Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Thaçi D, Simpson EL, Beck LA, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet 2015; published online Oct 8. http://dx.doi.org/10.1016/ S0140-6736(15)00388-8.
Transcript
Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.
Supplement to: Thaçi D, Simpson EL, Beck LA, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet 2015; published online Oct 8. http://dx.doi.org/10.1016/S0140-6736(15)00388-8.
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Supplementary Appendix Contents Page number Primary investigators 2 Inclusion and exclusion criteria 5 Prohibited concomitant medications 6
Patient narratives of serious treatment-emergent adverse events (TEAEs) of infection and respiratory disorder
Medical Center Tokyo, Tokyo; Makoto Kawashima, Tokyo Women’s Medical University, Tokyo
Poland:
Marcin Ambroziak, Klinika Ambroziak Estederm, Warszawa; Dorota Bystrzanowska, High-Med. Przychodnia
Specjalistyczna, Warszawa; Maria Czubek, Pomorskie Centrum Traumatologii im M Kopernika, Dermatologia,
Gdansk; Ingrid Dadej-Michalska, IMD Sp. z o.o. MEDIC-R Sp. k., Poznan; Maria Juszkiewicz-Borowiec,
Maxxmed, Centrum Zdrowia i Urody, Lublin; Andrzej Kaszuba, DERMED, Łódź; Roman Nowicki, Medical
University of Gdansk, Department of Dermatology, Venereology and Allergology, Gdansk; Jacek Szepietowski,
Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroclawiu, Wroclawiu; Anna Zerdzinska, Pro Familia Altera
sp. z o.o., Research Centre, Katowice
United States:
Alabama: Fred Bodie, Coastal Clinical Research, Inc, Dermatology, Mobile; Boni Elewski, University of
Alabama at Birmingham, Dermatology, Birmingham; Weily Soong, Clinical Research Center of
Alabama/Alabama Allergy & Asthma Center, Birmingham
Arizona: Norman Bystol, Radiant Research, Inc., Tucson
California: Jeffrey Crowley, Bakersfield Dermatology and Skin Cancer Medical Group, Bakersfield; Lawrence
Eichenfield, Rady Children’s Hospital, Pediatric Dermatology, San Diego; Tissa Hata, UCSD,
Medicine/Dermatology, San Diego; Howard Sofen, Dermatology Research Associates, Los Angeles; Paul
Yamauchi, Clinical Science Institute, Santa Monica
Florida: Michael Bernhardt, Jacksonville Center for Clinical Research, Jacksonville; Douglas Robins, Leavitt
Medical Associates of Florida d/b/a Ameriderm Research, Jacksonville; James Solomon, Leavitt Medical
Associates of Florida d/b/a Amiderm Research, Ormond Beach
Illinois: Sarah Kasprowicz, NorthShore University Health System,Dermatology, Skokie
Louisiana: Erin Boh, Tulane University Health Sciences Center, New Orleans
Massachusetts: David Rosmarin, Tufts Medical Center, Boston; Alexandra Kimball, Massachusetts General
Hospital, Boston; Jeffrey Sobell, Ora Clinical, Andover
Michigan: George Murakawa, Somerset Skin Centre, Troy
Missouri: Maria Hurley, Saint Louis University, Department of Dermatology, Saint Louis
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New York: Lisa Beck, University of Rochester Medical Center, Dermatology, Rochester; Neil Sadick, Sadick
Dermatology, Dermatology, New York; John Tu, Skin Search of Rochester, Inc., Rochester
North Carolina: Gil Yosipovitch, Wake Forest University Health Sciences, Dermatology Clinical Studies,
Winston-Salem
Oregon: Andrew Blauvelt, Oregon Medical Research Center, PC, Portland; Eric Simpson, Oregon Health &
Science University, Department of Dermatology, Portland
Pennsylvania: Laura Ferris, UPMC, Department of Dermatology, Pittsburgh
Rhode Island: Ellen Frankel, Clinical Partners, LLC., Johnston
South Carolina: John Humeniuk, Radiant Research, Inc., Greer
Tennessee: Michael Gold, Tennessee Clinical Research Center, Nashville
Texas: William Jennings, Radiant Research, Inc., San Antonio; Mark Lee, Progressive Clinical Research, PA,
San Antonio; Stephen Tyring, Center for Clinical Studies, Dermatology, Houston
Washington: Peter Jenkin, Dermatology Associates, Seattle
