A Randomised, Double-blind, Placebo-controlled, Phase 3 Trial to Evaluate the Efficacy and Safety of Tralokinumab Monotherapy in Subjects With Moderate to Severe Atopic Dermatitis Who Are Candidates for Systemic Therapy
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- LEO Pharma
- 入组人数
- 794
- 试验地点
- 114
- 主要终点
- Subjects With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 16.
研究概览
简要总结
Primary objective:
To evaluate the efficacy of tralokinumab compared with placebo in treating moderate to severe atopic dermatitis (AD).
Secondary objectives:
To evaluate the efficacy of tralokinumab on severity and extent of AD, itch, and health related quality of life compared with placebo.
Maintenance objective:
To evaluate maintenance of effect with continued tralokinumab dosing up to 52 weeks compared to placebo for subjects achieving clinical response at Week 16.
详细描述
Subjects found eligible following the screening period were randomized 3:1 to initial treatment with tralokinumab 300 mg every 2 weeks (Q2W) or placebo. Randomization was stratified by region (Asia, Australia, Europe, and North America) and disease severity (Investigator's Global Assessment [IGA] 3 or 4).
Subjects achieving a clinical response at Week 16 (defined as IGA of 0 or 1 on a 5-point scale ranging from 0 [clear] to 4 [severe], or at least 75% reduction in Eczema Area and Severity Index [EASI] score from baseline [EASI75]) continued into maintenance treatment that continued until Week 52.
Subjects randomized to tralokinumab in the initial treatment period and who achieved a clinical response at Week 16 (defined by IGA 0 or 1, or EASI75) were re-randomized 2:2:1 to one of the following Q2W maintenance regimens stratified by region (Asia, Australia, Europe, and North America) and IGA response at Week 16 (IGA 0/1 or IGA >1):
- Tralokinumab 300 mg Q2W.
- Tralokinumab 300 mg Q4W (alternating dose administrations tralokinumab 300 mg and placebo).
- Placebo.
Subjects randomized to placebo in the initial treatment period who achieved a clinical response at Week 16 (defined by IGA 0 or 1, or EASI75) continued to receive placebo Q2W in the maintenance treatment period.
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)
盲法说明
Neither the subject nor any of the investigator or LEO staff who are involved in the treatment or clinical evaluation and monitoring of the subjects will be aware of the treatment received. The packaging and labelling of the investigational medicinal products (IMPs) will contain no evidence of their identity.
Since tralokinumab and placebo are visually distinct and not matched for viscosity, IMP will be handled and administered by a qualified, unblinded healthcare professional (HCP) at the site who will not be involved in the management of trial subjects and who will not perform any of the assessments.
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
- •Written informed consent and any locally required authorisation obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
- •Age 18 and above.
- •Diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria for AD (33; Appendix 5).
- •Diagnosis of AD for ≥1 year.
- •Subjects who have a recent history (within 1 year before the screening visit) of inadequate response to treatment with topical medications or for whom topical treatments are otherwise medically inadvisable (e.g., due to important side effects or safety risks).
- •Inadequate response is defined as failure to achieve and maintain remission or a low disease activity state (comparable to IGA 0=clear to 2=mild) despite treatment with a daily regimen of TCS of medium to higher potency (±TCI as appropriate), applied for at least 28 days or for the maximum duration recommended by the product prescribing information (e.g., 14 days for super potent TCS), whichever is shorter.
- •Subjects with documented systemic treatment for AD in the past year are also considered as inadequate responders to topical treatments and are potentially eligible for treatment with tralokinumab after appropriate washout.
- •Important side effects or safety risks are those that outweigh the potential treatment benefits and include intolerance to treatment, hypersensitivity reactions, significant skin atrophy, and systemic effects, as assessed by the investigator or by the subject's treating physician.
- •AD involvement of ≥10% body surface area at screening and baseline (visit 3).
- •An EASI score of ≥12 at screening and 16 at baseline.
- •An IGA score of ≥3 at screening and at baseline.
