A Phase 2, Randomized, Double-blind, Placebo-controlled, Efficacy and Safety Study of Daxdilimab Subcutaneous Injection in Adult Participants With Inadequately Controlled Dermatomyositis or Anti-synthetase Inflammatory Myositis.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 12
- 试验地点
- 17
- 主要终点
- Efficacy of daxdilimab compared to placebo as measured by Total Improvement Score (TIS)
研究概览
简要总结
The primary efficacy objective:
To evaluate the effect of daxdilimab compared with placebo in reducing disease activity at Week 24.
The secondary efficacy objectives include:
- To evaluate the effect of daxdilimab compared with placebo in reducing disease activity at Week 24.
- To evaluate the effect of daxdilimab compared with placebo on skin symptoms at Week 24.
- To evaluate the effect of daxdilimab on decreasing the use of corticosteroid at Week 24.
Other secondary objectives include:
- To characterize the pharmacokinetics (PK) and immunogenicity of daxdilimab in participants.
- To evaluate the safety and tolerability of daxdilimab in participants.
详细描述
The study will enroll participants with 2 idiopathic inflammatory myositis populations:
- Population 1 or dermatomyositis (DM): participants with DM with definite or probable myositis according to the American College of Rheumatology/European League Against Rheumatism 2017 (ACR/EULAR 2017) criteria and a DM rash.
- Population 2 or anti-synthetase inflammatory myositis (ASIM): participants with ASIM with definite or probable myositis according to ACR/EULAR 2017 criteria and a positive ASIM associated antibody.
Participants will be randomized by population in a 1:1 ratio and receive investigational product (IP) daxdilimab or placebo by subcutaneous injection.
The estimated total study duration will be up to 36 weeks (up to 60 weeks for those participants who entered the open-label extension prior to amendment 2.)
Acquired from Horizon in 2024.
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult men or women 18 and ≤ 75 years of age at the time of signing the informed consent (ICF).
- •A diagnosis of definite or probable myositis according to American College of Rheumatology/European League Against Rheumatism 2017 (ACR/EULAR 2017) criteria:
- •Population 1: DM
- •Diagnosis of DM with DM rash current or historical, or
- •Population 2: ASIM
- •Anti-histidyl tRNA synthetase-(Anti-Jo-1) antibodies must be positive during screening by central laboratory testing, or
- •One of following antibodies must be positive by historical testing: directed against anti-alanyl- (anti-PL-12), anti-threonyl-(anti PL-7), anti-asparaginyl-(anti-KS), anti-glycyl-(anti-EJ), anti-isoleucyl-(anti-OJ), anti-phenylalanyl-transfer RNA synthetase-(anti-ZO), anti-tyrosil-YRS(HA).
- •Currently active myositis with all the following (a, b, and c) during screening:
- •Manual Muscle Testing (MMT 8) score < 142
- •At least 2 other abnormal core set measures (CSM) from the following list:
- •Patient global disease activity (PtGDA) ≥ 2 cm in a 10 cm visual analog scale (VAS)
- •Physician's Global Disease Activity (PhGDA) ≥ 2 cm in a 10 cm VAS
- •Extramuscular activity ≥ 2cm in a 10 cm VAS
- •At least one muscle enzyme 1.5 times upper limit of normal (ULN)
- •Health assessment questionnaire-disability index (HAQ-DI) ≥ 0.5
- •Global muscle damage score ≤ 5 on a 10 cm VAS on the myositis damage index (MDI).
- •Participants should be on stable standard of care therapy if tolerated; if they are not able to tolerate it or have failed standard of care, medications should have a washed out period.
- •Participants should be willing to taper corticosteroid dose per protocol when stable or improving.
排除标准
- •Any condition that, in the opinion of the investigator or sponsor, would interfere with the evaluation of investigational product (IP) or interpretation of participant safety or study results.
- •Weight > 160 kg (352 pounds) at screening.
- •Breastfeeding or pregnant women or women who intend to become pregnant anytime from signing the ICF through 6 months after receiving the last dose of IP.
- •History of clinically meaningful cardiac disease including unstable angina, myocardial infarction, congestive heart failure within 6 months prior to randomization; arrhythmia requiring active therapy, except for clinically insignificant extra systoles, or minor conduction abnormalities; or presence of clinically meaningful abnormality on electrocardiogram (ECG) if, in the opinion of the Investigator, it would increase the risk of study participation.
- •History of cancer within the past 5 years except cutaneous basal cell or squamous cell carcinoma treated with curative therapy.
- •Any underlying condition that in the opinion of the Investigator significantly predisposes the participant to infection (eg. hepatitis C).
- •Known history of a primary immunodeficiency or an underlying condition, such as known human immunodeficiency virus (HIV) infection, or a positive result for HIV infection per central laboratory.
- •All participants will undergo testing for hepatitis B virus serology as defined in the protocol.
- •Active tuberculosis (TB), or a positive interferon gamma (IFN-γ) release assay (IGRA) test at screening, unless documented history of appropriate treatment for active or latent TB according to local guidelines.
- •Any severe herpes virus family infection (including Epstein-Barr virus, cytomegalovirus [CMV]) at any time prior to randomization.
- •Opportunistic infection requiring hospitalization or parenteral antimicrobial treatment within 2 years prior to randomization.
- •Significant organ system involvement or myositis damage (global muscle damage score > 5 on a 10 cm VAS scale on the MDI) that poses risks in the study or impedes assessments.
- •Diagnosis of immune-mediated necrotizing myopathy (IMNM) [(positive 3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGR), anti-signal recognition particle (anti- SRP), or antibody negative)], inclusion body myositis (IBM) (including positive anti-cytosolic 5'-nucleotidase 1A (anti cN1A), or drug-induced myositis.
