Supplemental Table S2a Summary statistics for hematology laboratory parameters: red blood cells and platelets ... 6

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Laboratory Safety of Dupilumab in Patients Aged 6 to 11 years with Severe Atopic Dermatitis:

Results from a Phase III Clinical Trial Electronic Supplemental Material

Amy S. Paller¹· Andreas Wollenberg²· Elaine Siegfried³· Diamant Thaçi⁴· Michael J. Cork⁵· Peter D. Arkwright⁶· Melinda Gooderham^7,8· Xian Sun⁹· John T. O’Malley¹⁰· Faisal A. Khokhar⁹· Jignesh Vakil¹¹· Ashish Bansal⁹· Karli Rosner¹²· Brad Shumel⁹· Noah A. Levit⁹

1 Northwestern University Feinberg School of Medicine, Chicago, IL, USA

2 Ludwig Maximilian University of Munich, Munich, Germany

3 Saint Louis University, St. Louis, MO, USA

4 Institute and Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany

5 Sheffield Dermatology Research, University of Sheffield, Sheffield, UK

6 Lydia Becker Institute of Immunology & Inflammation, University of Manchester, Manchester, UK

7 Probity Medical Research, Peterborough, ON, Canada

8 SKiN Centre for Dermatology, Peterborough, Queen's University, Kingston, ON, Canada

9 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA

10 Sanofi, Cambridge, MA, USA

11 Sanofi, Bridgewater, NJ, USA

12 Sanofi Genzyme, Cambridge, MA, USA Corresponding author: Noah A. Levit, MD, PhD, FAAD

Address: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY, 10591-6707, USA Phone: +1 (914) 255-6084

Email: noah.levit@regeneron.com ORCID: 0000-0002-0797-5121

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Table of Contents

Supplementary Methods ... 3

Supplemental Table S1 Laboratory assessments, a hematology and b serum chemistry and urinalysis ... 4

Supplemental Table S2a Summary statistics for hematology laboratory parameters: red blood cells and platelets ... 6

Supplemental Table S2b Proportion of patients with Grades 1–4 thrombocytopenia, n1/N1 (%) ... 9

Supplemental Table S2c Proportion of patients with Grades 1–3 anemia, n1/N1 (%) ... 10

Supplemental Table S3a Summary statistics for hematology laboratory parameters: white blood cells .... 11

Supplemental Table S3b Proportion of patients with Grades 1–4 neutropenia, n1/N1 (%) ... 16

Supplemental Table S4a Summary statistics for serum chemistry laboratory parameters: metabolic function ... 17

Supplemental Table S4b Summary statistics for serum chemistry laboratory parameters: electrolytes ... 19

Supplemental Table S4c Summary statistics for serum chemistry laboratory parameters: renal function . 21 Supplemental Table S4d Summary statistics for serum chemistry laboratory parameters: liver function . 23 Supplemental Table S4e Summary statistics for serum chemistry laboratory parameters: lipid panel ... 26

Supplemental Table S4f Shift from baseline: LDH (U/L) ... 28

Supplemental Table S5a Proportion of patients with Grades 1–4 increases in ALP, n1/N1 (%) ... 29

Supplemental Table S5b Proportion of patients with Grades 1–4 increases in bilirubin, n1/N1 (%) ... 31

Supplemental Table S5c Proportion of patients with Grades 1–4 increases in ALT, n1/N1 (%) ... 33

Supplemental Table S5d Proportion of patients with Grades 1–4 increases in AST, n1/N1 (%) ... 35

Supplemental Table S5e Proportion of patients with Grades 1–4 increases in creatinine, n1/N1 (%) ... 37

Supplemental Table S5f Proportion of patients with Grades 1–4 increases in potassium, n1/N1 (%) ... 38

Supplemental Table S6 Summary statistics for urinalysis laboratory parameters ... 39

Supplemental Fig. S1 Absolute platelet counts... 40

Supplemental Fig. S2 Platelet counts in the patient who had Grade 3 thrombocytopenia... 41

Supplemental Fig. S3 Eosinophil counts in individual patients with Grade 3 eosinophilia ... 42

Reference ... 44

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Supplementary Methods

Severity of treatment-emergent adverse events (TEAEs)

• Any TEAE:

–

Mild: Does not interfere in a significant manner with the patient’s normal functioning level. It may be an annoyance. Prescription drugs are not ordinarily needed for relief of symptoms, but may be given because of personality of the patient

–

Moderate: Produces some impairment of functioning but is not hazardous to health. It is uncomfortable or an embarrassment. Treatment for symptom may be needed

–

Severe: Produces significant impairment of functioning or incapacitation and is a definite hazard to the patient’s health. Treatment for symptom may be given and/or patient hospitalized

• Additional information for laboratory value treatment-emergent adverse events (TEAEs):

–

If a laboratory value is considered a TEAE, its severity will be based on the degree of physiological impairment the value indicates

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Supplemental Table S1 Laboratory assessments, a hematology and b serum chemistry and urinalysis (a) Hematology

Red blood cell and platelet parameters White blood cell parameters

Erythrocyte mean corpuscular hemoglobin concentration (g/dL) Basophil count (× 10⁹/L) Erythrocyte mean corpuscular hemoglobin (pg) Basophils/leukocytes (%) Erythrocyte mean corpuscular volume (fL) Eosinophil count (× 10⁹/L)

Erythrocyte count (× 10¹²/L) Eosinophils/leukocytes (%)

Hematocrit (%) Leukocyte count (× 10⁹/L)

Hemoglobin (g/L) Lymphocyte count (× 10⁹/L)

Platelet count (× 10⁹/L) Lymphocytes/leukocytes (%)

Monocyte count (× 10⁹/L) Monocytes/leukocytes (%) Neutrophil count (× 10⁹/L) Neutrophils/leukocytes (%)

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(b) Serum chemistry and urinalysis

Serum chemistry

(metabolic function) Serum chemistry

(electrolytes) Serum chemistry

(renal function) Serum chemistry

(liver function) Serum chemistry

(lipids) Urinalysis

Albumin (g/L) Bicarbonate (mmol/L) Blood urea nitrogen

(mmol/L) Alkaline phosphatase

(U/L) Cholesterol (mmol/L) Specific gravity Creatinine kinase (U/L) Calcium (mmol/L) Creatinine (μmol/L) Alanine

aminotransferase (U/L) High-density

lipoprotein (mmol/L) pH Glucose (mmol/L) Chloride (mmol/L) Urate (μmol/L) Aspartate

aminotransferase (U/L) Low-density lipoprotein (mmol/L)

Protein (g/L) Potassium (mmol/L) Bilirubin (μmol/L) Triglycerides (mmol/L)

Sodium (mmol/L) Direct bilirubin

(μmol/L) Indirect bilirubin (μmol/L)

Lactate dehydrogenase (U/L)

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Supplemental Table S2a Summary statistics for hematology laboratory parameters: red blood cells and platelets

Laboratory parameter Measurement Study

week Placebo + TCS (n = 120)

Dupilumab

300 mg q4w + TCS (n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Hematocrit (%) NR Age 1–6 years

