Placebo response in phase 2 and 3 trials of systemic and biological therapies for atopic dermatitis—a systematic review and meta‐analysis

Andreasen, Thomas Holger; Christensen, Maria O.; Halling, Anne‐Sofie; Egeberg, Alexander; Thyssen, Jacob P.

doi:10.1111/jdv.16163

Cited by 11 publications

(15 citation statements)

References 42 publications

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“…In all of the AD studies the daily use of emollients was a requirement and in six studies the use of topical steroids was dictated. At week 12, the pooled proportion of placebo-treated AD patients that obtained various benchmarks of therapy success was significantly higher than the pooled proportion of placebo-treated psoriasis patients reaching comparable therapy goals [136]. However, placebo rates in clinical trials in general do not allow for dissociating between "true placebo responses" (induced by positive expectation, doctor-patient communication, or prior experience) and natural fluctuations in the underlying disease unless a "no treatment"/"natural history" arm is included [10,11,15,17].…”

Section: Allergic Reactionsmentioning

confidence: 83%

“…These nocebo-induced itch sensations are associated with the activation of brain regions such as the dorsolateral prefrontal cortex and the striatum in patients with AD when applying saline while patients expected an allergen [99]. Substantial reductions in itch and severity of skin lesions in the placebo arms of clinical trials suggest that placebo responses are important for clinical practice Dermatology 2021;237:857-871 DOI: 10.1159/000513445 in the therapy of AD patients [13,136]. A recent systematic review and meta-analysis investigated the placebo response in clinical trials evaluating the effect of systemic and biological therapies in adult AD patients compared with psoriasis patients.…”

Section: Allergic Reactionsmentioning

confidence: 99%

“…These results emphasize the more fluctuating nature of AD compared to psoriasis. Furthermore, it is conceivable that the expectation of disease reduction when participating in a clinical trial had additional positive effects on AD in itself [136].…”

Section: Allergic Reactionsmentioning

confidence: 99%

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Effects of Patients’ Expectation in Dermatology: Evidence from Experimental and Clinical Placebo Studies and Implications for Dermatologic Practice and Research

Sondermann

Reinboldt-Jockenhöfer

Dissemond

et al. 2021

Dermatology

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Patients’ expectations towards the benefit of a treatment are key determinants of placebo responses and can affect the development and course of medical conditions and the efficacy and tolerability of active medical treatment. The mechanisms mediating these placebo and nocebo effects have been best described in the field of experimental pain and placebo analgesia. However, also in dermatology experimental and clinical studies demonstrate that various skin diseases such as inflammatory dermatoses and allergic reactions can be modulated by patients’ expectations. Dermatologists should consider the important modulatory role of patients’ expectations on the efficacy and tolerability of specific treatments and the key role of verbal information, patients’ prior treatment experiences (associative learning), and the quality and quantity of doctor-patient communication in shaping treatment expectation. As a consequence, techniques aiming at maximizing patients’ expectation effects should be implemented into daily clinical routine. By contrast, in clinical studies expectation effects should be maximally controlled and harmonized to improve the “assay sensitivity” to detect new compounds. Further translational studies, also in dermatoses that have not been investigated yet, are needed to better characterize the mechanisms underlying patients’ expectation and to gain further insights into potential clinical implications of these effects in dermatologic conditions. Therefore, in this review, we provide a brief overview on the concept of expectation effects on treatment outcome in general, summarize what is already known about this topic for dermatologic diseases, and finally present the relevance of this topic in clinical dermatology.

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Section: Allergic Reactionsmentioning

confidence: 83%

Section: Allergic Reactionsmentioning

confidence: 99%

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Effects of Patients’ Expectation in Dermatology: Evidence from Experimental and Clinical Placebo Studies and Implications for Dermatologic Practice and Research

Sondermann

Reinboldt-Jockenhöfer

Dissemond

et al. 2021

Dermatology

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“…Patients with recent (within the past year) or active suicidal ideation or clinically significant depression (based on a total score ≥15 on the Patient Health Questionnaire‐8 items) were ineligible for this trial, although ˜17% of patients met criteria for depression according to baseline HADS. Use of background medicated topical therapy and emollients in this trial increases the applicability of these findings to real‐world settings, but may have increased the placebo effect 32 . The study was not designed to evaluate the superiority of abrocitinib over dupilumab using statistical testing in these PRO endpoints (abrocitinib vs. dupilumab comparisons were performed for the key secondary endpoint [≥4‐point improvement from baseline in PP‐NRS at week 2] and are reported elsewhere) 16 .…”

Section: Discussionmentioning

confidence: 99%

Patient‐reported outcomes from the JADE COMPARE randomized phase 3 study of abrocitinib in adults with moderate‐to‐severe atopic dermatitis

Thyssen

Yosipovitch

Paul³

et al. 2021

Acad Dermatol Venereol

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Background In JADE COMPARE, abrocitinib improved severity of atopic dermatitis (AD) and demonstrated rapid itch relief. Objectives We examined clinically meaningful improvements in selected patient‐reported outcomes (PROs). Methods JADE COMPARE was a multicentre, phase 3 randomized, double‐blind, placebo‐controlled trial. Adults with moderate‐to‐severe AD were randomized 2:2:2:1 to receive 16 weeks of oral abrocitinib 200 or 100 mg once daily, dupilumab 300 mg subcutaneous injection every 2 weeks, or placebo, with background topical therapy. PROs included Dermatology Life Quality Index (DLQI), Patient‐Oriented Eczema Measure (POEM), Night Time Itch Scale (NTIS), Pruritus and Symptoms Assessment for Atopic Dermatitis, Patient Global Assessment, SCORing Atopic Dermatitis, and Hospital Anxiety and Depression Scale. Results At week 16, the proportion of patients achieving POEM scores <3 was 21.3% and 11.7% for 200 and 100 mg abrocitinib, 12.4% for dupilumab, and 4.8% for placebo (vs. abrocitinib, P < 0.0001 and P = 0.04). Proportion achieving ≥4‐point improvement from baseline in NTIS severity was 64.3% and 52.4% for 200 and 100 mg abrocitinib, 54.0% for dupilumab, and 34.4% for placebo (vs. abrocitinib, P < 0.0001 and P = 0.007). Proportion achieving ≥4‐point improvement from baseline in DLQI was 85.0% and 74.4% for 200 and 100 mg abrocitinib, 83.4% for dupilumab, and 59.7% for placebo (vs. abrocitinib, P < 0.0001 and P = 0.005). Conclusion Significant improvements in PROs were demonstrated with both abrocitinib doses vs. placebo, and abrocitinib 200 mg provided numerically greater effects compared with dupilumab in patients with moderate‐to‐severe AD.

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“…Specifically, adolescents with AD are more likely to suffer from psychosocial and mental health problems, 13–15 including sleep disturbance, 12 depression and anxiety disorders, 13–16 lower quality of interpersonal relationships 12,17 and interference with physical activities 12,18 . Given the considerable disease burden of AD, it is important to assess patient‐reported signs/symptoms and QoL when evaluating treatment response in adolescents 11,19,20 …”

Section: Introductionmentioning

confidence: 99%

Impact of oral abrocitinib on signs, symptoms and quality of life among adolescents with moderate‐to‐severe atopic dermatitis: an analysis of patient‐reported outcomes

Cork

McMichael

Teng

et al. 2021

Acad Dermatol Venereol

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Background A significant improvement in clinical signs was demonstrated with abrocitinib relative to placebo in adolescents with moderate-to-severe atopic dermatitis (AD) in three phase 3, randomized, double-blinded, placebo-controlled studies (JADE TEEN [ClinicalTrials.gov, NCT03796676], JADE MONO-1 [NCT03349060] and JADE ).Objectives To evaluate the impact of abrocitinib on patient-reported signs/symptoms, including sleep loss and quality of life among adolescents with moderate-to-severe AD.Methods JADE TEEN, JADE MONO-1 and JADE MONO-2 were conducted in the Asia-Pacific region, Europe and North America and included patients aged 12-17 years with moderate-to-severe AD and inadequate response to ≥ 4 consecutive weeks of topical medication or treatment with systemic therapy for AD. Patients were randomly assigned (1 : 1 : 1, JADE TEEN; 2 : 2 : 1, JADE MONO-1/-2) to receive once-daily oral abrocitinib (200 or 100 mg) or placebo for 12 weeks in combination with topical therapy (JADE TEEN) or as monotherapy (JADE MONO-1/-2). Data from adolescent patients in JADE MONO-1/-2 were pooled for these analyses.Results At week 12, more adolescents treated with abrocitinib (200 or 100 mg) vs. placebo achieved a ≥ 4-point improvement from baseline in the Patient-Oriented Eczema Measure in JADE TEEN (83.9% and 77.0% vs. 60.2%) and JADE MONO-1/-2 (83.0% and 69.4% vs. 43.5%) and a ≥ 6-point improvement from baseline in the Children's Dermatology Life Quality Index in JADE TEEN (73.8% and 67.5% vs. 56.5%) and JADE MONO-1/-2 (70.0% and 57.1% vs.19.0%). Significant improvements in SCORing Atopic Dermatitis Visual Analog Scale for sleep loss scores were demonstrated with abrocitinib vs. placebo at weeks 2-12 in JADE TEEN and JADE MONO-1/-2.Conclusions Patient-reported signs/symptoms, including reduction of sleep loss and quality of life, were substantially improved with abrocitinib monotherapy or combination therapy relative to placebo in adolescents with moderate-to-severe AD.

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Placebo response in phase 2 and 3 trials of systemic and biological therapies for atopic dermatitis—a systematic review and meta‐analysis

Cited by 11 publications

References 42 publications

Effects of Patients’ Expectation in Dermatology: Evidence from Experimental and Clinical Placebo Studies and Implications for Dermatologic Practice and Research

Effects of Patients’ Expectation in Dermatology: Evidence from Experimental and Clinical Placebo Studies and Implications for Dermatologic Practice and Research

Patient‐reported outcomes from the JADE COMPARE randomized phase 3 study of abrocitinib in adults with moderate‐to‐severe atopic dermatitis

Impact of oral abrocitinib on signs, symptoms and quality of life among adolescents with moderate‐to‐severe atopic dermatitis: an analysis of patient‐reported outcomes

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