A Phase 3 Study Investigating the Efficacy, Safety, and Tolerability of Dupilumab Administered to Adult Patients With Severe Atopic Dermatitis Who Are Not Adequately Controlled With or Are Intolerant to Oral Cyclosporine A, or When This Treatment is Not Medically Advisable
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 325
- 试验地点
- 7
- 主要终点
- Percentage of Participants With Eczema Area and Severity Index (EASI) 75 (≥75% Improvement From Baseline) at Week 16
研究概览
简要总结
The main objective of the trial is to evaluate the efficacy of 2 dose regimens of dupilumab compared to placebo, administered with concomitant topical corticosteroids (TCS), in adult patients with severe AD who are not adequately controlled with, or are intolerant to, oral Cyclosporine A (CSA), or when this treatment is currently not medically advisable.
The secondary objective is to assess the safety and tolerability of 2 dose regimens of dupilumab compared to placebo, administered with concomitant TCS, in adult patients with severe AD who are not adequately controlled with, or are intolerant to, oral CSA, or when this treatment is currently not medically advisable.
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)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, 18 years or older
- •Severe, Chronic AD, (according to American Academy of Dermatology Consensus Criteria [Eichenfield 2014]) for whom treatment with potent TCS is indicated
- •EASI score ≥20 at the screening and baseline visits
- •IGA score ≥3 (on the 0 to 4 IGA scale) at the screening and baseline visits
- •≥10% body surface area (BSA) of AD involvement at the screening and baseline visits
- •Documented recent history (within 6 months before the screening visit) of inadequate response to treatment with TCS
- •Have applied a stable dose of topical emollient (moisturizer) twice daily for at least the 7 consecutive days immediately before the baseline visit
- •Documented history by a physician of either:
- •No prior CSA exposure and not currently a candidate for CSA treatment due to:
- •medical contraindications (eg, uncontrolled hypertension on medication), or
- •use of prohibited concomitant medications (eg, statins, digoxin, macrolide, antibiotics, barbiturates, anti-seizure, nonsteroidal anti-inflammatory drugs, diuretics, angiotensin-converting-enzyme inhibitors, St John's Wort, etc), or
- •increased susceptibility to CSA-induced renal damage (elevated creatinine) and liver damage (elevated function tests), or
- •increased risk of serious infections, or
- •hypersensitivity to CSA active substance or excipients OR
- •Previously exposed to CSA, and CSA treatment should not be continued or restarted due to:
- •intolerance and/or unacceptable toxicity (eg, elevated creatinine, elevated liver function tests, uncontrolled hypertension, paraesthesia, headache, nausea, hypertrichosis, etc), or
- •inadequate response to CSA (defined as flare of AD on CSA tapering after a maximum of 6 weeks of high dose [5 mg/kg/day] to maintenance dose [2 to 3 mg/kg/day] or a flare after a minimum of 3 months on maintenance dose). Flare is defined as increase in signs and/or symptoms leading to escalation of therapy, which can be an increase in dose, a switch to a higher-potency class of TCS, or the start of another systemic non-steroidal immunosuppressive drug or
- •requirement for CSA at doses >5 mg/kg/day, or duration beyond those specified in the prescribing information (>1 year)
排除标准
- •Participation in a prior dupilumab clinical study
- •Treatment with an investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer, before the screening visit
- •Hypersensitivity and/or intolerance to corticosteroids or to any other ingredients contained in the TCS product used in the study
- •Systemic CSA, systemic corticosteroids, or phototherapy within 4 weeks prior to screening, and azathioprine (AZA), methotrexate (MTX), mycophenolate mofetil (MMF), or Janus kinase (JAK) inhibitors within 8 weeks prior to screening
- •Treatment with TCI within 1 week before the screening visit
- •Treatment with biologics as follows:
- •Any cell-depleting agents including but not limited to rituximab: within 6 months before the screening visit, or until lymphocyte count returns to normal, whichever is longer
- •Other biologics: within 5 half-lives (if known) or 16 weeks prior to the screening visit, whichever is longer
- •Regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks of the screening visit
- •Treatment with a live (attenuated) vaccine within 12 weeks before the screening
- •Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 2 weeks before the screening or superficial skin infections within 1 week before the screening visit. NOTE: patients may be rescreened no sooner than 2 weeks after infection resolves
- •Known or suspected history of immunosuppression, including history of invasive opportunistic infections (eg, tuberculosis [TB], histoplasmosis, Listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution; or unusually frequent, recurrent, or prolonged infections, per investigator judgment
- •Presence of any 1 of the following TB criteria:
- •A positive tuberculin skin test at the screening visit
- •A positive blood QuantiFERON®-TB or T-Spot test at the screening visit
- •Chest x-ray (posterior-anterior and lateral views) at screening or within 3 months before the screening visit (radiology report must be available) with results consistent with prior TB infection (including but not limited to apical scarring, apical fibrosis, or multiple calcified granuloma). This does not include non-caseating granulomata.