Male: 31.0–37.7 Female: 31.2–37.8 Age 7–12 years

Male: 32.2–39.8 Female: 32.4–39.5

Median (Q1, Q3), n1

BL 39.7 (37.5, 41.0), 119 39.9 (38.0, 41.65), 120 40.5 (38.2, 41.8), 121 4 39.6 (38.1, 41.5), 113 40.1 (38.0, 41.3), 110 39.9 (38.3, 41.5), 114 8 40.0 (38.5, 41.6), 110 39.6 (38.15, 41.15), 108 39.4 (37.8, 41.6), 107 16 39.5 (37.8, 41.4), 109 39.2 (37.9, 41.1), 114 39.9 (37.8, 41.6), 116

Mean change from baseline (± SD), n1

4 0.31 (2.343), 113 −0.10 (2.419), 110 −0.37 (2.385), 113 8 0.47 (2.434), 110 −0.17 (2.366), 108 −0.46 (2.962), 106 16 0.02 (3.115), 109 −0.49 (2.786), 114 −0.49 (2.844), 115 Hemoglobin (g/L)

NR Age 1–6 years Male: 102–127 Female: 102–127 Age 7–12 years

Male: 107–134 Female: 106–132

Median (Q1, Q3), n1

BL 132 (125, 137), 119 135 (128, 140), 120 134 (128, 139), 121 4 133 (127, 138), 113 134 (129, 138), 110 133 (127, 138), 114 8 133 (128, 138), 110 133 (128 (138), 108 132 (127, 138), 107 16 132 (126, 138), 109 132 (127, 138), 114 134 (126, 139), 116

4 1.3 (7.20), 113 −0.7 (7.34), 110 −1.1 (7.04), 113

8 1.5 (7.64), 110 −0.7 (7.35), 108 −1.1 (8.99), 106

16 0.4 (9.55), 109 −1.6 (8.86), 114 −1.5 (9.00), 115

Erythrocyte mean corpuscular hemoglobin (pg)

NR Age 1–6 years Male: 23.7–28.3

Median (Q1, Q3), n1

BL 28.0 (26.6, 28.7), 119 28.2 (27.4, 29.1), 120 28.1 (27.1, 28.9), 121 4 28.1 (26.7, 28.9), 113 28.4 (27.4, 29.1), 110 28.1 (27.0, 29.1), 114 8 27.9 (26.5, 28.9), 110 28.1 (27.5, 29.1), 108 28.1 (27.1, 29.1), 107 16 27.9 (26.4, 28.8), 109 28.2 (27.4, 29.0), 114 28.2 (27.1, 29.0), 116

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Dupilumab

300 mg q4w + TCS (n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Female: 23.7–28.6 Age 7–12 years

Male: 24.9–29.2

Female: 24.8–29.5 Mean change from baseline (± SD), n1

4 0.02 (0.462), 113 −0.02 (0.542), 110 0.01 (0.543), 113 8 0.01 (0.487), 110 −0.02 (0.526), 108 0.06 (0.609), 106 16 0.03 (0.692), 109 0.06 (0.696), 114 0.08 (0.711), 115 Erythrocyte mean

corpuscular hemoglobin concentration (g/dL) NR Age 1–6 years

Male: 32.2–34.9 Female: 31.8–34.6

Median (Q1, Q3), n1

BL 33.3 (32.7, 33.8), 119 33.6 (33.2, 34.1), 120 33.3 (32.9, 33.8), 121 4 33.4 (32.9, 33.9), 113 33.6 (33.1, 34.0), 110 33.5 (32.8, 33.9), 114 8 33.3 (32.7, 33.8), 110 33.5 (33.0, 33.9), 108 33.5 (33.0, 33.9), 107 16 33.3 (32.8, 33.8), 109 33.55 (33.1, 34.1), 114 33.3 (32.9, 33.8), 116

4 0.06 (0.828), 113 −0.10 (0.836), 110 0.03 (0.797), 113 8 −0.02 (0.767), 110 −0.06 (0.871), 108 0.10 (0.896), 106 16 0.11 (1.065), 109 0.02 (0.915), 114 0.03 (0.832), 115 Erythrocyte mean

corpuscular volume (fL) NR Age 1–6 years

Male: 74.4–86.1 Female: 75.9–87.6

Median (Q1, Q3), n1

BL 83.4 (79.7, 85.9), 119 84.0 (81.6, 86.4), 120 84.4 (81.1, 87.0), 121 4 83.7 (80.3, 85.9), 113 84.0 (82.4, 86.7), 110 84.5 (80.9, 86.8), 114 8 83.6 (80.4, 85.8), 110 84.0 (82.2, 86.4), 108 84.4 (80.8, 86.6), 107 16 83.5 (79.1, 85.4), 109 84.0 (82.2, 86.2), 114 84.4 (81.4, 86.8), 116

4 −0.08 (1.323), 113 0.17 (1.560), 110 −0.07 (1.491), 113 8 0.05 (1.401), 110 0.06 (1.513), 108 −0.08 (1.921), 106 16 −0.16 (1.838), 109 0.07 (2.013), 114 0.12 (2.123), 115 Erythrocytes (× 10¹²/L)

NR Median (Q1, Q3), n1 BL 4.75 (4.60, 5.04), 119 4.77 (4.54, 4.98), 120 4.78 (4.57, 5.03), 121 4 4.79 (4.54, 5.05), 113 4.74 (4.51, 4.90), 110 4.74 (4.51, 4.96), 114

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Dupilumab

300 mg q4w + TCS (n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Age 1–6 years Male: 3.89–4.97 Female: 3.84–4.92 Age 7–12 years

Male: 3.96–5.03 Female: 3.90–4.96

8 4.84 (4.53, 5.11), 110 4.72 (4.51, 4.94), 108 4.70 (4.49, 4.96), 107 16 4.78 (4.57, 5.04), 109 4.70 (4.45, 4.93), 114 4.72 (4.48, 4.97), 116

4 0.043 (0.2728), 113 −0.021 (0.2705), 110 −0.040 (0.2476), 113 8 0.053 (0.2875), 110 −0.026 (0.2699), 108 −0.047 (0.3081), 106 16 0.012 (0.3539), 109 −0.062 (0.3164), 114 −0.065 (0.3152), 115 Platelets (× 10⁹/L)

NR Age 1–6 years Male: 197–382 Female: 213–363 Age 7–12 years

Male: 175–311 Female: 130–314

Median (Q1, Q3), n1

BL 314 (267, 361), 117 302 (269, 353), 115 317 (274, 374), 116 4 325 (267, 367), 108 299 (260, 347), 100 302 (268, 360), 108 8 320 (271, 367), 107 294 (263, 330), 101 308 (252, 353), 102 16 320 (266, 362), 107 286 (255, 322), 111 301 (257, 337), 109

4 2.1 (53.54), 107 −6.3 (51.30), 99 −11.1 (59.56), 105

8 4.4 (62.78), 106 −6.1 (70.67), 97 −20.6 (64.44), 101

16 5.0 (58.40), 106 −18.8 (64.45), 107 −19.3 (71.37), 106

BL baseline, n total number of patients in the treatment group, n1 number of patients with assessment at visit, NR normal range, Q1 quartile 1, Q3 quartile 3, q2w every 2 weeks, q4w every 4 weeks, SD standard deviation, TCS topical corticosteroid