- •A Worst Daily Pruritus numeric rating scale (NRS) average score of ≥4 during the week prior to baseline.
- •Worst Daily Pruritus NRS at baseline will be calculated from daily assessments of worst itch severity (Worst Daily Pruritus NRS) during the 7 days immediately preceding randomisation (Day 6 to 0). A minimum of 4 Worst Daily Pruritus NRS scores out of the 7 days is required to calculate the baseline average score. For subjects who do not have at least 4 scores reported during the 7 days immediately preceding the planned randomisation date, randomisation should be postponed until this requirement is met, but without exceeding the 6 weeks maximum duration for screening.
- •Subjects must have applied a stable dose of emollient twice daily (or more, as needed) for at least 14 days before randomisation (refer to exclusion criterion no. 8 for limitations regarding emollients).
- •Women of childbearing potential must use a highly effective* form of birth control (confirmed by the investigator) throughout the trial and at least for 16 weeks (5 half lives) after last administration of IMP.
- •A highly effective method of birth control is defined as one which results in a low failure rate (less than 1% per year) such as bilateral tubal occlusion, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), sexual abstinence (when this is in line with the preferred and usual life style of the subject), vasectomised partner (given that the subject is monogamous). The subjects must have used the contraceptive method continuously for at least 1 month prior to the pregnancy test at baseline. A female is defined as not being of child-bearing potential if she is postmenopausal (at least 12 months with no menses without an alternative medical cause prior to screening), or surgically sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy).
排除标准
- •Concurrent enrolment in another clinical trial where the subject is receiving an IMP.
- •Previous randomisation in tralokinumab trials.
- •Active dermatologic conditions that may confound the diagnosis of AD or would interfere with assessment of treatment, such as scabies, cutaneous lymphoma, or psoriasis.
- •Known active allergic or irritant contact dermatitis that is likely to interfere with the assessment of severity of AD.
- •Use of tanning beds or phototherapy (narrow band ultraviolet B [NBUVB], ultraviolet B [UVB], ultraviolet A1 [UVA1], psoralen + ultraviolet A [PUVA]), within 6 weeks prior to randomisation.
- •Treatment with the following medications within 4 weeks prior to randomisation:
- •Systemic immunosuppressive/immunomodulating drugs (e.g. methotrexate, cyclosporine, azathioprine, mycophenolate mofetil, Janus kinase inhibitors etc.).
- •Systemic corticosteroid use (excludes topical, inhaled, or intranasal delivery).
- •Three or more bleach baths during any week within the 4 weeks.
- •Treatment with the following medications within 2 weeks prior to randomisation
- •Topical PDE 4 inhibitor.
- •Initiation of treatment of AD with prescription emollients or emollients containing additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products during the screening period (subjects may continue using stable doses of such emollients if initiated before the screening visit).
- •Receipt of live attenuated vaccines 30 days prior to the date of randomisation and during the trial including the safety follow-up period.
- •Receipt of inactive/killed vaccinations (e.g. inactive influenza) are allowed, provided they are not administered within 5 days before/after any study visit.
- •Receipt of any marketed (i.e. immunoglobulin, anti-IgE) or investigational biologic agent, including dupilumab:
- •Any cell-depleting agents including but not limited to rituximab: within 6 months prior to randomisation, or until lymphocyte count returns to normal, whichever is longer.
- •Other biologics: within 3 months or 5 half-lives, whichever is longer, prior to randomisation.
- •Receipt of any investigational non-biologic agent within 5 half-lives prior to randomisation.
- •Receipt of blood products within 4 weeks prior to screening.
- •Major surgery within 8 weeks prior to screening, or planned in-patient surgery or hospitalisation during the trial period.
- •Known or suspected allergy or reaction to any component of the IMP formulation.
- •History of any active skin infection within 1 week prior to randomisation.
