Determine Effectiveness of Anifrolumab In SYstemic Sclerosis (DAISY)

Study Overview
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Brief Summary
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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.

Detailed Description
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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), methotrexate, azathioprine, tacrolimus, and oral glucocorticoids. MMF or MPA, 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 120 mg 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 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 120 mg (subcutaneous) once weekly for 52 weeks (last dose at Week 103). Participation will involve in-clinic study visits at Weeks 52, 56, 64, 76. 88 and 104. 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).

Official Title
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A Multicenter, Randomized, Parallel-group, Double-blind,Two-arm Phase III Study to Evaluate the Safety and Efficacy of Anifrolumab Compared With Placebo in Male and Female Participants 18 to 70 Years of Age Inclusive With Systemic Sclerosis

Conditions
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Scleroderma, Systemic Sclerosis

Intervention / Treatment
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* Biological: Anifrolumab (blinded)
* Drug: Placebo (blinded)
* Biological: Anifrolumab (unblinded, open label)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Adult patients from 18 to 70 years of age inclusive Systemic sclerosis according to 2013 ACR/EULAR classification criteria Limited or diffuse cutaneous subsets Systemic sclerosis disease duration within 6 years from first non-Raynaud's phenomenon manifestation Either HAQ-DI score ≥ 0.25 points or PtGA score ≥ 3 points mRSS > 10 with early disease or rapid progression as defined by the protocol mRSS ≥ 15 with disease duration ≥ 18 months and active disease as defined by the protocol Stable background therapies can be used including hydroxychloroquine, methotrexate, azathioprine, mycophenolate mofetil, mycophenolic sodium, mycophenolic acid, oral glucocorticoids or tacrolimus Women of childbearing potential with a negative urine pregnancy test Uninvolved skin at injection sites Key Exclusion Criteria: Anticentromere antibody seropositivity on central laboratory Severe cardiopulmonary disease as defined by the protocol History of systemic sclerosis renal crisis within past 12 months (estimated glomerular filtration rate(eGFR) < 45 mL/min) 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) 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 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 Hematopoietic stem cell transplantation or solid organ/limb transplantation Any severe case of Herpes Zoster infection as defined by the protocol 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 Major surgery within 8 weeks prior to and/or during study enrollment Known active current or history of recurrent infections Severe cardiopulmonary disease 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be randomized in a 1:1 ratio to either anifrolumab or matching placebo for 52 weeks (double blind treatment period). At Week 52, all patients will be treated with 120 mg Anifrolumab for 52 weeks (open label treatment period).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anifrolumab (subcutaneous weekly injection)<br>Anifrolumab subcutaneous injection once weekly | Biological: Anifrolumab (blinded)<br>* Anifrolumab treatment delivered subcutaneously, once weekly for 52 weeks<br>* Other names: Treatment arm (blinded);Biological: Anifrolumab (unblinded, open label)<br>* At Week 52, all patients will receive Anifrolumab subcutaneously once weekly for 52 weeks<br>* Other names: Treatment arm (not blinded);|
| Placebo Comparator: matched placebo control (subcutaneous weekly injection)<br>matched placebo control subcutaneous injection once weekly | Drug: Placebo (blinded)<br>* matched placebo delivered subcutaneously, once weekly for 52 weeks<br>* Other names: Placebo arm (blinded);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 (≥5% increase for percent predicted Forced Vital Capacity (FVC) and/or≥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 (≥5% decrease percent predicted FVC and/or≥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≥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 | at Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in mRSS | Change from baseline in mRSS score. The mRSS scoring ranges from 0 (normal) to 51 (severe). | at Week 52 | 
| 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: ≥ 5% increase in percent predicted Forced Vital Capacity (FVC) ≥ 25% decrease in mRSS ≥ 25% decrease in HAQ-DI ≥25% decrease in PtGA ≥25% decrease in CGA | at Week 52 | 
| Change from baseline in chest computed tomography imaging | Change from baseline in quantitative interstitial lung disease score | at Week 52 | 
| Change from baseline in Scleroderma Skin Patient Reported Outcome | Change from baseline in the Scleroderma Skin Patient Reported Outcome scores | at Week 52 | 
| Change from baseline in FVC | Change from baseline in FVC (ml) in patients with interstitial lung disease Change from baseline in FVC (ml) in all patients | at Week 52 | 
| Change from baseline in percent predicted FVC | Change from baseline in percent predicted FVC in patients with interstitial lung disease Change from baseline in percent predicted FVC in all patient | at Week 52 | 
| 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) | Weeks 4, 16, 24, 36, 52, 56, 76, and 104 to follow-up (max 116 weeks) | 
| 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. | Double-blind treatment period: pre-dose (Day 1) Weeks 4, 16, 24, 52; open-label period: weeks 56, 76 and 104 | 
| 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. | Weeks 4, 16, 24, 36, 52, 56, 76, and 104 to follow-up (max 116 weeks) | 
| 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. | From screening to follow-up (max 126 weeks) | 
| 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. | From screening to follow-up (max 126 weeks) | 
| 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. | From screening to follow-up (max 126 weeks) | 
| 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. | From screening to end of treatment visit (max 110 weeks) | 
| 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. | From screening to follow-up (max 126 weeks) | 
| 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. | From screening to follow-up (max 126 weeks) | 
| 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. | From screening to follow-up (max 126 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Scleroderma, Systemic Sclerosis (SSc), Anifrolumab, Limited, Diffuse, Cutaneous, Interstitial lung disease (ILD), Autoimmune diseases, Immune system diseases, Immunosuppressants, Systemic Sclerosis interstitial lung disease (SSc- ILD)