ANISE-II; ANIfrolumab treatment for 24 weeks in patients with primary Sjögren’s syndrome – Efficacy and safety assessment in a randomized, double-blind, placebo-controlled phase-IIa proof-of-concept trial
- Registration Number
- 2024-516770-29-00
- Lead Sponsor
- Universitair Medisch Centrum Groningen
- Brief Summary
To explore the clinical efficacy of anifrolumab in patients with primary Sjögren’s syndrome
- Detailed Description
The aim is to evaluate safety and determine the effects of anifrolumab on essential clinical and biological parameters in patients with primary Sjögren's syndrome (pSS). Although the pathogenesis of pSS has not been fully elucidated, one of the key immune pathways involved is type-I IFN signalling. Since anifrolumab is a fully human, IgG1κ monoclonal antibody to type-I interferon receptor subunit 1, the hypothesis is that inhibition of type-I IFN signalling by anifrolumab may reduce glandular and systemic inflammation and attenuate disease activity in patients with pSS. The study population will consist of patients who fulfil 2016 ACR-EULAR criteria for pSS and have active disease, defined by a EULAR Sjögren Syndrome Disease Activity Index (ESSDAI) score ≥5 and/or an unacceptable patient symptom state (EULAR Sjögren Syndrome Patient Reported Index (ESSPRI) score ≥5. The primary endpoint is the Composite of Relevant Endpoints for Sjögren's Syndrome (CRESS) at week 24.
Recruitment & Eligibility
- Status
- Authorised, recruitment pending
- Sex
- Not specified
- Target Recruitment
- 30
Written informed consent
Female or male aged ≥18 years
Disease duration (time since diagnosis) ≤10 years. In case of pediatric-onset pSS a disease duration of ≤15 years is allowed if there is residual gland function (UWS≥0.01 or SWS≥0.1 ml/min).
Fulfilment of 2016 ACR-EULAR classification criteria for pSS, based on previous diagnostic examinations
Presence of anti-SSA antibodies
ESSDAI≥5 and/or ESSPRI≥5. ESSDAI≥5 implicates a moderate to high systemic disease activity and ESSPRI≥5 implicates that the patient-reported symptom state is unacceptable. At least 50% of patients need to fulfil the ESSDAI≥5 criterion. Inclusion of patients with low ESSDAI (<5) should be discontinued when 15 included patients (50%) have a low ESSDAI.
Willingness to undergo a repeated parotid gland biopsy at baseline and 24 weeks after start treatment. If a recent parotid gland biopsy (within ≤1 year before the baseline visit) is available, and enough material of this parotid gland biopsy is available, this biopsy can be used as baseline sample.
Use of reliable method of contraception for participants of reproductive potential.
Vaccinated against COVID-19 (at least two COVID-19 vaccinations) or previous confirmed COVID-19 infection (from which the patient is recovered) in combination with at least one COVID-19 vaccination or a previous confirmed COVID-19 infection (from which the patients has recovered) in combination with a positive anti-SARS-CoV-2 antibody test.
Presence of any other connective tissue disease.
Subjects with herpes zoster that resolved less than 12 weeks before potential enrollment or any severe case of herpes zoster in a subjects history, including, but not limited to, non-cutaneous herpes (ever), herpes encephalitis (ever), recurrent herpes zoster (defined as 2 episodes within 2 years) or ophthalmic herpes involving the retina (ever).
Any clinical cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection that has not completely resolved within 12 weeks prior to signing the ICF.
Any history of severe COVID-19 infection (e.g. requiring hospitalization, ICU care or assisted ventilation) or any prior COVID-19 infection with unresolved sequelae.
Subjects at risk for TB. Specifically excluded from this study will be subjects with a history of active TB; current clinical, radiographic, or laboratory evidence of active TB, which will be tested during screening; history of latent TB, with the exception of latent TB with documented completion of appropriate treatment.
Subjects who are positive for hepatitis B surface antigen, which will be tested during screening.
Subjects who are positive for hepatitis C antibody if the presence of hepatitis C virus was also shown with polymerase chain reaction or recombinant immunoblot assay, which will be tested during screening.
