Three-arm study of the clinical efficacy, safety and tolerability of ianalumab (VAY736) in patients with active Sjögren’s syndrome

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

4 Aug 2022 → ongoing

Decision date (initial)

2024-07-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2024-511068-10-00

EudraCT number

2021-005687-22

ClinicalTrials.gov

NCT05349214

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacokinetic, Safety, Others, Efficacy, Pharmacogenetic

To demonstrate superiority of ianalumab over placebo based on change from baseline in ESSDAI score at Week 48

Secondary objectives 13

1. To demonstrate superiority of ianalumab over placebo based on proportion of patients achieving ESSDAI response at Week 48
2. To demonstrate superiority of ianalumab over placebo based on proportion of patients achieving low systemic disease activity defined as ESSDAI score <5 at Week 48
3. Plan B only (EU, China, other non-US Regions and EU reference countries): To demonstrate superiority of ianalumab over placebo based on proportion of patients achieving ESSPRI response at Week 48
4. To demonstrate superiority of ianalumab over placebo based on change from baseline in stimulated whole salivary flow (sSF) rate at Week 48
5. To demonstrate superiority of ianalumab over placebo based on change from baseline in Physician’s Global Assessment (PhGA) at Week 48
6. To demonstrate superiority of ianalumab over placebo based on change from baseline in Patient’s Global Assessment (PaGA) at Week 48
7. To demonstrate superiority of ianalumab over placebo based on change from baseline in Functional Assessment of chronic Illness Therapy-Fatigue (FACIT-F) score at Week 48
8. To evaluate the safety and tolerability of ianalumab
9. To evaluate immunogenicity of ianalumab
10. To evaluate pharmacokinetics (PK) of ianalumab
11. To demonstrate superiority of ianalumab over placebo based (change from baseline in SSSD) at Week 48
12. Plan B only (EU, China, other non-US Regions and EU reference countries): To demonstrate superiority of ianalumab over placebo based on change from baseline in ESSPRI at Week 48
13. To demonstrate superiority of ianalumab over placebo based on proportion of patients achieving Sjögren’s Syndrome Symptom Diary (SSSD) response at Week 48

Conditions and MedDRA coding

Sjögren’s Syndrome

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Signed informed consent must be obtained prior to participation in the study
2. Women and men ≥ 18 years of age
3. Classification of Sjögren's syndrome according to the ACR/EULAR 2016 criteria (Shiboski et al 2017)
4. Time since diagnosis of Sjögren's of ≤ 7.5 years at screening
5. 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
6. Screening ESSDAI score of ≥5 within the following 8 domains: constitutional, lymphadenopathy, glandular, articular, cutaneous, renal, hematological and biologic.
7. Stimulated whole salivary flow (sSF) rate of ≥ 0.05 mL/min at screening
8. Ability to communicate well with the Investigator, understand and agree to comply with the requirements of the study
9. 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
10. 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 Protocol Section 6.2.1
11. Patients taking: • disease-modifying antirheumatic drugs (DMARDs) other than specifically allowed in inclusion criterion #9, 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 23

1. 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.
2. 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
3. Prior treatment with ianalumab
4. 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)
5. 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. (intravenous)/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
6. Use of corticosteroids (predniso(lo)ne or equivalent corticosteroid) at dose >10 mg/day
7. 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).
8. 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.
9. 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 (sucrose, L-histidine hydrochloride/ L-histidine, polysorbate 20).
10. 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.
11. Evidence of active tuberculosis (TB) infection is exclusionary. Patient 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)
12. History of major organ, hematopoietic stem cell or bone marrow transplant.
13. Required regular use of medications known to cause dry mouth/eyes as 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.
14. 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.
15. Receipt of live/attenuated vaccine within a 4-week period prior to randomization.
16. History of primary or secondary immunodeficiency, including a positive human immunodeficiency virus (HIV) (ELISA and Western blot) test result.
17. 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.
18. History of sarcoidosis
19. 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
20. 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
21. 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).
22. 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
23. United States (and other countries, if locally required): Sexually active males, unless they agree to use barrier protection during intercourse with a woman of child-bearing 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary efficacy endpoint is change from baseline in ESSDAI score at week 48

Secondary endpoints 9

1. ESSDAI response at Week 48
2. Low systemic disease activity (ESSDAI < 5)
3. ESSPRI response at Week 48
4. Changes from baseline in sSF at Week 48
5. Changes from baseline in PhGA at Week 48
6. Changes from baseline in PaGA at Week 48
7. Changes from baseline in FACIT-F at Week 48
8. SSSD response at Week 48
9. Change from baseline in ESSPRI score at Week 48

Investigational products

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

Test 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 19

Locations

11 EU/EEA countries · 51 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 118 files

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

Application history

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