Anifrolumab in Adults With Primary Antiphospholipid Syndrome (AnifAPS Trial)

Inclusion criteria

• Provision of written informed consent (ICF) prior to any study-specific procedures.
• Females/males aged 18 to 70 years at Screening (at the time of ICF signing).
• Weight ≥40.0 kg at Screening.
• Classified as having primary APS as per the 2023 ACR/EULAR APS classification criteria, i.e. fulfilling at least one documented clinical criterion [ie., macrovascular (venous thromboembolism and/or arterial thrombosis), established microvascular (livedoid vasculopathy, aPL nephropathy, pulmonary haemorrhage or myocardial disease), cardiac valve (valve thickening or valve vegetation) and/or haematology (thrombocytopenia)] and at least one laboratory criterion and scoring at least three points in each of the clinical and laboratory domains.

Note: Patients with obstetric manifestations will be excluded from this study.

• For females of childbearing potential only: Negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test at Screening.
• Females of childbearing potential must be willing to use a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) throughout their participation in the study, i.e., from Screening and for up to 20 weeks after the last dose of IP. Examples of highly effective methods of contraception are located in Appendix C, Contraceptive and Barrier Guidance.
• Male patients who are sexually active with a female partner of childbearing potential must be willing to use a condom (with spermicide where commercially available) throughout their participation in the study, i.e., from Screening and for up to 20 weeks after the last dose of IP.
• Male patients must not donate sperm during the course of the study and for up to 20 weeks after the last dose of the IP.
• Meeting all the following TB criteria:

• No history of latent or active TB prior to Screening, except for latent TB with documented completion of appropriate treatment as per local SoC Note: Subjects with no history of latent TB prior to the initial Screening visit, but who are diagnosed with latent TB during the Screening Period, may be considered eligible if appropriate treatment is initiated prior to first administration of IP as per local SoC. Such subjects may be re-screened if necessary to allow for local guidelines on latent TB treatment initiation.
• No signs or symptoms suggestive of active TB from medical history or physical examination
• No recent contact with a person with active TB OR if there has been such contact, referral to a physician specialising in TB to undergo additional evaluation prior to first administration of IP (documented appropriately in source), and, if warranted, receipt of appropriate treatment for latent TB at or prior to first administration of IP as per local SoC.
• Must meet 1 of the following criteria:

(i)Negative QuantiFERON-TB Gold (QFT-G) test result for TB obtained within 4 weeks prior to Week 0 (Day 1) OR (ii)Positive QFT-G test result for TB obtained during the Screening Period for which active TB has been ruled out and appropriate treatment for latent TB has been initiated prior to first administration of IP as per local SoC OR (iii)Indeterminate (confirmed on retest) QFT-G test result for TB obtained during the Screening Period with ongoing QFT-G testing for TB as clinically indicated.

• Chest x-ray [or lung CT*, where available] with no evidence of current active infection (eg, TB) or previous old active TB, malignancy, or clinically significant abnormalities (unless due to APS) obtained during the Screening Period or anytime within 12 weeks prior to signing the ICF.
• Negative SARs-CoV-2 polymerase chain reaction (PCR) or antigen test result as per local policies at Screening.
• Females with an intact cervix must have documentation of a normal Pap smear with no documented malignancy (e.g., cervical intraepithelial neoplasia grade III [CIN III], carcinoma in situ [CIS], or adenocarcinoma in situ [AIS]) within 2 years prior to Week 0 (Day 1) (see Appendix E for guidance on abnormal Pap smear results).

Note: Any abnormal Pap smear result documented within 2 years prior to randomisation must be repeated to confirm patient eligibility. See also Exclusion criterion 23b.

Exclusion criteria

• General exclusion criteria:

• Any condition that, in the opinion of the Investigator, would interfere with the efficacy or safety evaluation of the study intervention or put the participant at safety risk.
• Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site).
• Current participation in another clinical study with an IP.
• Lactating or pregnant females or females who intend to become pregnant anytime from initiation of Screening through the Safety Follow-up Period (12 weeks following last dose of IP).
• Current alcohol, drug or chemical abuse, or a history of such abuse within 12 months prior to Week 0 (Day 1).
• Major surgery within 8 weeks prior to Screening or elective major surgery planned anytime from initiation of Screening through the Safety Follow-up Period (12 weeks following last dose of IP).
• Spontaneous or induced abortion, still or live birth, or pregnancy ≤4 weeks prior to Screening.
• Any of the following laboratory abnormalities at Screening (within 4 weeks prior to Week 0 [Day 1]):

• aspartate aminotransferase (AST) >2.5 x upper limit of normal (ULN)
• alanine aminotransferase (ALT) >2.0 x ULN
• total bilirubin > ULN (unless due to Gilbert's syndrome)
• serum creatinine >2.5 mg/dL (or >181 μmol/L)
• urine protein/creatinine ratio (UACR) >2.0 mg/mg (or >226.30 mg/mmol)
• neutrophil count <1000/μL (or <1.0 x 109/L)
• PLT <25000/ μL (or <25 x 109/L)
• haemoglobin <8 g/dL (or <80 g/L)
• glycosylated haemoglobin (HbA1c) >8% (or >0.08) for diabetic subjects only Note: Abnormal screening laboratory tests may be repeated once on a separate sample before the subject is declared a screen failure.
• Major surgery within 8 weeks prior to Screening or elective major surgery planned anytime from initiation of Screening through the Safety Follow-up Period (12 weeks following last dose of IP).