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Supplemental Table S2b Proportion of patients with Grades 1–4 thrombocytopenia, n1/N1 (%)

Time point Grade Placebo + TCS

(n = 120)

Dupilumab

300 mg q4w + TCS (n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Baseline Grade 1 (Mild): 75 × 10⁹/L to < LLN 2/117 (1.7) 3/115 (2.6) 0/116

Grade 2 (Moderate): 50 × 10⁹/L to < 75 × 10⁹/L 0/117 1/115 (0.9) 0/116

Grade 3 (Severe): 25 × 10⁹/L to < 50 × 10⁹/L 0/117 0/115 0/116

Grade 4 (Potentially life-threatening): < 25 × 10⁹/L 0/117 0/115 0/116

Week 4 Grade 1 (Mild): 75 × 10⁹/L to < LLN 1/108 (0.9) 1/100 (1.0) 1/108 (0.9)

Grade 2 (Moderate): 50 × 10⁹/L to < 75 × 10⁹/L 0/108 0/100 0/108

Week 8 Grade 1 (Mild): 75 × 10⁹/L to < LLN 0/107 0/101 1/102 (1.0)

Grade 2 (Moderate): 50 × 10⁹/L to < 75 × 10⁹/L 0/107 0/101 1/102 (1.0)

Grade 3 (Severe): 25 × 10⁹/L to < 50 × 10⁹/L 0/107 1/101 (1.0) 0/102

Week 16 Grade 1 (Mild): 75 × 10⁹/L to < LLN 2/107 (1.9) 3/111 (2.7) 3/109 (2.8)

Grade 2 (Moderate): 50 × 10⁹/L to < 75 × 10⁹/L 0/107 0/111 0/109

Patients may have had a grade change at more than one time point

Grades were determined based on the U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE); version 5.0 [1]

LLN lower limit of normal, n total number of patients in the treatment group, n1/N1 number of patients with grade/number of patients with assessment at visit, q2w every 2 weeks, q4w every 4 weeks, TCS topical corticosteroid

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Supplemental Table S2c Proportion of patients with Grades 1–3 anemia, n1/N1 (%)

(n = 120)

Dupilumab 300 mg q4w + TCS (n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Baseline Grade 1 (Mild): < LLN–100 g/L 2/119 (1.7) 0/120 2/121 (1.7)

Grade 2 (Moderate): < 100–80 g/L 0/119 1/120 (0.8) 0/121

Grade 3 (Severe): < 80 g/L 0/119 0/120 0/121

Week 4 Grade 1 (Mild): < LLN–100 g/L 2/113 (1.8) 0/110 1/114 (0.9)

Grade 2 (Moderate): < 100–80 g/L 0/113 0/110 0/114

Grade 3 (Severe): < 80 g/L 0/113 0/110 0/114

Week 8 Grade 1 (Mild): < LLN–100 g/L 1/110 (0.9) 0/108 0/107

Grade 2 (Moderate): < 100–80 g/L 1/110 (0.9) 0/108 1/107 (0.9)

Grade 3 (Severe): < 80 g/L 0/110 0/108 0/107

Week 16 Grade 1 (Mild): < LLN–100 g/L 0/109 0/114 2/116 (1.7)

Grade 2 (Moderate): < 100–80 g/L 0/109 0/114 2/116 (1.7)

Grade 3 (Severe): < 80 g/L 0/109 0/114 0/116

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Supplemental Table S3a Summary statistics for hematology laboratory parameters: white blood cells

Dupilumab

300 mg q4w + TCS (n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Leukocytes (× 10⁹/L) NR Age 1–6 years

Male: 4.3–11.0 Female: 4.3–11.4

Median (Q1, Q3), n1

BL 7.7 (6.2, 10.0), 119 7.8 (6.1, 9.2), 120 8.1 (6.4, 9.8), 121 4 7.6 (6.4, 9.4), 113 7.6 (6.3, 8.9), 110 8.1 (6.3, 10.0), 114 8 7.6 (6.3, 9.9), 110 7.3 (6.1, 8.9), 108 8.1 (6.4, 10.0), 107 16 7.7 (6.2, 9.2), 109 7.6 (5.9, 8.9), 114 7.7 (6.2, 9.6), 116 Mean change

from baseline (± SD), n1

4 0.12 (2.375), 113 0.14 (2.114), 110 0.26 (2.311), 113 8 0.34 (2.584), 110 −0.16 (2.190), 108 0.31 (2.336), 106 16 −0.14 (2.482), 109 −0.19 (2.322), 114 −0.10 (2.347), 115 Basophils (× 10⁹/L)

NR Age 1–6 years All: 0.0–0.3 Age 7–12 years

All: 0.0–0.2

Median (Q1, Q3), n1

BL 0 (0, 0), 118 0 (0, 0), 119 0 (0, 0), 121

4 0 (0, 0), 111 0 (0, 0), 109 0 (0, 0), 111

8 0 (0, 0), 109 0 (0, 0), 107 0 (0, 0), 106

16 0 (0, 0), 106 0 (0, 0), 114 0 (0, 0), 115

4 0 (0.039), 111 0 (0.029), 108 0.01 (0.037), 110

8 0 (0.044), 109 0.01 (0.043), 106 0.01 (0.062), 105

16 0 (0.044), 106 0.01 (0.035), 113 0.01 (0.044), 114

Basophils/

leukocytes (%) NR Age 1–12 years

All: 1.0–2.0

Median (Q1, Q3), n1

BL 0.3 (0.2, 0.5), 118 0.3 (0.2, 0.5), 119 0.3 (0.2, 0.5), 121 4 0.4 (0.2, 0.5), 111 0.4 (0.2, 0.5), 109 0.3 (0.2, 0.5), 111 8 0.3 (0.2, 0.5), 109 0.4 (0.2, 0.5), 107 0.3 (0.2, 0.5), 106 16 0.4 (0.2, 0.5), 106 0.3 (0.2, 0.5), 114 0.4 (0.3, 0.6), 115

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Dupilumab

300 mg q4w + TCS (n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

4 0.05 (0.381), 111 0.04 (0.258), 108 0.01 (0.291), 110

8 0 (0.326), 109 0.07 (0.342), 106 0.04 (0.453), 105

16 0.04 (0.361), 106 0.04 (0.354), 113 0.06 (0.318), 114 Eosinophils (× 10⁹/L)

All: 0.0–0.5

Median (Q1, Q3), n1

BL 0.7 (0.4, 1.1), 118 0.8 (0.4, 1.1), 119 0.6 (0.4, 1.2), 121 4 0.7 (0.4, 1.1), 111 0.7 (0.4, 1.1), 109 0.6 (0.4, 1.2), 111 8 0.8 (0.5, 1.1), 109 0.7 (0.3, 1.2), 107 0.6 (0.3, 1.3), 106 16 0.8 (0.4, 1.1), 106 0.7 (0.3, 1.1), 114 0.8 (0.3, 1.4), 115 Mean change