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Inclusion and exclusion criteria Additional inclusion criteria: Inadequate response to topical medications, defined as failure to achieve and maintain remission or low
disease activity state (Investigator’s Global Assessment score = 0 [clear] to 2 [mild]) despite treatment with topical corticosteroids of medium to high potency applied daily for ≥28 days or for the maximum duration recommended for the treatment, whichever is shorter
Exclusion criteria: Prior treatment with dupilumab Treatment with any of the following before baseline:
– Investigational drug within 8 weeks or 5 half-lives, whichever is longer – Systemic corticosteroids, immunosuppressive/immunomodulatory drugs, or phototherapy for atopic
dermatitis (AD) within 4 weeks – Topical corticosteroids, tacrolimus, and/or pimecrolimus within 1 week – Regular use (>2 visits/week) of a tanning booth/parlour within 4 weeks – Biologics within 16 weeks to 5 years, depending on the type of biologic:
Cell-depleting agents including rituximab: within 6 months, or until lymphocyte and CD19+ lymphocyte count returns to normal, whichever is longer
Infliximab, adalimumab, golimumab, certolizumab pegol, abatacept, etanercept, anakinra: within 16 weeks, or within 5 years for dermatologic indications
Other biologics: within 5 half-lives (if known) or 16 weeks, whichever is longer During the screening period, initiation of treatment of AD with prescription moisturisers or moisturisers
containing additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products Infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or
antifungals within 4 weeks before screening or superficial skin infections within 1 week before screening Known or suspected immunosuppression Planned or anticipated use of any prohibited medications and procedures Treatment with a live (attenuated) vaccine within 12 weeks Presence of skin comorbidities that may interfere with study assessments History of any of the following:
– HIV or HIV seropositivity at screening – Positive or indeterminate hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody
at screening – Elevated transaminases (alanine transaminase or aspartate transaminase) ≥3 times the upper limit of
normal at screening (patients may be retested once, and would be eligible to participate in the study if the retest was normal)
– Clinical endoparasitosis (other than treated vaginal trichomoniasis) within 12 months before baseline – Malignancy within 5 years before baseline (except completely treated in situ cervical carcinoma or
non-metastatic squamous or basal cell carcinoma of the skin) – Non-malignant lymphoproliferative disorders – Alcohol or drug abuse within 2 years before screening
High risk of parasitic infection, unless medical assessments have ruled out the possibility of parasitic infection
Women who were pregnant or breast-feeding or planning to become pregnant or breast feed Women of reproductive potential unwilling to use birth control Presence of severe concomitant illness that would, in the investigator’s judgement, adversely affect the
patient’s participation in the study Any other medical or psychological condition that would represent an unreasonable risk to the patient,
make the patient’s participation unreliable, or interfere with study assessments
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Prohibited concomitant medications The following treatments were prohibited from baseline through Week 16: Medications used for the treatment of atopic dermatitis (AD), including topical calcineurin inhibitors, topical corticosteroids, prescription moisturisers or moisturisers containing additives such as ceramide, hyaluronic acid, urea, or filaggrin, systemic corticosteroids, systemic treatment for AD with an immunosuppressive/immunomodulating agent (eg, cyclosporin, mycophenolate-mofetil, azathioprine, methotrexate, interferon-gamma, or other biologics); allergen immunotherapy; live (attenuated vaccine); or investigational drug other than dupilumab.
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Patient narratives of serious treatment-emergent adverse events (TEAEs) of infection and respiratory disorder 1. Serious infections
a. Patient 1. Cellulitis: The patient was a 42-year-old female in the dupilumab 100 mg every 4 weeks (q4w) treatment group (country of origin for this event: Germany). The patient had a history of atopic dermatitis (AD), hypertension, and asthma. Concomitant medications included norgestrel, montelukast, fexofenadine hydrochloride, verapamil hydrochloride, telmisartan, beclometasone/fenoterol, and hydroxyzine. The patient received 8 doses of study drug, with the last dose received on Jan 2, 2014. On Apr 17, 2014, 3 months after the last dose of study drug, the patient developed painful swelling of the left leg with fever leading to hospitalization. At admission, physical examination showed general skin exanthemas, heart and lungs physically normal, heart action rhythmic, 70 beats per minute (bpm), blood pressure 170/90 mmHg; abdomen was clinically normal, general neurologic exam showed no pathologic findings. Left lower leg was distinctly swollen with skin very reddened. A deep vein thrombosis was ruled out via ultrasound. Blood culture showed no bacterial growth after 5 days. Chest X-ray was normal. Laboratory data showed elevated C-reactive protein at 200 mg/L. Cellulitis of the left leg was diagnosed. The patient was treated with intravenous (IV) antibiotics clindamycin phosphate, piperacillin sodium/tazobactam sodium, and also enoxaparin sodium. The final diagnosis was suspicion of erysipelas, left leg. The patient was discharged on Apr 24, 2014. This event was considered not related to the study drug.
b. Patient 2. Peritonsillar abscess: The patient was a 49-year-old male in the dupilumab 300 mg q4w treatment group (country of origin: United States). The patient had a history of left peritonsillar abscess, allergies to penicillin and clindamycin, eczema, acute pericarditis, fracture of neck of metacarpal bone, benign paroxysmal positional vertigo, open reduction of fracture with internal fixation, sleeve gastrectomy, and obstructive sleep apnoea. Concomitant medications included azithromycin, levofloxacin, hydromorphone hydrochloride, lidocaine hydrocochloride, epinephrine, and ondasetron hydrochloride. The patient had received 14 doses of the study drug, and completed study treatment on Mar 7, 2014. On Apr 1, 2014, 25 days after the last dose of study drug, the patient experienced a right peritonsillar abscess leading to hospitalisation. Previously, on Mar 20, 2014, the patient had developed a left peritonsillar abscess that was treated in the emergency department (ED) with incision and drainage of the abscess, and antibiotic treatment with azithromycin and IV vancomycin; following treatment failure, antibiotic treatment was switched to levofloxacin and methylprednisolone. After completion of levofloxacin, on Apr 1, 2014, the patient was admitted to the hospital after 2 days of sore throat with 1 day of fever (38·4°C). The patient had leucocytosis, right ear pain, and headache. His tonsils were enlarged with whitish exudate on the right, right peritonsillar abscess with uvular deviation to the left, muffled voice, right peritonsillar and soft palate oedema and erythema with soft palate fullness, fluctuant and tender. The patient had anterior and posterior cervical lymphadenopathies. On Apr 2, 2014, white blood cell (WBC) count was 27 400 cells/mm3, absolute neutrophil count was 17,100 cells/mm3, and monocyte count was 1800 cells/mm3. The patient was treated with incision and drainage of the right peritonsillar abscess after local anaesthesia with lidocaine and epinephrine; he received IV vancomycin, dexamethasone, and methylprednisolone. Cultures were positive for Streptococcus pyogenes. The patient was switched to oral antibiotic treatment with sulfamethoxazole-trimethoprim. The patient recovered and was discharged on Apr 13, 2014, with hydrocodone-acetaminophen and sulfamethoxazole-trimethoprim. This event was considered to be not related to the study drug.
c. Patient 3. Viral infection: The patient was a 19-year-old male in the dupilumab 300 mg weekly treatment group (country of origin: United States). The patient had a pre-existing condition of endocarditis and previous history of atrial septal defect repair. He had received 4 doses of the study drug beginning on Jul 26, 2013, prior to development of fever (38·8°C) of unknown aetiology with bandaemia on Aug 11, 2013. The patient was hospitalised on Aug 15, 2013 for investigation, and received one dose of IV antibiotics as prophylaxis. Cultures, including blood culture, were negative. Echocardiogram and magnetic resonance imaging did not show any abnormalities. Bandaemia was resolved. Procalcitonin was within normal limits. During hospitalisation, the patient received IV fluids, magnesium hydroxide, metoclopramide hydrochloride, ondansetron hydrochloride, zolpidem tartrate, paracetamol, daptomycin, and morphine. The patient’s fever subsided and he felt well on the day following admission. The patient was discharged on Aug 16, 2013. The final diagnosis was viral infection, and the event was considered moderate in severity. The patient resumed treatment with the
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study drug with no complications or injection-site reactions. The event was considered to be not related to the study drug.
2. Respiratory disorders a. Patient 1. Asthma exacerbation: The patient was a 25-year-old female in the dupilumab 100 mg q4w
treatment group (country of origin: Germany). She had a history of asthma, allergic rhinitis, multiple pets’ allergy, food allergy (fish and nuts), house-mite allergy, grass allergy, obesity, and gastritis. Concomitant medications included sertraline hydrochloride, quetiapine, formoterol hemifumarate, and tiotropium bromide. She started treatment with the study drug on Nov 12, 2013, and received a total of 14 doses of study drug, with the last dose on Jan 28, 2014, prior to the TEAE. On Jan 30, 2014, the patient developed exacerbation of endogenous bronchial asthma of moderate intensity leading to hospitalisation. The patient reported that she had been suffering from bronchitis since October, treated with antibiotics. For the past month, she developed progressive dyspnoea on exertion with no corticoid therapy. In the past week, discrete inappetance with vomiting was noted. She also presented with worsening of eczema. Physical examination showed blood pressure at 160/80 mmHg, heart rate at 79 bpm, temperature at 37·1°C, respiratory rate at 16 breaths/min, oxygen saturation at 98%, ubiquitous rhonchus, no rales, sonorous percussion sound, dyspnoea on exertion, cardiac sounds clear and rhythmic, and eczema. The patient was also diagnosed with asymptomatic urinary tract infection, which was not considered an adverse event (AE) as it was not clinically relevant; she was not treated for this event. The final diagnosis was an acute exacerbated asthma of intrinsic origin. As an allergen component to the bronchial asthma was suspected, an anti-obstructive inhalative therapy with formoterol was initiated. Presuming a spastic component also, a supplementation with a cortisone shock was given. Corrective treatment included IV prednisolone 50 mg until Feb 10, 2014, then oral prednisolone 25 mg until Feb 17, 2014, and salbutamol puffs as needed. The initial blood gases analysis showed a moderate oxygenation disorder, which returned to within normal range after treatment. The patient’s complaints were reduced under prednisolone; in addition, profound regression of the endogenous eczema was noted. The dyspnoea symptoms occurred during the course of an emotional symptomatic. Continuing the medicinal therapy with sertraline was recommended. The indication to permanently continue the inhalative corticoid therapy should be re-evaluated over the course of time. The patient recovered on Feb 4, 2014 from worsening of eczema and was discharged home in stable general condition. According to the investigator, the event continued as a non-serious TEAE until Feb 10, 2014. This event was considered to be not related to study drug.
b. Patient 2. Respiratory failure: The patient was a 19-year-old female in the dupilumab 200 mg every 2
weeks treatment group (country of origin: United States). She had a history of asthma, morbid obesity, peptic ulcer disease, Crohn’s disease, anaphylactic reactions to cashews and pistachios, migraine, attention-deficit hyperactivity disorder, cholecystectomy, and appendectomy. Concomitant medications included budesonide, lamotrigine, polycarbophil calcium, salbutamol sulfate, montelukast, triamcinolone acetonide, ipratropium/salbutamol, cyclobenzaprine, esomeprazole, cyanocobalamin, etonogestrel, and loratidine. The patient began treatment with study drug on Dec 10, 2013, and received three doses prior to onset of the serious AE on Dec 20, 2013, when the patient experienced anaphylactic shock to cashews after eating a candy bar that contained cashews. The patient complained of throat and lip swelling and diffuse body hives. She was given repeated doses of epinephrine in the ED. Physical examination on Dec 30, 2013 showed that she was alert and oriented, had tongue and lip swelling, and tachycardia. Respiratory examination was clear to auscultation. However, the patient was considered unresponsive to epinephrine and became somnolent. Subsequently, she became extremely short of breath with need of supplemental oxygen, and did not improve. The patient’s respiratory status decompensated; she was intubated in the ED and was transferred to the intensive care unit (ICU). In the ICU, she was placed on solumedrol IV and on ventilation. Her heart rate was elevated in the 150s bpm, which was most probably from the epinephrine; she was placed on diltiazem hydrocloride drip and a bolus of diltiazem hydrochloride. She was also complaining of lower extremity pain for which ultrasound was done, which did not indicate any deep vein thrombosis. Upon admission, laboratory tests showed WBC count was elevated (above 25,000). Computed tomography showed bilateral lower lobe consolidation, considered most likely at the time to be pneumonia, and the patient was placed on broad-spectrum antibiotics. Pulmonary embolus was ruled out. She continued on diphenhydramine and respiratory therapy, and her condition gradually improved. She was extubated while in the ICU. As her respiratory status and perioral/throat swelling and lower extremity hives improved, she was transferred from the ICU to the floor. It was considered that the intubation caused irritation, which
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was seen as possible pneumonia. The final diagnoses were anaphylactic shock, respiratory failure, and tachycardia. The tachycardia was considered to be due to the epinephrine administered in the ED. The patient recovered from anaphylactic shock and tachycardia on Dec 31, 2013, and from respiratory failure on Jan 5, 2014, but with sequel because she received additional respiratory therapy. She was discharged home on Jan 5, 2014 with antibiotic augmentin for 7 days and prednisone for 4 days. She missed visit 5 and did not receive treatment that week, and resumed investigational product injections on Jan 9, 2014. She completed the study on investigational product injections on Feb 4, 2014. This event was considered to be not related to the study drug.
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Online Table 1: Efficacy endpoints Endpoint Description Range MCID Eczema Area and Severity Index (EASI)1,2 Objective endpoint that assesses body surface area affected by erythema,
induration/papulation/oedema, excoriations, and lichenification 0–72* 6·6
Investigator’s Global Assessment (IGA) Objective endpoint that determines severity of AD and clinical response to treatment based on a 5-point scale ranging from 0 (clear) to 4 (severe)
0–4* NA
Pruritus numeric rating scale (NRS)3,4 Subjective (patient-reported) endpoint comprising two single-item 11-point scales that assess maximum and average intensity of itch within the previous 24 hours†
0–10* 3 (improvement), 2 (worsening)
SCORing in Atopic Dermatitis (SCORAD)5 Objective assessments of extent (0–100%), severity (erythema, oedema/papulation, oozing/crusts, excoriations, lichenification, and dryness, each on a 0–3 scale); and subjective assessments of itch and sleep loss, which are each measured on an 11-point VAS, averaged over the past 3 days
0–103* NA
Body surface area (BSA) with AD involvement (%) Objective endpoint that assesses BSA affected by AD for each major section of the body (head, trunk, arms, and legs) and reported as a percentage of all major body sections combined
0–100* NA
Dermatology Life Quality Index (DLQI)6,7 Subjective (patient-reported) endpoint is a 10-item questionnaire with Likert-type responses to evaluate the impact of skin conditions on health-related quality of life over the past week
0–30a 5
*Higher scores indicate greater severity. †Weekly peak intensity of pruritus NRS was determined by asking the patient: “On a scale of 0–10, with 0 being ‘no itch’ and 10 being the ‘worst itch imaginable’, how would you rate your itch at the worst moment
References 1 Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol 2001;
10: 11–8. 2 Schram ME, Spuls PI, Leeflang MM, Lindeboom R, Bos JD, Schmitt J. EASI, (objective) SCORAD and POEM for atopic eczema: responsiveness and minimal clinically important difference. Allergy 2012;
67: 99–106. 3 Phan NQ, Blome C, Fritz F, et al. Assessment of pruritus intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients with
chronic pruritus. Acta Derm Venereol 2012; 92: 502–7. 4 Reich A, Halupczok J, Ramus M, Ständer S, Szepietowski J. New data on the validation of VAS and NRS in pruritus assessment: minimal clinically important difference and itch frequency measurement.
Poster presented at the 6th International Workshop for the Study of Itch; Sept 4–6, 2011; Brest, France. Abstract PP39. Acta Derm Venereol 2011; 91: 636. 5 European Task Force on Atopic Dermatitis. Severity scoring of atopic dermatitis: the SCORAD index. Consensus report of the European Task Force on Atopic Dermatitis. Dermatology 1993;186: 23–31. 6 Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure for routine clinical use. Clin Exper Dermatol 1994; 19: 210–6. 7 Basra MK, Salek MS, Camilleri L, Sturkey R, Finlay AY. Determining the minimal clinically important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further data.
Dermatology 2015;230: 27–33.
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Online Table 2: Efficacy outcomes, baseline to week 16 (mixed-effect model with repeated measures analysis)
Endpoint Dupilumab 300 mg once a week (n=63)
Dupilumab 300 mg every 2 weeks (n=64)
Dupilumab 200 mg every 2 weeks (n=61)
Dupilumab 300 mg every 4 weeks (n=65)
Dupilumab 100 mg every 4 weeks (n=65)
Placebo once a week (n=61)
EASI score Baseline, mean (SD) 30·1 (11·2) 33·8 (14·5) 32·9 (15·5) 29·4 (11·5) 32·2 (13·5) 32·9 (13·8) Week 16, mean (SD) 6·3 (6·5) 8·7 (10·7) 8·2 (10·4) 7·1 (7·3) 14·3 (14·1) 20·5 (14·7) LS mean % change from baseline (SE) –74·1 (4·5) –70·8 (4·5) –70·4 (4·8) –66·3 (4·4) –45·5 (4·7) –23·6 (5·0) LS mean difference vs placebo (SE) –50·5 (6·5) –47·2 (6·5) –46·8 (6·7) –42·7 (6·5) –21·9 (6·6) 95% CI (–63·3 to –37·7) (–60·0 to –34·3) (–60·0 to –33·6) (–55·5 to –30·0) (–34·9 to –8·9) p value <0·0001 <0·0001 <0·0001 <0·0001 0·0011
SCORAD score Baseline, mean (SD) 65·0 (12·2) 68·5 (12·6) 68·3 (14·0) 67·2 (12·3) 68·2 (15·0) 67·1 (13·6) Week 16, mean (SD) 24·8 (15·1) 28·4 (17·7) 29·5 (20·1) 28·4 (15·8) 43·0 (24·4) 49·0 (20·9) LS mean % change from baseline (SE) –57·8 (3·8) –53·9 (3·8) –51·2 (4·1) –51·6 (3·7) –27·4 (3·9) –17·1 (4·2) LS mean difference vs placebo (SE) –40·7 (5·5) –36·8 (5·5) –34·1 (5·7) –34·5 (5·5) –10·3 (5·6) 95% CI (–51·5 to –29·9) (–47·6 to –25·9) (–45·3 to –22·9) (–45·3 to –23·7) (–21·4 to 0·7) p value <0·0001 <0·0001 <0·0001 <0·0001 0·0671
Body surface area with AD involvement, % Baseline, mean (SD) 48·4 (20·9) 53·2 (24·8) 50·8 (25·4) 50·8 (22·6) 48·7 (23·9) 51·1 (23·5) Week 16, mean (SD) 13·2 (12·9) 18·8 (19·6) 17·0 (20·4) 18·8 (17·6) 26·4 (23·2) 37·9 (25·1) LS mean % change from baseline (SE) –68·6 (5·8) –58·5 (5·8) –62·1 (6·2) –53·1 (5·7) –28·4 (6·0) –15·5 (6·4) LS mean difference vs placebo (SE) –53·1 (8·5) –43·0 (8·5) –46·6 (8·8) –37·6 (8·5) –12·9 (8·6) 95% CI (–69·8 to –36·4) (–59·7 to –26·3) (–63·9 to –29·3) (–54·3 to –21·0) (–29·9 to 4·1) p value <0·0001 <0·0001 <0·0001 <0·0001 0·1368
Peak weekly pruritus NRS scores Baseline, mean (SD) 6·54 (1·54) 6·74 (2·07) 6·98 (2·32) 6·84 (1·85) 6·71 (1·88) 6·34 (1·83) Week 16, mean (SD) 2·79 (1·91) 3·38 (2·21) 3·30 (2·18) 3·71 (2·28) 4·89 (2·54) 5·71 (2·36) LS mean % change from baseline (SE) –51·42 (4·53) –44·48 (4·58) –39·70 (4·86) –35·89 (4·52) –16·20 (4·71) 2·73 (5·10) LS mean difference vs placebo (SE) –54·15 (6·61) –47·21 (6·66) –42·44 (6·86) –38·62 (6·64) –18·93 (6·76) 95% CI (–67·15 to –41·15) (–60·32 to –34·10) (–55·93 to –28·94) (–51·68 to –25·57) (–32·23 to –5·63) p value <0·0001 <0·0001 <0·0001 <0·0001 0·0054
Dermatology Life Quality Index scores Baseline, mean (SD) 15·0 (7·80) 14·5 (7·20) 15·0 (7·07) 13·3 (7·29) 15·7 (6·61) 12·8 (6·20) Week 16, mean (SD) 4·1 (4·61) 6·0 (6·37) 5·6 (6·57) 5·6 (5·32) 10·6 (7·46) 10·2 (6·99) LS mean % change from baseline (SE) −62·9 (6·35) −45·6 (6·38) −49·6 (6·81) −45·0 (6·29) −14·0 (6·61) −4·1 (7·03) LS mean % difference vs placebo (SE) −58·7 (9·02) −41·4 (9·05) −45·4 (9·36) −40·9 (8·98) −9·9 (9·26) 95% CI (−76·5, −41·0) (−59·2, −23·6) (−63·9, −27·0) (−58·6, −23·2) (−28·1, 8·3) p value <0·0001 <0·0001 <0·0001 <0·0001 0·2867
EASI=Eczema Area and Severity Index; LS=least squares; NRS=numeric rating scale; q2w=every 2 weeks; q4w=every 4 weeks; SCORAD=SCORing in Atopic Dermatitis; SD=standard deviation; SE=standard error.
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Online Table 3. P-values vs placebo for least-squares mean percentage change from baseline in EASI, SCORAD, % body surface area with atopic dermatitis involvement, and peak weekly pruritus NRS at each study visit (mixed-effects model with repeated measures analysis)
EASI=Eczema Area and Severity Index; LS=least squares; MMRM, NRS=numeric rating scale; q2w=every 2 weeks; q4w=every 4 weeks; SCORAD=SCORing in Atopic Dermatitis; SD=standard deviation; SE=standard error.
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Online Table 4. P-values vs placebo for least-squares mean percentage change from baseline in EASI, SCORAD, % body surface area with atopic dermatitis involvement, and peak weekly pruritus NRS at each study visit (last observation carried forward)
Data are n or n (%). *TEAEs were categorized as serious if they were life-threatening or resulted in hospitalization, disability, congenital anomaly, or death; or were otherwise deemed an important medical event. †A patient who reported 2 or more TEAEs with the same PT was counted only once for that term. PT=Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term; q2w=every 2 weeks; q4w=every 4 weeks.
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Online Figure 1: Least squares (LS) mean percentage change from baseline for Eczema Area and Severity Index (EASI) (A), SCORing in Atopic Dermatitis (SCORAD) (B), percentage body surface area of atopic dermatitis (AD) involvement (%) (C), and peak weekly pruritus numeric rating scale (NRS) scores (D) using mixed-effect model with repeated measures analysis DPL, dupilumab; q2w=every 2 weeks; q4w=every 4 weeks.
