CTLA4-Fc Ig), anti-tumor necrosis factor alpha (TNFα) biologic agents, immunoglobulins (i.v./s.c.) plasmapheresis; • within 12 weeks prior to randomization: i.v. or oral cyclophosphamide, mycophenolate mofetil (MMF), i.v. or oral cyclosporine A or any other immunosuppressants (e.g., JAK inhibitors or other kinase inhibitors) unless explicitly allowed in inclusion criterion #9
- Use of corticosteroids (predniso(lo)ne or equivalent corticosteroid) at dose >10 mg/day
- Any one of the following laboratory values at screening: • Hemoglobin levels < 8.0 g/dL • White blood cells (WBC) count < 2.0 x 103/µL • Platelet count < 80 x 103/µL • Absolute neutrophil count (ANC) < 0.8 x 103/µL (one re-test is allowed during the screening period)
- Active viral, bacterial or other infections requiring systemic treatment at the time of screening or randomization, or history of recurrent clinically significant infection or of recurrent bacterial infections with encapsulated organisms
- History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes (e.g., mAb of IgG1 class) or to any of the constituents of the study drug formulation (sucrose, L-histidine hydrochloride/ L-histidine, polysorbate 20)
- History of major organ, hematopoietic stem cell or bone marrow transplant
- Required regular use of medications known to cause dry mouth/eyes as a regular and major side effect, and which have not been on a stable dose for at least 30 days prior to Screening, or any anticipated change in the treatment regimen during the course of the study
- Use of topical ocular prescription medications (excluding artificial tears, gels, lubricants) that have not been on a stable dose for at least 90 days prior to randomization, or any anticipated change in the treatment regimen during the course of the study
- Receipt of live/attenuated vaccine within a 4-week period prior to randomization
- History of primary or secondary immunodeficiency, including a positive human immunodeficiency virus (HIV) (ELISA and Western blot) test result
- History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer or Sjögren’s related lymphoma), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
- History of sarcoidosis
- Any surgical, medical (e.g., uncontrolled hypertension, heart failure or diabetes mellitus), psychiatric or additional physical condition that the Investigator feels may jeopardize the patient in case of participation in this study
- Chronic infection with hepatitis B (HBV) or hepatitis C (HCV). Positive serology for hepatitis B surface antigen (HBsAg) excludes the subject. • HBsAg negative subjects who are hepatitis B core antibody (HBcAb) positive are also excluded unless all of the following criteria are met: o HBV DNA is negative o hepatitis B monitoring is implemented - in these subjects monthly testing of HBsAg and HBV DNA must be performed while on study treatment and at least every 12 weeks after end of treatment for the entire duration of safety follow-up. o Antiviral prophylaxis must be implemented before the first administration of the study treatment and continued up to 12 months after end of study treatment. If antiviral therapy cannot be given or if the patient is not willing to comply with the antiviral treatment requirement, the patient is not eligible for the study. • Hepatitis C: Patients with positive Hep C antibody and HCV RNA at screening are excluded. Chronic hepatitis C patients who have completed HCV anti-viral treatment must be HCV-RNA negative at least 12 weeks after treatment before randomization to be eligible. Cases of spontaneous HCV clearance should be discussed with sponsor before enrollment.
- Evidence of active tuberculosis (TB) infection is exclusionary. Patients with previously treated TB and previously treated or newly diagnosed latent TB may be eligible (after anti-TB treatment, patients with history of or latent TB may become eligible according to national guidelines).
- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while on study treatment and for 6 months after stopping of investigational medication. Highly effective contraception methods include: • Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) total hysterectomy or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment • Male sterilization (at least 6 months prior to screening). For female participant on the study, the vasectomized male partner should be the sole partner for that participant. • Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Contraception should be used in accordance with locally approved prescribing information of concomitant medications administered. Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate history of vasomotor symptoms). Women are considered not of child-bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child-bearing potential. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the informed consent form (ICF).
- Patients with a known history of non-compliance to medication, or who were unable or unwilling to complete PRO questionnaires, or who are unable or unwilling to use the device for collection of PROs.
- United States (and other countries, if locally required): Sexually active males, unless they agree to use barrier protection during intercourse with a woman of childbearing potential while taking study treatment. As condom use alone has a reported failure rate exceeding 1% per year, it is recommended that female partners of male study participants use a second method of birth control. Although ianalumab is not teratogenic and/or genotoxic, and not transferred to semen, male contraception is required, as requested by FDA. Globally, for all sexually active males, contraception should be used in accordance with locally approved prescribing information of concomitant medications administered.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 28 Jul 2022 | 8 |
 Belgium | Not Recruiting | 28 Jul 2022 | 5 |
 Czechia | Not Recruiting | 28 Jul 2022 | 14 |
 France | Not Recruiting | 28 Jul 2022 | 10 |
 Germany | Not Recruiting | 28 Jul 2022 | 26 |
 Lithuania | Not Recruiting | 28 Jul 2022 | 6 |
 Poland | Not Recruiting | 28 Jul 2022 | 26 |
 Portugal | Not Recruiting | 28 Jul 2022 | 16 |
 Spain | Not Recruiting | 28 Jul 2022 | 17 |
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 |
|---|---|---|---|---|---|---|
VAY736 | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS USE | 300 | 52 | PRD11298902 |
- | Other | PHF00231MIG | ORAL | 50 | 1 | H02AB |
Placebo to VAY736 150 mg/1 mL Solution for injection in pre-filled syringe | Placebo | N/A | — | — | — | N/A |