Exclusion criteria

related to APS and/or other medical conditions/diseases:

• Meeting ACR/EULAR classification criteria for SLE or other systemic autoimmune diseases.
• History or current diagnosis of catastrophic APS within 12 months prior to Screening.
• Any medical or psychiatric condition (including severe or unstable neuropsychiatric APS) that, in the opinion of the Investigator, could jeopardize or would compromise the study participant's ability to participate in this study.
• Current evidence of moderately severe depression as indicated by a score ≥15 in the PHQ-9 questionnaire at Screening.
• Known history of suicidal behaviour in the past 12 months prior to Screening or current evidence of suicidal ideation as indicated by a positive response (i.e., selecting 1: "Several days", 2: "More than half the days" or 3: "Nearly every day") to Question 9 of the PHQ-9 questionnaire irrespective of total score at Screening.

Exclusion criteria

related to infection and malignancy risk factors:

• Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the subject to infection or a positive result for humanimmunodeficiency virus (HIV) antibody or infection confirmed by the local laboratory at Screening.

Note: An HIV test must be performed during the Screening Period, and the result should be available prior to Week 0 (Day 1). Patients refusing to perform HIV testing during the Screening Period will be excluded from study participation.

• Confirmed seropositivity for hepatitis B at Screening, i.e.:

• Positive result for hepatitis B surface antigen (HBsAg), OR
• Positive result for hepatitis B core antibody (HBcAb) AND hepatitis B virus (HBV) DNA detected above the lower limit of quantification (LLQ) by reflex testing by the local laboratory.

Note: Patients who are HBcAb-positive at Screening will be tested every 3 months for HBV DNA. To remain eligible for the study, the patient's HBV DNA levels must remain below the LLQ as per the local laboratory.

• Positive result for hepatitis C antibody at Screening.
• Any severe herpes zoster infection at any time prior to Week 0 (Day 1), 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 herpes zoster, cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection that has not completely resolved within 12 weeks prior to Screening.
• Any history of severe COVID-19 infection or any prior COVID-19 infection with documented long-COVID and/or clinically significant unresolved sequelae within 12 months prior to Week 0 (Day 1) or mild/asymptomatic acute COVID-19 infection (lab confirmed or suspected based on clinical signs/symptoms) within 6 weeks prior to Week 0 (Day 1).
• Any opportunistic infection requiring hospitalisation or treatment with IV antibiotics within 3 years prior to Screening.
• Any of the following:

• Clinically significant chronic infection (e.g. osteomyelitis, bronchiectasis, etc.) within 8 weeks prior to Week 0 (Day 1) (chronic nail infections are allowed)
• Any infection requiring hospitalization or treatment with IV antibiotics not completed at least 4 weeks prior to Week 0 (Day 1)
• Any infection requiring oral antibiotics (including antivirals) within 2 weeks prior to Week 0 (Day 1).
• History of malignancy except for:

• squamous or basal cell carcinoma of the skin with documented success of curative therapy of ≥3 months prior to Week 0 (Day 1), OR
• cervical cancer in situ (CIS) treated with documented success of curative therapy ≥12 months prior to Week 0 (Day 1)

Exclusion criteria

related to prior/concomitant medications:

• Currently receiving direct oral anticoagulants (DOACs).
• Prior treatment with any of the following:

• anifrolumab
• any investigational product (small molecule or biologic agent) within 90 days or 5 half-lives prior to Screening, whichever is greater
• any commercially available biologic agent, including but not limited to B-cell depleting therapies [i.e. rituximab, other anti-CD20, anti-CD22 or anti-CD38 agents], anti-TNF-α agents, belimumab, abatacept or any other, within 90 days or 5 half-lives prior to Screening, whichever is greater
• any commercially available protein kinase inhibitor including but not limited to Janus kinase (JAK) inhibitors or Bruton's tyrosine kinase (BTK) inhibitors within 90 days or 5 half-lives prior to Screening, whichever is greater
• conventional immunomodulators or immunosuppressants (e.g., cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, etc.) or IV immunoglobulin within 90 days prior to Screening
• intraarticular, intramuscular, or intravenous corticosteroids within 30 days prior to Screening.
• any live or attenuated vaccine within 8 weeks prior to Screening.
• Current treatment with oral corticosteroids except for patients with severe thrombocytopenia or pulmonary haemorrhage who have started oral corticosteroids (up to 40 mg/day prednisone or equivalent) within 30 days Week 0 (Day 1).
• Blood transfusion or receipt of blood products within 4 weeks prior to Screening.
• Known history of allergy or reaction to any component of the IP formulation or history of anaphylaxis to any human gamma globulin therapy.

For procedures for withdrawal of incorrectly enrolled subjects, see Section 3.4.