- •NOTE: Any of these 3 TB tests will be performed on a country-by-country basis according to local guidelines only if required by regulatory authorities or ethics boards.
- •History of human immunodeficiency virus (HIV) infection or positive HIV serology at screening
- •Positive hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBc Ab), or hepatitis C antibody (HCV Ab) at the screening visit
研究组 & 干预措施
Placebo QW + TCS
Participants received one subcutaneous (SC) injection of dupilumab matching placebo once per week (QW) (following two SC injections on day 1) from Week 1 to Week 15. All participants were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, participants could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Participants who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).
干预措施: Matching Placebo (Drug)
Dupilumab 300 mg Q2W + TCS
Participants received one subcutaneous (SC) injection of dupilumab 300 mg every 2 weeks (Q2W) from Week 1 to Week 15 (following a SC loading dose of 600 mg on day 1). During weeks in which dupilumab was not administered, participants received matching placebo. All participants were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, participants could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Participants who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).
干预措施: Dupilumab (Drug)
Dupilumab 300 mg QW + TCS
Participants received one subcutaneous (SC) injection of dupilumab 300 mg once per week (QW) (following an SC loading dose of 600 mg on day 1) from Week 1 to Week 15. All participants were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, participants could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Participants who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).
干预措施: Dupilumab (Drug)
结局指标
主要结局
Percentage of Participants With Eczema Area and Severity Index (EASI) 75 (≥75% Improvement From Baseline) at Week 16
时间窗: Baseline, Week 16
The EASI score is used to measure the severity and extent of atopic dermatitis (AD) and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. EASI-75 responders were the participants who achieved ≥75% overall improvement in EASI score from baseline to Week 16. The analysis population for efficacy analyses is the Full Analysis Set (FAS) which included all randomized participants. Efficacy analyses were based on the treatment allocated (as randomized).
次要结局
- Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Score at Week 16(Baseline, Week 16)
- Change From Baseline in Percent Body Surface Area (BSA) Involvement With Atopic Dermatitis (AD) at Week 16(Baseline, Week 16)
- Percentage of Participants Achieving SCORAD 50 (≥50% Improvement From Baseline) at Week 16(Baseline, Week 16)
- Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score at Week 16(Baseline, Week 16)
- Change From Baseline in Mean Weekly Dose of Topical Corticosteroid (TCS) Use During Treatment Period(Baseline to week 16)
- Percentage of Participants With Skin Infection Treatment Emergent Adverse Events (TEAEs) (Excluding Herpetic Infections) From Baseline Through Treatment Period(Baseline to Week 16)
- Percentage of Participants With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus NRS From Baseline to Week 16(Baseline to Week 16)
- Change From Baseline in the Patient Oriented Eczema Measure (POEM) at Week 16(Baseline, Week 16)
- Percentage of Participants With Eczema Area and Severity Index (EASI) Score (≥75% Improvement From Baseline) at Week 16 for Participants With Prior CSA Use(Baseline, Week 16)
- Percentage of Participants With Investigator Global Assessment (IGA) 0 or 1 (on the 0 to 4 IGA Scale) and a Reduction From Baseline of ≥2 Points at Week 16(Baseline, Week 16)
- Change From Baseline in the Dermatology Life Quality Index (DLQI) at Week 16(Baseline, Week 16)
- Change From Baseline in Total Hospital Anxiety and Depression Scale (HADS) Score at Week 16(Baseline, Week 16)
- Percent Change From Baseline in Weekly Average of Peak Pruritus Numerical Rating Scale (NRS) at Week 16(Baseline, Week 16)
- Percent Change From Baseline in the Total Global Individual Signs Score (GISS) at Week 16 (Erythema, Infiltration/ Papulation, Excoriations, Lichenification)(Baseline, Week 16)
- Percentage of Participants Having at Least One Treatment-Emergent Adverse Event (TEAE) Leading to Treatment Discontinuation Through Treatment Period(Baseline to Week 16)
- Percent Change From Baseline in Weekly Average of Peak Pruritus Numerical Rating Scale (NRS) Score at Week 2(Baseline, Week 2)
- Percentage of Participants Having at Least One Serious Treatment Emergent Adverse Event (TEAE) Through Treatment Period(Baseline to Week 16)
- Percentage of Participants With Treatment-Emergent Adverse Events Through Treatment Period(Baseline to Week 16)