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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitair Medisch Centrum Groningen

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

9 Oct 2022 → 21 Aug 2025

Decision date (initial)

2024-11-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-516770-29-00

EudraCT number

2022-000609-28

ClinicalTrials.gov

NCT05383677

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To explore the clinical efficacy of anifrolumab in patients with primary Sjögren’s syndrome

Secondary objectives 1

1. To determine the safety of anifrolumab and effects of anifrolumab on clinical, functional, subjective, laboratory and histopathological parameters in patients with primary Sjögren’s syndrome

Conditions and MedDRA coding

Sjogren's disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Written informed consent
2. Female or male aged ≥18 years
3. 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).
4. Fulfilment of 2016 ACR-EULAR classification criteria for pSS, based on previous diagnostic examinations
5. Presence of anti-SSA antibodies
6. 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.
7. 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.
8. Use of reliable method of contraception for participants of reproductive potential.
9. 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.

Exclusion criteria 28

1. Presence of any other connective tissue disease.
2. Positive pregnancy test (urinary HCG) at screening or breast-feeding.
3. History of alcohol or drug abuse.
4. 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.
5. 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.
6. History of chronic or recurrent serious infections. (e.g. chronic pyelonephritis, osteomyelitis or bronchiectasis).
7. Subjects with serious bacterial infections within the last 3 months, unless treated and resolved with antibiotics.
8. Opportunistic infection requiring hospitilization or IV antimicrobial treatment within 3 years of randomization.
9. Any infection requiring hospitalization or treatment with IV anti-infective medications not completed at least 4 weeks prior to signing the ICF.
10. 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).
11. Any clinical cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection that has not completely resolved within 12 weeks prior to signing the ICF.
12. 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.
13. 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.
14. Subjects who are positive for hepatitis B surface antigen, which will be tested during screening.
15. 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.
16. Subjects who have received any live or attenuated vaccines within 8 weeks prior to signing the ICF.
17. Blood transfusion or receipt of blood products within 4 weeks prior to signing the ICF.
18. 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.
19. Preceding treatment with biological DMARDs, including abatacept, anti-TNF or other monoclonal antibodies within 6 months, and rituximab within 12 months from baseline.
20. Use of high-dose prednisone, less than 2 weeks before inclusion. Stable low dose (≤10 mg) is allowed.
21. Use of hydroxychloroquine, methotrexate, cyclophosphamide, cyclosporine, azathioprine, MMF and leflunomide less than 3 months ago.
22. Use of pilocarpine less than 1 month ago.
23. 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.
24. Any other laboratory test results that, in the opinion of the investigator, might place a subject at unacceptable risk for participation in the study.
25. A known history of allergy or reaction to any component of the IP formulation or history of anaphylaxis to any human gamma globuline therapy.
26. Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site).
27. Previous enrolment or randomisation in the present study
28. Participation in another clinical study with an investigational drug during the last 6 months, or local investigational product during the last month.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 endpoints 21

1. 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
2. Total CRESS response at week 12
3. 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)
4. ESSDAI (continuous) (weeks 0, 4, 8, 12, 20, 24)
5. 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)
6. 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)
7. Physician GDA (weeks 0, 8, 12, 20, 24)
8. DAS-28 (weeks 0, 8, 12, 20, 24)
9. Patient GDA (weeks 0, 8, 12, 20, 24)
10. NRS score oral, ocular, and vaginal dryness and mental fatigue (weeks 0, 8, 12, 20, 24)
11. PASS question (weeks 0, 8, 12, 20, 24)
12. EQ-5D measure of health-related quality of life (weeks 0, 8, 12, 20, 24)
13. SF-36 health survey (weeks 0, 12, 24)
14. MFI scale (weeks 0, 12, 24)
15. FSFI in females (weeks 0, 12, 24)
16. Raynaud questionnaire (weeks 0, 12, 24)
17. SWS (weeks 0, 12, 24)
18. SGUS OMERACT score (screening, 12, 24)
19. SGUS OMERACT colour Doppler score (screening, 12, 24)
20. Parotid gland histology at baseline vs. week 24: focus score and area fraction of CD45+ infiltrate
21. Serum levels of anti-SSA/-SSB, complement (C3/C4), lymphocyte count, and presence of cryoglobulinemia (weeks 0, 8, 12, 20, 24)

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitair Medisch Centrum Groningen

Sponsor organisation

Universitair Medisch Centrum Groningen

Address

Hanzeplein 1

City

Groningen

Postcode

9713 GZ

Country

Netherlands

Scientific contact point

Organisation

Universitair Medisch Centrum Groningen

Contact name

H. Bootsma

Public contact point

Organisation

Universitair Medisch Centrum Groningen

Contact name

H. Bootsma

Locations

1 EU/EEA country · 1 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 4 files

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

Application history

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