Clinical trial NCT05925803: Determine Effectiveness of Anifrolumab In SYstemic Sclerosis (DAISY)
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Systemic Sclerosis
Scleroderma
Keywords: Systemic Sclerosis (SSc)
Scleroderma
Anifrolumab
Limited
Diffuse
Cutaneous
Interstitial lung disease (ILD)
Autoimmune diseases
Immune system diseases
Immunosuppressants
Systemic Sclerosis interstitial lung disease (SSc- ILD)
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2023-06-29
Enrollment: 306
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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 Anifrolumab for 52 weeks (open label treatment period).
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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

Primary outcomes:
measure: Number of participants responding to treatment based on the Revised Composite Response Index in Systemic Sclerosis (CRISS-25)
timeFrame: at Week 52
Secondary outcomes:
measure: Change from baseline in mRSS
timeFrame: at Week 52
measure: Number of patients with improvement in individual revised Composite Response Index in Systemic Sclerosis (CRISS-25)
timeFrame: at Week 52
measure: Change from baseline in chest computed tomography imaging
timeFrame: at Week 52
measure: Change from baseline in Scleroderma Skin Patient Reported Outcome
timeFrame: at Week 52
measure: Change from baseline in FVC
timeFrame: at Week 52
measure: Change from baseline in percent predicted FVC
timeFrame: at Week 52
measure: Anifrolumab pharmacokinetic parameters in serum
timeFrame: Weeks 4, 16, 24, 36, 52, 56, 76, and 104 to follow-up (max 116 weeks)
measure: Anifrolumab pharmacodynamics via changes in type I IFN 21-gene signature generated from blood
timeFrame: Double-blind treatment period: pre-dose (Day 1) Weeks 4, 16, 24, 52; open-label period: weeks 56, 76 and 104
measure: Prevalence of anti-drug antibodies to Anifrolumab
timeFrame: Weeks 4, 16, 24, 36, 52, 56, 76, and 104 to follow-up (max 116 weeks)
measure: Incidence of adverse events
timeFrame: From screening to follow-up (max 126 weeks)
measure: Incidence of abnormal vital signs
timeFrame: From screening to follow-up (max 126 weeks)
measure: Incidence of abnormal laboratory parameters
timeFrame: From screening to follow-up (max 126 weeks)
measure: Incidence of abnormal ECG findings
timeFrame: From screening to end of treatment visit (max 110 weeks)
measure: Incidence of abnormal physical exam findings
timeFrame: From screening to follow-up (max 126 weeks)
measure: Number of subjects with suicidal ideation and behavior and suicide attempts via Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: From screening to follow-up (max 126 weeks)
measure: Total score of Personal Health Questionnaire Depression Scale-8 (PHQD-8)
timeFrame: From screening to follow-up (max 126 weeks)
Other outcomes:
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Study officials:
References: