The purpose of this study is to evaluate the efficacy and safety of treatment with subcutaneous anifrolumab versus placebo in adult participants with systemic sclerosis. The target population for this study includes patients who meet the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification for systemic sclerosis, either limited or diffuse cutaneous subsets, with a disease duration of less than 6 years from first non-Raynaud's phenomenon symptom.

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).

Key Inclusion Criteria:

1. Adult patients from 18 to 70 years of age inclusive
2. Systemic sclerosis according to 2013 ACR/EULAR classification criteria
3. Limited or diffuse cutaneous subsets
4. Systemic sclerosis disease duration within 6 years from first non-Raynaud's phenomenon manifestation at the time of signing the ICF
5. Either HAQ-DI score ≥ 0.25 points or PtGA score ≥ 3 points
6. mRSS > 10 with early disease or rapid progression as defined by the protocol
7. mRSS ≥ 15 with disease duration ≥ 18 months and active disease as defined by the protocol
8. Stable background therapies can be used including hydroxychloroquine, methotrexate, azathioprine, mycophenolate mofetil, mycophenolate sodium, mycophenolic acid, oral glucocorticoids or tacrolimus
9. Women of childbearing potential with a negative urine pregnancy test
10. Uninvolved skin at injection sites

Key Exclusion Criteria:

1. Anticentromere antibody seropositivity on central laboratory
2. Severe cardiopulmonary disease as defined by the protocol
3. History of systemic sclerosis renal crisis within past 12 months (estimated glomerular filtration rate(eGFR) < 45 mL/min/1.73m2)
4. Overlap syndromes, systemic lupus erythematosus with anti-double-stranded deoxyribonucleic acid antibody seropositivity or anti-citrullinated protein antibodies-positive rheumatoid arthritis, or SSc mimics (eg, scleromyxedema, eosinophilic fasciitis)
5. History of, or current, any other inflammatory diseases, eg, inflammatory bowel disease, skin disease, that, in the opinion of the investigator, could interfere with efficacy and safety assessments or require immunomodulatory therapy
6. Evidence of moderately severe concurrent nervous system, renal, endocrine, hepatic (eg, underlying chronic liver disease [Child Pugh A, B, C hepatic impairment]), or gastrointestinal disease (eg, clinical signs of malabsorption or needing parenteral nutrition) not related to SSc, as determined by the investigator
7. Hematopoietic stem cell transplantation or solid organ/limb transplantation
8. Any severe case of Herpes Zoster infection as defined by the protocol
9. Known malignancy or a history of malignancy within 5 years, with exception of excised/cured local basal or squamous cell carcinoma of the skin or carcinoma in situ of the uterine cervix
10. Major surgery within 8 weeks prior to and/or during study enrollment
11. Known active current or history of recurrent infections
12. Any condition that, in the opinion of the investigator or AstraZeneca, would interfere with the efficacy or safety evaluation of the study intervention or put participant at safety risk

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AstraZeneca disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AstraZeneca group of companies sponsored clinical trials are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. The timelines vary per request and can take up to a year upon full submission of the request for analysis, decision, anonymisation and sharing of the requested data or documents. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved, AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Double blind period- masking -everyone will be masked to the treatment allocation during the first 52 weeks Open label period - no masking- beginning at week 52, all participants will receive Anifrolumab for 52 weeks. During the open label period, there is no masking of study treatment, however, the treatment that participants received in the double blind period (first 52 weeks) will remain masked until the end of the study.