- •History of a clinically significant infection within 4 weeks prior to randomisation which, in the opinion of the investigator or sponsor's medical expert, may compromise the safety of the subject in the trial, interfere with evaluation of the IMP, or reduce the subject's ability to participate in the trial. Clinically significant infections are defined as:
- •a systemic infection.
- •a serious skin infection requiring parenteral (intravenous or intramuscular) antibiotics, antiviral, or antifungal medication.
- •A helminth parasitic infection within 6 months prior to the date informed consent is obtained that has not been treated with, or has failed to respond to, standard of care therapy.
- •History of anaphylaxis following any biologic therapy.
- •History of immune complex disease.
- •History of cancer:
- •Subjects who have had basal cell carcinoma, localised squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the subject is in remission and curative therapy was completed at least 12 months prior to the date informed consent was obtained.
- •Subjects who have had other malignancies are eligible provided that the subject is in remission and curative therapy was completed at least 5 years prior to the date informed consent was obtained.
- •Tuberculosis requiring treatment within the 12 months prior to screening. Evaluation will be according to local guidelines as per local standard of care.
- •History of any known primary immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test at screening, or the subject taking antiretroviral medications as determined by medical history and/or subject's verbal report.
- •History of chronic alcohol or drug abuse within 12 months prior to screening, or any condition associated with poor compliance as judged by the investigator.
- •History of attempted suicide or is at significant risk of suicide (either in the opinion of the investigator or defined as a "yes" to suicidal ideation questions no. 4 or 5 or answering "yes" to suicidal behaviour on the Columbia-Suicide Severity Rating Scale [C-SSRS] Screening version).
- •Any disorder, including but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, immunological, psychiatric, or major physical impairment that is not stable, in the opinion of the investigator, and could:
- •Affect the safety of the subject throughout the trial.
- •Influence the findings of the trial or their interpretations.
- •Impede the subject's ability to complete the entire duration of trial.
- •Any clinically significant abnormal findings in physical examination, vital signs, electrocardiogram (ECG), haematology, clinical chemistry, or urinalysis during the screening period, which in the opinion of the investigator, may put the subject at risk because of his/her participation in the trial, or may influence the results of the trial, or the subject's ability to complete entire duration of the trial.
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.0 times the ULN (upper limit of normal) at screening.
- •Positive hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb) or hepatitis C virus antibody (anti-HCV) serology at screening. Subjects with positive HBsAb may be randomised provided they are hepatitis B vaccinated and have negative HBsAg and HBcAb.
- •Subjects who are not willing to abstain from donating blood and/or plasma from the time of informed consent and for 16 weeks (5 half-lives) after last dose of IMP.
- •Subjects who are legally institutionalised.
- •Pregnant, breastfeeding, or lactating women.
- •Employees of the trial site or any other individuals directly involved with the planning or conduct of the trial, or immediate family members of such individuals.
研究组 & 干预措施
Initial treatment period - Tralokinumab Q2W
Week 0 to Week 16
Two subcutaneous (SC) injections of tralokinumab as a loading dose on Day 0, followed by a SC injection of tralokinumab Q2W regimen for 16 weeks
干预措施: Tralokinumab (Drug)
Initial treatment period - Placebo
Week 0 to Week 16 (Initial treatment period):
Two subcutaneous (SC) injections of placebo as a loading dose on Day 0 followed by a SC injection of placebo Q2W regimen for 16 weeks
干预措施: Placebo (Drug)
Maintenance treatment period - Tralokinumab Q2W
Week 16 to Week 52
Tralokinumab responders from the initial treatment period re-randomised at Week 16 and administered tralokinumab maintenance subcutaneous injection regimen Q2W for 36 weeks
干预措施: Tralokinumab (Drug)
Maintenance treatment period - Tralokinumab Q4W
Week 16 to Week 52
Tralokinumab responders from the initial treatment period re-randomised at Week 16 and administered tralokinumab maintenance subcutaneous injection regimen Q4W for 36 weeks.