4 −0.02 (0.464), 111 0.08 (0.680), 108 0.13 (0.742), 110

8 0.1 (0.700), 109 0.17 (0.893), 106 0.18 (0.739), 105

16 −0.01 (0.546), 106 0.1 (0.896), 113 0.25 (0.776), 114 Eosinophils/

leukocytes (%) NR Age 1–12 years All: 1.0–5.0

Median (Q1, Q3), n1

BL 8.9 (6.1, 13.8), 118 8.9 (5.8, 13.7), 119 9.1 (4.7, 13.3), 121 4 8.3 (5.3, 13), 111 9.0 (5.2, 15.2), 109 8.4 (4.8, 13.6), 111 8 9.3 (6.3, 13.9), 109 10.6 (4.9, 16.7), 107 8.8 (4.7, 15.4), 106 16 9.3 (5.8, 13.7), 106 9.3 (4.1, 16), 114 9.6 (5.5, 16.3), 115 Mean change

4 −0.35 (4.495), 111 0.33 (5.466), 108 0.65 (6.332), 110 8 0.44 (4.589), 109 1.71 (6.817), 106 1.35 (7.028), 105 16 0.03 (5.695), 106 1.08 (7.212), 113 2.3 (7.300), 114 Lymphocytes (× 10⁹/L)

NR

Median (Q1, Q3), n1

BL 2.5 (2.0, 2.9), 118 2.7 (2.1, 3.2), 119 2.6 (2.1, 3.2), 121 4 2.4 (2.1, 3.0), 111 2.8 (2.2, 3.2), 109 2.8 (2.3, 3.4), 111

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Dupilumab

300 mg q4w + TCS (n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Age 1–6 years All: 2.0–8.0 Age 7–12 years

All: 1.5–6.5

8 2.5 (2.1, 3.2), 109 2.5 (2.1, 3.1), 107 2.6 (2.1, 3.4), 106 16 2.4 (2.1, 3.0), 106 2.5 (2.0, 3.1), 114 2.6 (2.3, 3.2), 115 Mean change

4 −0.01 (0.695), 111 0.08 (0.682), 108 0.22 (0.640), 110 8 0.05 (0.788), 109 0.01 (0.716), 106 0.13 (0.696), 105 16 −0.03 (0.883), 106 −0.05 (0.693), 113 0.07 (0.694), 114 Lymphocytes/

All: 30.0–60.0 Age 7–12 years

All: 25.0–55.0

Median (Q1, Q3), n1

BL 33.7 (27.8, 39.6), 118 34.4 (30.1, 38.9), 119 33.7 (27.9, 40.9), 121 4 33.4 (27.1, 39.2), 111 36.1 (31.0, 41.2), 109 35.6 (30.4, 40.8), 111 8 33.8 (26.8, 40.1), 109 36.6 (32.0, 40.8), 107 34.3 (29.2, 39.3), 106 16 32.8 (27.9, 39.0), 106 36.2 (29.2, 43.0), 114 35.2 (30.4, 39.5), 115 Mean change

from baseline (±SD), n1

4 −0.38 (8.452), 111 0.90 (8.723), 108 2.21 (10.346), 110 8 −0.56 (8.35), 109 1.44 (8.517), 106 0.59 (8.596), 105 16 0.28 (9.334), 106 1.46 (10.598), 113 1.59 (9.320), 114 Monocytes (× 10⁹/L)

All: 0.2–1.1

Median (Q1, Q3), n1

BL 0.5 (0.3, 0.6), 118 0.4 (0.4, 0.6), 119 0.5 (0.3, 0.6), 121 4 0.5 (0.4, 0.6), 111 0.4 (0.4, 0.6), 109 0.4 (0.3, 0.6), 111 8 0.5 (0.4, 0.6), 109 0.4 (0.3, 0.5), 107 0.4 (0.3, 0.6), 106 16 0.5 (0.4, 0.6), 106 0.4 (0.3, 0.5), 114 0.4 (0.3, 0.5), 115 Mean change

4 0.02 (0.214), 111 0 (0.245), 108 −0.02 (0.180), 110

8 0 (0.185), 109 −0.04 (0.208), 106 −0.02 (0.192), 105

16 −0.02 (0.197), 106 −0.05 (0.207), 113 −0.05 (0.183), 114

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Dupilumab

300 mg q4w + TCS (n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Monocytes/

leukocytes (%) NR Age 1–12 years All: 2.0–8.0

Median (Q1, Q3), n1

BL 6.0 (4.8, 7.2), 118 6.2 (4.9, 7.5), 119 5.8 (4.6, 7.2), 121 4 6.5 (5.1, 7.6), 111 6.1 (5.1, 7.4), 109 5.5 (4.6, 7.0), 111 8 6.2 (4.8, 7.5), 109 6.0 (4.4, 7.1), 107 5.6 (4.4, 6.6), 106 16 5.9 (4.9, 7.8), 106 5.7 (4.2, 7.7), 114 5.4 (4.4, 7.0), 115 Mean change

4 −0.01 (2.435), 111 −0.08 (2.212), 108 −0.37 (1.95), 110 8 −0.37 (2.258), 109 −0.41 (2.196), 106 −0.53 (2.131), 105 16 −0.14 (2.344), 106 −0.37 (2.238), 113 −0.51 (2.140), 114 Neutrophils (× 10⁹/L)

All: 1.8–8.0

Median (Q1, Q3), n1

BL 3.7 (2.7, 5.1), 118 3.6 (2.8, 4.7), 119 3.9 (2.9, 5.0), 121 4 3.7 (2.9, 4.9), 111 3.4 (2.8, 4.2), 109 3.7 (2.8, 4.7), 111 8 3.8 (2.9, 5.2), 109 3.4 (2.4, 4.1), 107 3.9 (2.9, 4.8), 106 16 3.9 (2.7, 5.1), 106 3.4 (2.4, 4.5), 114 3.4 (2.8, 4.4), 115 Mean change

4 0.10 (2.040), 111 −0.09 (1.624), 108 −0.12 (2.030), 110 8 0.20 (2.009), 109 −0.38 (1.632), 106 0.02 (1.851), 105 16 −0.06 (2.049), 106 −0.26 (1.942), 113 −0.36 (1.738), 114 Neutrophils/

All: 17.0–53.0 Age 7–12 years

All: 30.0–60.0

Median (Q1, Q3), n1

BL 48.8 (41.9, 55.2), 118 48.0 (43.2, 55.1), 119 48.8 (43.3, 55.7), 121 4 49.1 (44.3, 57.0), 111 46.8 (39.5, 54.3), 109 46.7 (39.6, 53.0), 111 8 49.1 (42.5, 55.7), 109 46.8 (38.2, 52.9), 107 48.7 (40.9, 53.1), 106 16 49.0 (42.7, 56.1), 106 46.4 (36.9, 54.1), 114 46.6 (38.7, 52.9), 115 4 0.70 (11.153), 111 −1.19 (10.340), 108 −2.50 (12.305), 110

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15

Dupilumab

300 mg q4w + TCS (n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

8 0.49 (9.998), 109 −2.82 (10.961), 106 −1.45 (10.008), 105 16 −0.21 (12.047), 106 −2.18 (12.755), 113 −3.44 (10.348), 114

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16

Supplemental Table S3b Proportion of patients with Grades 1–4 neutropenia, n1/N1 (%)

(n = 120)

Dupilumab

300 mg q4w + TCS (n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Baseline Grade 1 (Mild): 1.5 × 10⁹/L to < LLN 4/118 (3.4) 3/119 (2.5) 6/121 (5.0)

Grade 2 (Moderate): 1.0 × 10⁹ to < 1.5 × 10⁹/L 3/118 (2.5) 1/119 (0.8) 2/121 (1.7)

Grade 3 (Severe): 0.5 × 10⁹/L to < 1.0 × 10⁹/L 0/118 1/119 (0.8) 0/121

Grade 4 (Potentially life-threatening): < 0.5 × 10⁹/L 0/118 0/119 0/121

Week 4 Grade 1 (Mild): 1.5 × 10⁹/L to < LLN 1/111 (0.9) 1/109 (0.9) 3/111 (2.7)

Grade 2 (Moderate): 1.0 × 10⁹/L to < 1.5 × 10⁹/L 1/111 (0.9) 3/109 (2.8) 2/111 (1.8)

Grade 3 (Severe): 0.5 × 10⁹/L to < 1.0 × 10⁹/L 0/111 0/109 0/111

Grade 3 (Severe): 0.5 × 10⁹/L to < 1.0 × 10⁹/L 0/109 0/107 0/106

Grade 3 (Severe): 0.5 × 10⁹/L to < 1.0 × 10⁹/L 1/106 (0.9) 0/114 1/115 (0.9)

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17

Supplemental Table S4a Summary statistics for serum chemistry laboratory parameters: metabolic function

Dupilumab

100/200 mg q2w + TCS (n = 122)

Albumin (g/L) NR Age 4–6 years All: 25.0–52.0 Age 7–17 years All: 37.0–56.0

Median (Q1, Q3), n1

BL 46 (44, 48), 120 46 (44, 48), 120 46 (44, 48), 122

4 46 (44, 48), 117 46 (44, 48), 114 45 (43, 48), 119

8 46 (44, 47), 114 46 (44, 48), 115 46 (44, 48), 115

16 46 (44,48), 115 45 (44, 48), 114 46 (44, 47), 120

4 −0.2 (2.82), 117 0.1 (3.01), 114 −0.4 (2.49), 119 8 −0.3 (2.85), 114 −0.2 (2.85), 115 −0.3 (2.84), 115 16 −0.2 (3.23), 115 −0.1 (2.92), 114 −0.3 (2.77), 120 Creatine kinase

(U/L)

NR Age 2–17 years Male: 50–297 Female: 33–198

Median (Q1, Q3), n1

BL 102 (84, 135), 120 103 (82.5, 141), 120 104 (77, 125), 122

4 108 (86, 152), 117 106 (91, 138), 114 107 (82, 140), 119

8 111 (83, 137), 114 108 (88, 134), 114 108 (87, 137), 115

16 98 (81, 138), 115 107 (89, 132), 114 108 (84, 142), 120

4 12.0 (92.02), 117 0.3 (47.47), 114 4.2 (42.43), 119

8 4.4 (46.82), 114 −4.8 (39.48), 114 18.3 (76.62), 115

16 9.4 (87.15), 115 −1.3 (49.57), 114 9.0 (45.17), 120

Glucose (mmol/L) NR Age 1–17 years All: 3.61–5.83

Median (Q1, Q3), n1

BL 4.75 (4.33, 5.11), 120 4.77 (4.39, 5.27), 120 4.83 (4.39, 5.22), 122 4 4.72 (4.39, 5.16), 117 4.77 (4.27, 5.19), 112, 4.77 (4.33, 5.22), 119 8 4.77 (4.33, 5.22), 111 4.83 (4.50, 5.33), 113 4.77 (4.44, 5.16), 113 16 4.83 (4.33, 5.27), 114 4.88 (4.61, 5.38), 112 4.94 (4.50, 5.30), 120

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18

Dupilumab

100/200 mg q2w + TCS (n = 122)

4 −0.021 (0.8752), 117 −0.079 (0.8536), 112 −0.014 (0.9440), 119 8 −0.033 (0.8312), 111 0.114 (0.9213), 113 0.006 (0.8337), 113 16 0.012 (0.9600), 114 0.078 (0.8585), 112 0.111 (0.8616), 120 Protein (g/L)

NR (all ages) All: 60.0–80.0

Median (Q1, Q3), n1

BL 72 (70, 75), 120 74 (71, 77), 120 74 (71, 78), 122

4 73 (71, 76), 117 73 (71, 76), 113 73 (70, 77), 119

8 73 (70, 76), 113 72 (70, 75), 116 73 (70, 76), 114

16 74 (71, 77), 114 72 (69, 77), 113 72 (70, 76), 119

4 0.7 (4.17), 117 0.0 (4.79), 113 −0.6 (3.81), 119

8 0.7 (4.31), 113 −0.9 (4.11), 116 −1.0 (4.48), 114

16 0.9 (5.28), 114 −0.5 (4.65), 113 −0.8 (4.72), 119

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19

Supplemental Table S4b Summary statistics for serum chemistry laboratory parameters: electrolytes

Dupilumab

100/200 mg q2w + TCS (n = 122)

Bicarbonate (mmol/L)

NR (age ≤ 15 years) All: 20.0–28.0

Median (Q1, Q3), n1

BL 22 (20, 23), 120 22 (20, 23), 120 21 (20, 22), 122

4 21 (20, 23), 117 22 (20, 23), 112 22 (20, 23), 118

8 21 (20, 23), 113 22 (20, 23), 114 22 (20, 23), 115

16 21 (20, 23), 114 21 (20, 22), 113 21 (20, 23), 120

4 −0.1 (2.49), 117 0 (2.83), 112 0.3 (2.62), 118

8 0.1 (2.89), 113 0.1 (3.39), 114 0.4 (2.72), 115

16 −0.2 (3.15), 114 −0.6 (2.93), 113 0.1 (2.34), 120 Calcium

(mmol/L) NR Age 4–6 years

Male: 2.18–2.55 Female: 2.15–2.55

Median (Q1, Q3), n1

BL 2.42 (2.38, 2.48), 120 2.40 (2.35, 2.48), 120 2.42 (2.35, 2.48), 122 4 2.42 (2.35, 2.48), 117 2.42 (2.35, 2.50), 111 2.42 (2.35, 2.50), 119 8 2.42 (2.38, 2.50), 113 2.42 (2.38, 2.48), 116 2.41 (2.35, 2.48), 114 16 2.45 (2.38, 2.50), 115 2.42 (2.38, 2.48), 113 2.42 (2.38, 2.50), 120 Mean change

4 −0.001 (0.0896), 117 0.014 (0.0956), 111 0.012 (0.845), 119

8 0.013 (0.802), 113 0.011 (0.0872), 116 0.002 (0.0891), 114

16 0.014 (0.0984), 115 0.014 (0.0965), 113 0.015 (0.0877), 120 Chloride

(mmol/L)