- •Current musculoskeletal, joint, or inflammatory disease, including significant joint contractures or calcinosis that in the opinion of the investigator, could interfere with the muscle strength assessments and confound the disease activity assessments.
- •Wheelchair bound participants.
- •Current inflammatory skin disease other than DM or ASIM that, in the opinion of the investigator, could interfere with the inflammatory skin assessments or confound the disease activity assessments.
- •Severe interstitial lung disease where respiratory symptoms limit participant function or progressive pulmonary fibrosis.
- •Myositis in overlap with another connective tissue disease that precludes the accurate assessment of a treatment response (for example, difficulty in assessing muscle strength in a scleroderma patient with associated myositis).
研究组 & 干预措施
Daxdilimab
Daxdilimab will be administered by subcutaneous (SC) injection during the 24-week treatment period followed by an 8-week safety follow up.
Prior to amendment 2 participants could enter an open-label extension period from weeks 24-48. For those participants already in the open-label extension, they will stop dosing and enter the safety follow up.
干预措施: Daxdilimab (Drug)
Placebo
Matching placebo will be administered by SC injection during the 24-week treatment period followed by an 8-week safety follow up.
Prior to amendment 2 participants could enter an open-label extension period from weeks 24-48 and receive daxdilimab. For those participants already in the open-label extension, they will stop dosing and enter the safety follow up.
干预措施: Daxdilimab (Drug)
Placebo
Matching placebo will be administered by SC injection during the 24-week treatment period followed by an 8-week safety follow up.
Prior to amendment 2 participants could enter an open-label extension period from weeks 24-48 and receive daxdilimab. For those participants already in the open-label extension, they will stop dosing and enter the safety follow up.
干预措施: Placebo (Drug)
结局指标
主要结局
Efficacy of daxdilimab compared to placebo as measured by Total Improvement Score (TIS)
时间窗: At Week 24
TIS is a composite endpoint based on improvement in the 6 Disease Activity Core Set Measure (CSM) scores and range from 0 to 100 (2016 European League Against Rheumatism \[EULAR\]/American College of Rheumatology \[ACR\] Myositis Response Criteria) where a higher score is indicative of more improvement
Mean Total Improvement Score (TIS) at Week 24
时间窗: At Week 24
Total improvement score was derived from standardized clinical response criteria which was calculated by sum of improvement scores of 6 core set measures (CSMs) included physician global disease activity (PhGDA), patient global disease activity (PtGDA), manual muscle testing 8 (MMT8) bilateral, health assessment questionnaire-disability index (HAQ-DI), extramuscular global assessment (EGA), and laboratory muscle enzymes (LME). Total improvement score was ranged from 0 to 100, where higher scores indicated greater improvement. The TIS improvement categories are defined as minimal (TIS greater than or equal to \[≥\]20), moderate (TIS ≥40) and major improvement (TIS ≥60). Mean TIS at week 24 was reported in this outcome measure.
次要结局
- Proportion of participants with improvement of TIS ≥ 40 and without deterioration at 2 consecutive visits at 24 weeks(At 24 Weeks)
- Proportion of participants with improvement of TIS ≥ 20 and without deterioration at 2 consecutive visits at 24 weeks(At 24 Weeks)
- Change in the cutaneous dermatomyositis disease area and severity index (CDASI) activity score from Baseline (Day 1) to Week 24(Baseline (Day1) to Week 24)
- Proportion of participants on an oral corticosteroid (OCS) dose ≥ 10 mg of prednisone or equivalent at baseline who achieve a clinically meaningful reduction in the OCS dose at Week 24(Baseline to Week 24)
- Serum concentration of daxdilimab over time(Baseline to Week 56)
- Proportion of the participants with anti-drug antibodies (ADA) positive post-baseline only or boosted their pre-existing ADA during the study period.(Baseline to Week 56)
- Incidence of ADA directed against daxdilimab over time(Baseline to Week 56)
- Titer of ADA to daxdilimab over time(Baseline to Week 56)
- Incidence of treatment emergent adverse events (TEAEs)(Baseline to Week 56)
- Incidence of treatment emergent serious adverse events (TESAEs)(Baseline to Week 56)
- Incidence of treatment emergent adverse events of special interest (TEAESIs)(Baseline to Week 56)
- Percentage of Participants With Improvement of TIS ≥ 40 and Without Deterioration at 2 Consecutive Visits at 24 Weeks(Up to Week 24)
- Percentage of Participants With Improvement of TIS ≥ 20 and Without Deterioration at 2 Consecutive Visits at 24 Weeks(Up to Week 24)
- Change in the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) Activity Score From Baseline (Day 1) to Week 24(From Baseline (Day 1) to Week 24)
- Percentage of Participants With Clinically Meaningful Oral Corticosteroid (OCS) Reduction at Week 24(Up to Week 24)
- Serum Concentration of Daxdilimab During Stage I(Stage I: Day 1 (predose and 2 hours postdose), predose on Weeks 4, 8, 12, 16, and any time on Week 24)
- Serum Concentration of Daxdilimab During Stage II(Stage II: Predose on Week 36 and Week 48)
- Number of Participants Who Developed Anti-drug Antibodies (ADA)(Up to Week 56)
- Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious AEs (TESAEs), and Treatment-emergent AEs of Special Interest (TEAESIs) During Stage I(From first dose of trial intervention in stage I, to first dose of trial intervention in stage II or study end for non-stage II participants; median (min, max) duration was 24 (3, 34) weeks)
- Number of Participants Who Experienced TEAEs, TESAEs, and TEAESIs During Stage II(From first dose of trial intervention in stage II to study end; median (min, max) duration was 24 (18, 33) weeks)