Participants in this group receive alternating doses of tralokinumab SC injection and placebo SC injection every 2 weeks
干预措施: Tralokinumab (Drug)
Maintenance treatment period - Tralokinumab Q4W
Week 16 to Week 52
Tralokinumab responders from the initial treatment period re-randomised at Week 16 and administered tralokinumab maintenance subcutaneous injection regimen Q4W for 36 weeks.
Participants in this group receive alternating doses of tralokinumab SC injection and placebo SC injection every 2 weeks
干预措施: Placebo (Drug)
Maintenance treatment period - Placebo
Week 16 to Week 52
Tralokinumab responders from initial treatment period randomised at Week 16 and administered placebo subcutaneous maintenance injection for 36 weeks
干预措施: Placebo (Drug)
Maintenance treatment period - Placebo (tralokinumab naive)
Week 16 to Week 52
Placebo responders from the initial treatment period re-assigned at Week 16 and administered placebo maintenance subcutaneous injection regimen Q2W for 36 weeks
干预措施: Placebo (Drug)
Open-label treatment - Tralokinumab 300 mg Q2W + optional TCS
Week 16 to Week 52
Subjects receiving initial treatment with tralokinumab Q2W or placebo Q2W assigned to open-label treatment at Week 16 and administered tralokinumab subcutaneous (SC) injection + optional TCS* regimen Q2W
OR
Subjects receiving maintenance treatment with tralokinumab Q2W/Q4W or placebo assigned to open-label treatment after Week 16 and administered tralokinumab SC injection + optional TCS regimen Q2W
• TCS = topical corticosteroids
干预措施: Tralokinumab (Drug)
结局指标
主要结局
Subjects With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 16.
时间窗: At Week 16
The IGA is an instrument used in clinical trials to rate the severity of the subject's global AD and is based on a 5-point scale ranging from 0 (clear) to 4 (severe).
Subjects Achieving at Least 75% Reduction in Eczema Area and Severity Index [EASI].
时间窗: At Week 16
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity and extent of AD. The EASI is a composite index with scores ranging from 0 to 72, with higher values indicating more severe and/or more extensive condition.
次要结局
- Change in Scoring Atopic Dermatitis (SCORAD) From Baseline to Week 16.(Week 0 to Week 16)
- Reduction of Worst Daily Pruritus Numeric Rating Scale (Weekly Average) of at Least 4 From Baseline to Week 16.(Week 0 to Week 16)
- Change in Dermatology Life Quality Index (DLQI) Score From Baseline to Week 16.(Week 0 to Week 16)
- Subjects With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 52 Among Subjects With IGA of 0/1 at Week 16(At Week 52)
- Subjects With at Least 75% Reduction in Eczema Area and Severity Index [EASI] at Week 52 Among Subjects With EASI75 at Week 16(At Week 52)
- Safety and Tolerability: Adverse Event (AE) /Serious Adverse Event (SAE) Frequency(Week 0 to Week 16)
- Subjects Achieving at Least 50% Reduction in Eczema Area and Severity Index [EASI] at Week 16(At Week 16)
- Frequency of Anti-drug Antibodies(Week 0 to Week 16)
- Subjects Achieving at Least 90% Reduction in Eczema Area and Severity Index [EASI] at Week 16.(At Week 16)
- Change From Baseline to Week 16 in Eczema Area and Severity Index [EASI] Score(At Week 16)
- Subjects Achieving at Least 75% Reduction in Scoring Atopic Dermatitis (SCORAD) at Week 16.(At Week 16)
- Subjects Achieving at Least 50% Reduction in Scoring Atopic Dermatitis (SCORAD) at Week 16.(At Week 16)
- Change From Baseline to Week 16 in Worst Daily Pruritus NRS (Weekly Average).(Baseline to Week 16)
- Reduction of Worst Daily Pruritus NRS (Weekly Average) ≥3 From Baseline to Week 16.(Baseline to Week 16)
- Reduction From Baseline to Week 16 of Dermatology Life Quality Index (DLQI) of ≥4 Points Among Subjects With Baseline DLQI ≥4.(Baseline to Week 16)