NR (age 1–17 years) All: 95.0–110.0

Median (Q1, Q3), n1

BL 101 (99, 102), 120 101 (99, 102), 120 101 (99, 103), 122

4 101 (100, 103), 117 101 (99, 103), 113 101 (100, 102), 119

8 101 (100, 103), 114 101 (100, 103), 116 101 (100, 102), 115

16 101 (100, 103), 115 102 (101, 102), 114 101 (100, 103), 120

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20

Dupilumab

100/200 mg q2w + TCS (n = 122)

4 0.2 (2.69), 117 0.3 (2.77), 113 0.2 (2.68), 119

8 0.2 (2.70), 114 0.6 (2.59), 116 0.3 (2.47), 115

16 0.5 (2.56), 115 0.7 (2.58), 114 0.4 (2.65), 120

Potassium (mmol/L) NR (age 1–17 years)

All: 3.5–5.0 Median (Q1, Q3), n1

BL 4.3 (4.1, 4.6), 120 4.3 (4.1, 4.5), 120 4.3 (4.1, 4.4), 122 4 4.3 (4.1, 4.6), 117 4.3 (4.1, 4.5), 111 4.3 (4.1, 4.5), 119 8 4.3 (4.1, 4.6), 114 4.3 (4.1, 4.5), 116 4.3 (4.1, 4.5), 114 16 4.3 (4.1, 4.5), 115 4.3 (4.1, 4.5), 114 4.3 (4.1, 4.5), 120 Mean change

4 0.01 (0.335), 117 0.03 (0.345), 111 0.01 (0.358), 119

8 0.08 (0.450), 114 0.06 (0.387), 116 0.04 (0.418), 114

16 0 (0.348), 115 −0.01 (0.401), 114 0.01 (0.432), 120

Sodium (mmol/L)

NR (age 1–17 years) All: 133.0–145.0

Median (Q1, Q3), n1

BL 140 (138, 141), 120 139 (138, 141), 120 140 (138, 141), 122

4 140 (139, 141), 117 140 (138, 141), 113 140 (139, 141), 119

8 140 (139, 141), 114 140 (139, 141), 116 140 (138, 141), 115

16 140 (139, 141), 115 140 (139, 141), 114 140 (139, 141), 120 Mean change

4 0.2 (2.45), 117 0 (2.33), 113 0.3 (2.44), 119

8 0.3 (2.03), 114 0.3 (2.27), 116 0.2 (2.14), 115

16 0.1 (2.14), 115 0.4 (2.02), 114 0.1 (2.44), 120

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21

Supplemental Table S4c Summary statistics for serum chemistry laboratory parameters: renal function

Dupilumab

100/200 mg q2w + TCS (n = 122)

Blood urea nitrogen (mmol/L) NR Age 4–6 years

Male: 1.78–6.43 Female: 1.78–5.71

Median (Q1, Q3), n1

BL 3.93 (3.21, 5.00), 120 3.93 (3.21, 5.00), 120 4.11 (3.21, 5.00), 122 4 4.28 (3.57, 4.64), 117 3.93 (3.21, 5.00), 113 4.28 (3.21, 5.00), 119 8 4.28 (3.57, 5.00), 113 3.93 (3.21, 4.64), 115 4.28 (3.57, 4.64), 114 16 4.28 (3.21, 5.00), 114 3.93 (3.21, 4.64), 113 3.93 (3.21, 4.64), 120

4 −0.028 (0.8578), 117 0.091 (1.0080), 113 0.033 (1.2578), 119 8 0.044 (1.2059), 113 −0.050 (0.9876), 115 0.031 (1.1066), 114 16 0.006 (1.1573), 114 −0.042 (1.1430), 113 −0.080 (1.1542), 120 Creatinine

(μmol/L)

NR Age 4–6 years All: 44–71 Age 7–9 years

All: 44.0–80.0 Age 10–12 years All: 53.0–88.0

Median (Q1, Q3), n1

BL 35 (27, 35), 120 35 (27, 35), 120 35 (27, 44), 122

4 35 (27, 35), 117 35 (27, 35), 112 35 (27, 44), 119

8 35 (35, 44), 113 35 (27, 44), 114 35 (27, 44), 113

16 35 (27, 35), 114 35 (27, 35), 113 35 (27, 35), 120

4 0.1 (8.07), 117 −0.2 (6.88), 112 0.3 (10.89), 119

8 0.9 (8.15), 113 0.9 (7.20), 114 0.2 (7.74), 113

16 0.1 (7.77), 114 1.2 (8.02), 113 −1.9 (6.94), 120

Urate (μmol/L) NR Age 4–6 years

All: 131–280 Age 7–9 years

All: 119–297

Median (Q1, Q3), n1

BL 232 (196, 277), 120 238 (196, 274), 120 244 (208, 280), 122 4 238 (202, 286), 117 238 (202, 262), 113 244 (202, 286), 119 8 244 (208, 286), 113 235 (208, 268), 114 238 (208, 274), 114 16 232 (202, 274), 114 232 (190, 268), 113 232 (196, 268), 120

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22

Dupilumab

100/200 mg q2w + TCS (n = 122)

Age 10–11 years Male: 137–321 Female: 178–280 Age 12–13 years

Male: 161–399 Female: 178–345

4 6.1 (45.10), 117 0.6 (55.87), 113 −3.5 (38.47), 119

8 11.0 (40.02), 113 −1.1 (39.92), 114 −7.2 (45.91), 114

16 −2.0 (43.34), 114 −3.4 (41.80), 113 −17.2 (40.20), 120

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23

Supplemental Table S4d Summary statistics for serum chemistry laboratory parameters: liver function

Dupilumab

100/200 mg q2w + TCS (n = 122)

Alkaline

phosphatase (U/L) NR Age 4–6 years

Male: 93–309 Female: 96–297 Age 7–9 years

Male: 86–315 Female: 69–325 Age 10–12 years

Male: 42–362 Female: 51–332

Median (Q1, Q3), n1

BL 223.5 (173.5, 268), 120 217.5 (179, 247), 120 222 (180, 249), 122 4 218 (175, 273), 117 225 (196, 259), 111 225 (188, 268), 117 8 224 (173, 277), 113 230 (208, 281), 115 235 (199, 276), 115 16 223 (179, 263), 114 237 (203, 284), 113 241 (211, 295), 120

4 −0.2 (30.44), 117 10.7 (31.14), 111 9.0 (24.55), 117 8 −0.3 (32.79), 113 20.8 (34.02), 115 17.7 (35.08), 115

16 1.5 (41.39), 114 29.0 (47.18), 113 30.5 (40.66), 120

Alanine

aminotransferase (U/L)

NR Age 4–6 years Male: 10.0–25.0 Female: 10.0–25.0 Age 7–11 years

Male: 10.0–35.0 Age 7–9 years

Female: 10.0–35.0 Age 12–13 years:

Male:10.0–55.0 Age 10–13 years

Female: 10.0–30.0

Median (Q1, Q3), n1

BL 15 (12, 19), 120 16 (13, 19), 120 17 (13, 20), 122

4 15 (13, 18), 117 15 (12, 18), 113 15 (12, 18), 119

8 15 (12, 18), 113 14 (12, 17), 114 15 (12, 18), 114

16 15 (12, 18), 114 14 (12, 17), 113 14 (12, 17), 120

4 1.21 (7.489), 117 −0.58 (5.008), 113 −0.35 (6.793), 119

8 0.23 (4.396), 113 −1.39 (4.735), 114 −0.48 (6.062), 114

16 0.53 (8.548), 114 −1.48 (5.994), 113 −1.71 (5.416), 120

Aspartate aminotransferase

(U/L) Median (Q1, Q3),

n1

BL 25 (22, 29), 120 26 (23, 31), 120 27 (23, 31), 122

4 25 (22, 30), 117 27 (23, 29), 112 25 (22, 29), 118

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24

Dupilumab

100/200 mg q2w + TCS (n = 122)

NR (age 1–17 years) All: 11.0–41.0

8 25 (21, 30), 113 25 (22, 28), 116 26 (23, 29), 114

16 25 (22, 29), 114 25 (23, 29), 113 25 (22, 29), 120

4 0.8 (6.27), 117 −0.4 (4.68), 112 −1.4 (5.69), 118

8 0.4 (5.12), 113 −1.0 (5.15), 116 −0.5 (5.57), 114

16 0.6 (6.82), 114 −0.9 (5.73), 113 −1.5 (5.15), 120

Direct bilirubin (μmol/L)

NR (age 1–17 years) All: 0–6.8

Median (Q1, Q3), n1

BL 7.6 (6.8, 8.4), 2 NA NA

4 7.4 (7.4, 7.4), 1 9.1 (9.1, 9.1), 1 NA

8 NA 7.7 (7.7, 7.7), 1 7.7 (7.7, 7.7), 1

16 NA 8.4 (8.4, 8.4), 1 6.6 (6.2, 7.0), 2

4 −1.0 (NA), 1 NA NA

8 NA NA NA

16 NA NA NA

Bilirubin (μmol/L)

NR (age 1–17 years) All: NA–18.8

Median (Q1, Q3), n1

BL 3.9 (2.7, 5.4), 120 4.1 (3.1, 5.5), 120 3.9 (2.9, 5.3), 122 4 4.3 (2.7, 6.5), 117 4.3 (2.9, 5.5), 111 3.8 (3.1, 5.3), 118 8 3.8 (2.9, 5.6), 113 3.8 (2.7, 5.3), 114 4.4 (2.7, 6.0), 113 16 3.9 (2.9, 5.5), 114 4.1 (3.1, 5.8), 113 3.9 (2.9, 5.9), 120 Mean change

4 0.449 (2.1306), 117 0.396 (2.5958), 111 −0.067 (2.0558), 118 8 0.183 (2.4698), 113 −0.093 (2.2432), 114 0.179 (2.6347), 113 16 0.079 (2.1744), 114 0.335 (2.5070), 113 0.231 (2.4301), 120

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25

Dupilumab

100/200 mg q2w + TCS (n = 122)

Indirect bilirubin (μmol/L)

NR (age 1–17 years) All: 1.7–18.8

Median (Q1, Q3), n1

BL 14.2 (13.0, 15.4), 2 NA NA

4 15.2 (15.2, 15.2), 1 19.3 (19.3, 19.3), 1 NA

8 NA 12.0 (12.0, 12.0), 1 13.5 (13.5, 13.5), 1

16 NA 10.9 (10.9, 10.9), 1 15.55 (14.9, 16.2), 2

4 −0.20 (NA), 1 NA NA

8 NA NA NA

16 NA NA NA

Lactate dehydrogenase (U/L)

NR (age 2–17 years) All: 84.0–378.0

Median (Q1, Q3), n1

BL 265 (237, 314), 115 272 (237, 319), 119 285 (249, 315), 121 4 265 (233, 313), 115 247 (227, 269), 113 247 (224, 279), 117 8 263 (234, 308), 106 244 (223, 264), 113 252 (234, 288), 114 16 262 (236, 317), 112 241 (221, 275), 112 254 (227, 281), 119 Mean change

4 0.3 (47.49), 111 −34.3 (69.50), 112 −43.9 (62.21), 116

8 4.8 (58.63), 103 −40.6 (66.21), 112 −36.4 (77.40), 113

16 −0.4 (57.61), 107 −39.4 (68.49), 112 −42.2 (68.89), 118

BL baseline, n total number of patients in the treatment group, n1 number of patients with assessment at visit, NA not assessed, NR normal range, Q1 quartile 1, Q3 quartile 3, q2w every 2 weeks, q4w every 4 weeks, SD standard deviation, TCS topical corticosteroid

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26

Supplemental Table S4e Summary statistics for serum chemistry laboratory parameters: lipid panel

Dupilumab

100/200 mg q2w + TCS (n = 122)

Cholesterol (mmol/L) NR (all ages)

All: 3.24–5.18

Median (Q1, Q3), n1

BL 3.82 (3.43, 4.25), 120 3.86 (3.51, 4.24), 120 4.11 (3.52, 4.45), 122 4 3.81 (3.44, 4.17), 117 3.83 (3.42, 4.25), 113 4.04 (3.55, 4.45), 119 8 3.83 (3.44, 4.25), 113 3.81 (3.54, 4.19), 116 3.99 (3.47, 4.48), 115 16 3.86 (3.34, 4.30), 114 3.83 (3.44, 4.12), 113 4.04 (3.54, 4.42), 120 Mean change

from baseline (±SD), n1

4 0.024 (0.4108), 117 0.003 (0.4070), 113 −0.072 (0.4517), 119

8 0.077 (0.4088), 113 −0.026 (0.4043), 116 −0.076 (0.5073), 115 16 0.004 (0.5412), 114 −0.056 (0.4217), 113 −0.090 (0.5013), 120 HDL cholesterol

(mmol/L) NR (all ages)

All: 1.04–1.55

Median (Q1, Q3), n1

BL 1.30 (1.11, 1.49), 120 1.32 (1.17, 1.54), 120 1.37 (1.19, 1.55), 122 4 1.30 (1.11, 1.50), 117 1.35 (1.22, 1.55), 113 1.35 (1.19, 1.53), 119 8 1.30 (1.14, 1.53), 113 1.32 (1.17, 1.53), 116 1.35 (1.17, 1.55), 115 16 1.27 (1.09, 1.45), 114 1.32 (1.17, 1.55), 113 1.37 (1.22, 1.58), 120 Mean change

4 −0.001 (0.2146), 117 0.020 (0.2205), 113 −0.015 (0.2138), 119 8 −0.013 (0.1893), 113 −0.002 (0.2007), 116 −0.003 (0.2217), 115 16 −0.038 (0.2089), 114 0.015 (0.2308), 113 −0.001 (0.1869), 120 LDL cholesterol

All: 1.30–4.14

Median (Q1, Q3), n1

BL 1.96 (1.68, 2.35), 120 1.97 (1.68, 2.35), 120 2.07 (1.76, 2.59), 122 4 2.02 (1.63, 2.33), 117 2.07 (1.61, 2.36), 111 2.10 (1.79, 2.46), 117 8 2.05 (1.71, 2.38), 113 1.99 (1.58, 2.25), 114 1.99 (1.71, 2.46), 115 16 2.01 (1.63, 2.43), 114 1.89 (1.61, 2.18), 113 2.06 (1.75, 2.45), 120

