Determine Effectiveness of Anifrolumab In SYstemic Sclerosis (DAISY)

This is a multicenter, randomized, double-blind, placebo-controlled, Phase III study to evaluate the efficacy and safety of anifrolumab in the treatment of adult participants with Systemic Sclerosis (SSc) who may be taking one or a combination of protocol-specified standard therapies. The use of one of the following standard immunosuppressant therapies is permitted at a stable dose, but not mandated: hydroxychloroquine, mycophenolate mofetil (MMF), mycophenolic acid or mycophenolate sodium (MPA/MPS), methotrexate, azathioprine, tacrolimus, and oral glucocorticoids. MMF or MPA/MPS, azathioprine, and methotrexate may be used in combination with hydroxychloroquine and/or low-dose oral glucocorticoids \[≤ 10 mg/day\].

Approximately 306 eligible participants will be randomized in a 1:1 ratio to receive either anifrolumab (or matching placebo) given subcutaneously once weekly for 52 weeks. The study will be stratified by the following factors:

* Interstitial lung disease (ILD) (yes, no) at Week 0 (Day1);

* MMF or MPA/MPS use (yes ,no) at Week 0 (Day 1); and

* Disease duration, defined as the time from the first non-Raynaud's symptom attributable to SSc (\<18 months, ≥ 18 months) at Week 0 (Day 1)

Study treatment will be administered subcutaneously via an accessorized prefilled syringe by study staff or by the participant or carer, either in the clinic or at home, with most doses being administered at home. The study consists of 4 periods: a 6-week screening period, a 52-week, double-blind, placebo-controlled period, a 52-week open-label active treatment period, and a 12-week safety follow-up period. There are a total of 16 study visits with most visits in the treatment period occurring every 8 to 12 weeks. The periods are described below:

* Screening Period: This may involve one or more visits to the study site.

* Double Blind Treatment Period: Treatment Period when participants will receive once weekly injections of anifrolumab or matching placebo. Participation will involve in-clinic study visits at Weeks 0 (Day 1), 1, 4, 8\*, 16, 24, 36, 48 and 52. \*The visit at Week 8 may be either by telephone or in person.

* Open Label Treatment Period: At Week 52, all participants will be given anifrolumab (subcutaneous) once weekly for 52 weeks (last dose at Week 103). Participation will involve in-clinic study visits at Weeks 52, 53\*, 56, 64, 76. 88 and 104. \*The visit at Week 53 may be either by telephone or in person.

* Safety Follow-up Period: All participants will return to the clinic for a 12-week post treatment visit. This will occur post Double Blind Treatment Period (Week 52 or Double Blind Period early discontinuation) or post Open Label Treatment Period (Week 104 or Open Label Period early discontinuation).

Primary Outcome Measures

1. Number of participants responding to treatment based on the Revised Composite Response Index in Systemic Sclerosis (CRISS-25)
   Number of participants meeting all the criteria: * Improvement in at least 2 components (&ge;5% increase for percent predicted Forced Vital Capacity (FVC) and/or&ge;25% decrease for Modified Rodnan Skin Score (mRSS), Health Assessment Questionnaire Disability Index (HAQ-DI), Patient Global Assessment (PtGA), Clinician Global Assessment (CGA) * Worsening in no more than one component (&ge;5% decrease percent predicted FVC and/or&ge;25% increase for mRSS, HAQ-DI, PtGA, CGA) * No significant SSc-related event as defined by: New scleroderma renal crisis New decline in percent predicted FVC&ge;15% in established interstitial lung disease or new percent predicted FVC below 80% predicted New onset of left ventricular failure requiring treatment New onset of pulmonary arterial hypertension requiring treatment Gastrointestinal dysmotility requiring enteral or parenteral nutrition Digital ischemia with gangrene, amputation, or hospitalization requiring treatment -Otherwise, a participant is a non-responder

Secondary Outcome Measures

1. Change from baseline in mRSS
   Change from baseline in mRSS score. The mRSS scoring ranges from 0 (normal) to 51 (severe).
2. Number of patients with improvement in individual revised Composite Response Index in Systemic Sclerosis (CRISS-25)
   Number of participants who have improvements in the following improvement components, evaluated separately: * &ge; 5% increase in percent predicted Forced Vital Capacity (FVC) * &ge; 25% decrease in mRSS * &ge; 25% decrease in HAQ-DI * &ge;25% decrease in PtGA * &ge;25% decrease in CGA
3. Change from baseline in chest computed tomography imaging
   Change from baseline in quantitative interstitial lung disease score
4. Change from baseline in Scleroderma Skin Patient Reported Outcome
   Change from baseline in the Scleroderma Skin Patient Reported Outcome scores
5. Change from baseline in FVC
   1. Change from baseline in FVC (ml) in patients with interstitial lung disease 2. Change from baseline in FVC (ml) in all patients
6. Change from baseline in percent predicted FVC
   1. Change from baseline in percent predicted FVC in patients with interstitial lung disease 2. Change from baseline in percent predicted FVC in all patient
7. Anifrolumab pharmacokinetic parameters in serum
   Anifrolumab serum concentrations will be summarised using descriptive statistics at each visit. Due to sparse pharmacokinetic sampling, the pharmacokinetic assessment will be primarily based on observed serum trough concentrations (Ctrough)
8. Anifrolumab pharmacodynamics via changes in type I IFN 21-gene signature generated from blood
   Type I Interferon inducible gene signature will be assessed by a 21-gene assay in whole blood. The suppression of the type I IFN 21-gene signature will be showed as a percent of baseline through study completion, during both the double-blind treatment and open label periods.
9. Prevalence of anti-drug antibodies to Anifrolumab
   Anti-drug antibodies and titer determination in anti-drug antibody positive participants. The presence of neutralizing anti-drug antibodies will also be tested in all anti-drug positive samples.
10. Incidence of adverse events
    Adverse events (non-serious, serious, and adverse event of special interest (AESI)) are assessed as variables of safety and tolerability of anifrolumab. The AESIs are non-opportunistic serious infections, opportunistic infections, malignancy, herpes zoster, Tuberculosis (TB) (including latent TB), injection site reactions, and major adverse cardiac events.
11. Incidence of abnormal vital signs
    Change from baseline of pulse rate, blood pressure, respiration rate, and body temperature will be assessed by visit and treatment group including participants with treatment-emergent changes.
12. Incidence of abnormal laboratory parameters
    Changes from baseline in haematology, clinical chemistry and lipid variables will be assessed by visit and treatment including participants with treatment-emergent changes.
13. Incidence of abnormal ECG findings
    Observed values of heart rate, QRS duration, PR interval, RR interval and QT interval will be summarised by visit and treatment group including participants with clinically significant abnormal results.
14. Incidence of abnormal physical exam findings
    Changes from baseline in weight (kilograms) will be assessed by visit and treatment and medically significant changes from the screening physical examination will be recorded as adverse events.
15. Number of subjects with suicidal ideation and behavior and suicide attempts via Columbia-Suicide Severity Rating Scale (C-SSRS)
    The C-SSRS is used to assess suicidal ideation, behavior, and suicide on a graded scale from 1 to 5. 1 indicates as low suicidal and 5 as high suicidal behavior.
16. Total score of Personal Health Questionnaire Depression Scale-8 (PHQD-8)
    PHQ-8 is an 8-item self-report scale, all items are rated on a score of 0-3, for a total range of 0-24. PHQD-8 assesses symptoms of depression over the previous 2 weeks. Higher scores indicate more depressive symptoms.