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

Prior treatment

• 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 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.
• Preceding treatment with biological DMARDs, including abatacept, anti-TNF or other monoclonal antibodies within 6 months, and rituximab within 12 months from baseline.
• Use of high-dose prednisone, less than 2 weeks before inclusion. Stable low dose (≤10 mg) is allowed.
• 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.
• Any infection requiring hospitalization or treatment with IV anti-infective medications not completed at least 4 weeks prior to signing the ICF.

Other illness

• Presence of any other connective tissue disease.
• 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.
• 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.
• A known history of allergy or reaction to any component of the IP formulation or history of anaphylaxis to any human gamma globuline therapy.
• 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.

Lab values

• 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.
• 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.

Other

• Positive pregnancy test (urinary HCG) at screening or breast-feeding.
• Use of hydroxychloroquine, methotrexate, cyclophosphamide, cyclosporine, azathioprine, MMF and leflunomide less than 3 months ago.
• Use of pilocarpine less than 1 month ago.
• Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site).

• 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.