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
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- AstraZeneca
- 入组人数
- 314
- 试验地点
- 152
- 主要终点
- Number of participants responding to treatment based on the Revised Composite Response Index in Systemic Sclerosis (CRISS-25)
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 at the time of signing the ICF
- •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, mycophenolate sodium, mycophenolic acid, oral glucocorticoids or tacrolimus
- •Women of childbearing potential with a negative urine pregnancy test
- •Uninvolved skin at injection sites
排除标准
- •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/1.73m2)
- •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
- •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
研究组 & 干预措施
Anifrolumab (subcutaneous weekly injection)
Anifrolumab subcutaneous injection once weekly
干预措施: Anifrolumab (unblinded, open label) (Combination Product)
Anifrolumab (subcutaneous weekly injection)
Anifrolumab subcutaneous injection once weekly
干预措施: Anifrolumab (blinded) (Combination Product)
matched placebo control (subcutaneous weekly injection)
matched placebo control subcutaneous injection once weekly
干预措施: Placebo (blinded) (Drug)
结局指标
主要结局
Number of participants responding to treatment based on the Revised Composite Response Index in Systemic Sclerosis (CRISS-25)
时间窗: at Week 52
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
次要结局
- Change from baseline in chest computed tomography imaging(at Week 52)
- Change from baseline in FVC(at Week 52)
- Incidence of abnormal vital signs(From screening to follow-up (max 126 weeks))
- Number of patients with improvement in individual revised Composite Response Index in Systemic Sclerosis (CRISS-25)(at Week 52)
- Change from baseline in Scleroderma Skin Patient Reported Outcome(at Week 52)
- Incidence of abnormal laboratory parameters(From screening to follow-up (max 126 weeks))
- Prevalence of anti-drug antibodies to Anifrolumab(Weeks 4, 16, 24, 36, 52, 56, 76, and 104 to follow-up (max 116 weeks))
- Incidence of adverse events(From screening to follow-up (max 126 weeks))
- Change from baseline in mRSS(at Week 52)
- Change from baseline in percent predicted FVC(at Week 52)
- Anifrolumab pharmacokinetic parameters in serum(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(Double-blind treatment period: pre-dose (Day 1) Weeks 4, 16, 24, 52; open-label period: weeks 56, 76 and 104)
- Incidence of abnormal physical exam findings(From screening to follow-up (max 126 weeks))
- Incidence of abnormal ECG findings(From screening to end of treatment visit (max 110 weeks))
- Number of subjects with suicidal ideation and behavior and suicide attempts via Columbia-Suicide Severity Rating Scale (C-SSRS)(From screening to follow-up (max 126 weeks))
- Total score of Personal Health Questionnaire Depression Scale-8 (PHQD-8)(From screening to follow-up (max 126 weeks))