Subjects who have received any live or attenuated vaccines within 8 weeks prior to signing the ICF.
Blood transfusion or receipt of blood products within 4 weeks prior to signing the ICF.
Underlying cardiac, pulmonary, metabolic, renal, hepatic, gastrointestinal, hematological or neurological conditions, chronic or latent infectious diseases or immune deficiency which places the patient at an unacceptable risk for participation in the study.
Preceding treatment with biological DMARDs, including abatacept, anti-TNF or other monoclonal antibodies within 6 months, and rituximab within 12 months from baseline.
Positive pregnancy test (urinary HCG) at screening or breast-feeding.
Use of high-dose prednisone, less than 2 weeks before inclusion. Stable low dose (≤10 mg) is allowed.
Use of hydroxychloroquine, methotrexate, cyclophosphamide, cyclosporine, azathioprine, MMF and leflunomide less than 3 months ago.
Use of pilocarpine less than 1 month ago.
Lab abnormalities: Serum creatinine > 2.8 mg/dl (250 μmol/l), ASAT or ALAT outside 2.5 x upper normal range of the laboratory, Hb < 9 g/dl (5.6 mmol/l) for males and 8.5 g/dl (5.3 mmol/l) for females, Neutrophil granulocytes less than 0.5 x 109/l, Platelet count less than 50 x 109/l.
Any other laboratory test results that, in the opinion of the investigator, might place a subject at unacceptable risk for participation in the study.
A known history of allergy or reaction to any component of the IP formulation or history of anaphylaxis to any human gamma globuline therapy.
Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site).
Previous enrolment or randomisation in the present study
Participation in another clinical study with an investigational drug during the last 6 months, or local investigational product during the last month.
History of alcohol or drug abuse.
History of malignancy or with a current suspicion for cancer, apart from local MALT lymphoma, squamous or basal cell carcinoma of the skin treated with documented success of curative therapy ≥3 months prior to week 0 or cervical cancer in situ treated with apparent success with curative therapy ≥1 year prior to week 0.
Subjects with evidence (as assessed by the investigator) of active or latent bacterial or viral infections at the time of potential enrollment, including subjects with evidence of HIV which will be tested during screening.
History of chronic or recurrent serious infections. (e.g. chronic pyelonephritis, osteomyelitis or bronchiectasis).
Subjects with serious bacterial infections within the last 3 months, unless treated and resolved with antibiotics.
Opportunistic infection requiring hospitilization or IV antimicrobial treatment within 3 years of randomization.
Any infection requiring hospitalization or treatment with IV anti-infective medications not completed at least 4 weeks prior to signing the ICF.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo 10 patients will receive placebo treatment Anifrolumab Anifrolumab 20 patients will receive anifrolumab treatment
- Primary Outcome Measures
Name Time Method The selected primary outcome measure is the Composite of Relevant Endpoints for Sjögren’s Syndrome (CRESS) response at week 24. The CRESS is a recently developed composite endpoint which consists of five clinically relevant items for pSS: a systemic disease activity, patient-reported symptoms, tear gland, salivary gland and serology item. A CRESS responder is someone who reached response on at least three out of five items. The selected primary outcome measure is the Composite of Relevant Endpoints for Sjögren’s Syndrome (CRESS) response at week 24. The CRESS is a recently developed composite endpoint which consists of five clinically relevant items for pSS: a systemic disease activity, patient-reported symptoms, tear gland, salivary gland and serology item. A CRESS responder is someone who reached response on at least three out of five items.
- Secondary Outcome Measures
Name Time Method Safety (adverse events and tolerability) of anifrolumab by monitoring SAE and AE, treatment discontinuation related to SAE and AE, and lab abnormalities at week 0, 4, 8, 12, 16, 20 and 24 Safety (adverse events and tolerability) of anifrolumab by monitoring SAE and AE, treatment discontinuation related to SAE and AE, and lab abnormalities at week 0, 4, 8, 12, 16, 20 and 24
Total CRESS response at week 12 Total CRESS response at week 12
Individual CRESS items (continuous): ClinESSDAI (weeks 0, 8, 12, 20, 24), ESSPRI (weeks 0, 8, 12, 20, 24), Schirmer's test (weeks 0, 12, 24), OSS (weeks 0, 12, 24), UWS (weeks 0, 12, 24), RF and total IgG concentration in blood (weeks 0, 8, 12, 20, 24) Individual CRESS items (continuous): ClinESSDAI (weeks 0, 8, 12, 20, 24), ESSPRI (weeks 0, 8, 12, 20, 24), Schirmer's test (weeks 0, 12, 24), OSS (weeks 0, 12, 24), UWS (weeks 0, 12, 24), RF and total IgG concentration in blood (weeks 0, 8, 12, 20, 24)
ESSDAI (continuous) (weeks 0, 4, 8, 12, 20, 24) ESSDAI (continuous) (weeks 0, 4, 8, 12, 20, 24)
The (Clin)ESSDAI minimal clinically important improvement (MCII, defined as decrease of ≥3 points) and low disease activity (LDA, defined as score<5) (weeks 8, 12, 20, 24) The (Clin)ESSDAI minimal clinically important improvement (MCII, defined as decrease of ≥3 points) and low disease activity (LDA, defined as score<5) (weeks 8, 12, 20, 24)
The ESSPRI MCII (defined as decrease of ≥1 point or ≥15%) and ESSPRI patient acceptable symptom state (PASS, defined as score <5) (weeks 8, 12, 20, 24) The ESSPRI MCII (defined as decrease of ≥1 point or ≥15%) and ESSPRI patient acceptable symptom state (PASS, defined as score <5) (weeks 8, 12, 20, 24)
Physician GDA (weeks 0, 8, 12, 20, 24) Physician GDA (weeks 0, 8, 12, 20, 24)
DAS-28 (weeks 0, 8, 12, 20, 24) DAS-28 (weeks 0, 8, 12, 20, 24)
Patient GDA (weeks 0, 8, 12, 20, 24) Patient GDA (weeks 0, 8, 12, 20, 24)
NRS score oral, ocular, and vaginal dryness and mental fatigue (weeks 0, 8, 12, 20, 24) NRS score oral, ocular, and vaginal dryness and mental fatigue (weeks 0, 8, 12, 20, 24)
PASS question (weeks 0, 8, 12, 20, 24) PASS question (weeks 0, 8, 12, 20, 24)
EQ-5D measure of health-related quality of life (weeks 0, 8, 12, 20, 24) EQ-5D measure of health-related quality of life (weeks 0, 8, 12, 20, 24)
SF-36 health survey (weeks 0, 12, 24) SF-36 health survey (weeks 0, 12, 24)
MFI scale (weeks 0, 12, 24) MFI scale (weeks 0, 12, 24)
FSFI in females (weeks 0, 12, 24) FSFI in females (weeks 0, 12, 24)
Raynaud questionnaire (weeks 0, 12, 24) Raynaud questionnaire (weeks 0, 12, 24)
SWS (weeks 0, 12, 24) SWS (weeks 0, 12, 24)
SGUS OMERACT score (screening, 12, 24) SGUS OMERACT score (screening, 12, 24)
SGUS OMERACT colour Doppler score (screening, 12, 24) SGUS OMERACT colour Doppler score (screening, 12, 24)
Parotid gland histology at baseline vs. week 24: focus score and area fraction of CD45+ infiltrate Parotid gland histology at baseline vs. week 24: focus score and area fraction of CD45+ infiltrate
Serum levels of anti-SSA/-SSB, complement (C3/C4), lymphocyte count, and presence of cryoglobulinemia (weeks 0, 8, 12, 20, 24) Serum levels of anti-SSA/-SSB, complement (C3/C4), lymphocyte count, and presence of cryoglobulinemia (weeks 0, 8, 12, 20, 24)
Related Research Topics
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Trial Locations
- Locations (1)
Universitair Medisch Centrum Groningen
🇳🇱Groningen, Netherlands
Universitair Medisch Centrum Groningen🇳🇱Groningen, NetherlandsHednrika BootsmaSite contact+31503612645h.bootsma@umcg.nl