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27

Dupilumab

100/200 mg q2w + TCS (n = 122)

4 0.039 (0.3685), 117 −0.008 (0.3745), 111 −0.049 (0.4126), 117 8 0.055 (0.3528), 113 −0.016 (0.3457), 114 −0.086 (0.3964), 115 16 0.002 (0.4573), 114 −0.050 (0.3525), 113 −0.084 (0.4214), 120 Triglycerides

All: 0.51–2.26

Median (Q1, Q3), n1

BL 0.98 (0.68, 1.37), 120 1.06 (0.75, 1.39), 120 0.99 (0.72, 1.49), 122 4 0.89 (0.66, 1.23), 117 0.93 (0.69, 1.41), 111 0.96 (0.71, 1.30), 118 8 0.92 (0.69, 1.47), 113 0.97 (0.70, 1.39), 115 0.98 (0.70, 1.31), 115 16 0.96 (0.67, 1.47), 114 0.89 (0.64, 1.29), 113 0.95 (0.68, 1.39), 120 Mean change

4 −0.031 (0.5759), 117 −0.018 (0.6094), 111 0.002 (0.5899), 118 8 0.077 (0.5659), 113 −0.001 (0.6194), 115 0.028 (0.6936), 115 16 0.090 (0.6204), 114 −0.041 (0.6128), 113 −0.015 (0.5795), 120 BL baseline, HDL high-density lipoprotein, LDL low-density lipoprotein, n total number of patients in the treatment group, n1 number of patients with assessment at visit, NR normal range, Q1 quartile 1, Q3 quartile 3, q2w every 2 weeks, q4w every 4 weeks, SD standard deviation, TCS topical corticosteroid

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28

Supplemental Table S4f Shift from baseline: LDH (U/L)

Study

week Evaluation n1/N2 (%)

Placebo + TCS (n = 120) Dupilumab

300 mg q4w + TCS (n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Baseline status

Low Normal High Low Normal High Low Normal High

4

Low 0/0 0/104 0/7 0/0 0/102 0/10 0/0 0/102 0/14

Normal 0/0 100/104 (96.2) 4/7 (57.1) 0/0 100/102 (98.0) 10/10 (100) 0/0 102/102 (100) 11/14 (78.6)

High 0/0 4/104 (3.8) 3/7 (42.9) 0/0 2/102 (2.0) 0/10 0/0 0/102 3/14 (21.4)

8

Low 0/0 0/95 0/8 0/0 0/102 0/10 0/0 0/98 0/15

Normal 0/0 90/95 (94.7) 4/8 (50.0) 0/0 102/102 (100) 9/10 (90.0) 0/0 96/98 (98.0) 12/15 (80.0)

High 0/0 5/95 (5.3) 4/8 (50.0) 0/0 0/102 1/10 (10.0) 0/0 2/98 (2.0) 3/15 (20.0)

16

Low 0/0 0/99 0/8 0/0 0/101 0/11 0/0 1/104 (1.0) 0/14

Normal 0/0 92/99 (92.9) 5/8 (62.5) 0/0 100/101 (99.0) 10/11 (90.9) 0/0 102/104 (98.1) 13/14 (92.9)

High 0/0 7/99 (7.1) 3/8 (37.5) 0/0 1/101 (1.0) 1/11 (9.1) 0/0 1/104 (1.0) 1/14 (7.1)

Normal range, age 2–17 years, 84.0–378.0 U/L

LDH lactate dehydrogenase, n total number of patients in the treatment group, n1 number of patients with evaluation level (low, normal, high) at visit, N2 number of patients with baseline status, q2w every 2 weeks, q4w every 4 weeks, TCS topical corticosteroid

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Supplemental Table S5a Proportion of patients with Grades 1–4 increases in ALP, n1/N1 (%)

Time

point Grade Placebo + TCS

(n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Baseline

Grade 1 (Mild): > ULN–2.5 × ULN if baseline was normal;

2.0–2.5 × ULN if baseline was abnormal 0/120 0/120 0/122

Grade 2 (Moderate): > 2.5–5.0 × ULN if baseline was normal;

> 2.5 –5.0 × baseline if baseline was abnormal 0/120 0/120 0/122

Grade 3 (Severe): > 5.0–20.0 × ULN if baseline was normal;

> 5.0–20.0 × baseline if baseline was abnormal 0/120 0/120 0/122

Grade 4 (Potentially life-threatening): > 20.0 × ULN if baseline

was normal; > 20.0 × baseline if baseline was abnormal 0/120 0/120 0/122

Week 4

2.0–2.5 × ULN if baseline was abnormal 4/117 (3.4) 2/111 (1.8) 1/117 (0.9)

Week 8

2.0–2.5 × ULN if baseline was abnormal 0/113 3/115 (2.6) 2/115 (1.7)

Week 16

2.0–2.5 × ULN if baseline was abnormal 4/114 (3.5) 5/113 (4.4) 7/120 (5.8)

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ALP alkaline phosphatase, n total number of patients in the treatment group, n1/N1 number of patients with grade/number of patients with assessment at visit, q2w every 2 weeks, q4w every 4 weeks, TCS topical corticosteroid, ULN upper limit of normal

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Supplemental Table S5b Proportion of patients with Grades 1–4 increases in bilirubin, n1/N1 (%)

Time

(n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Baseline

1.0–1.5 × baseline if baseline was abnormal 0/120 0/120 0/122

>1.5–3.0 × baseline if baseline was abnormal 0/120 0/120 0/122

Grade 4 (Potentially life-threatening): > 10.0 × ULN if baseline was

normal; > 10.0 × baseline if baseline was abnormal 0/120 0/120 0/122

Week 4

> 1.5–3.0 × baseline if baseline was abnormal 0/117 1/111 (0.9) 0/118

Week 8

1.0–1.5 × baseline if baseline was abnormal 0/113 1/114 (0.9) 1/113 (0.9)

Week 16

1.0–1.5 × baseline if baseline was abnormal 0/114 0/113 2/120 (1.7)

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n total number of patients in the treatment group, n1/N1 number of patients with grade/number of patients with assessment at visit, q2w every 2 weeks, q4w every 4 weeks, TCS topical corticosteroid, ULN upper limit of normal

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Supplemental Table S5c Proportion of patients with Grades 1–4 increases in ALT, n1/N1 (%)

Time

(n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Baseline

Week 4

1.5–3.0 × baseline if baseline was abnormal 5/117 (4.3) 2/113 (1.8) 4/119 (3.4)

> 3.0–5.0 × baseline if baseline was abnormal 1/117 (0.9) 0/113 0/119

Week 8

Week 16

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ALT alanine aminotransferase, n total number of patients in the treatment group, n1/N1 number of patients with grade/number of patients with assessment at visit, q2w every 2 weeks, q4w every 4 weeks, TCS topical corticosteroid, ULN upper limit of normal

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Supplemental Table S5d Proportion of patients with Grades 1–4 increases in AST, n1/N1 (%)

Time

(n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Baseline

Week 4

Week 8

Week 16

1.5–3.0 × baseline if baseline was abnormal 3/114 (2.6) 3/113 (2.7) 0/120

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AST aspartate aminotransferase, n total number of patients in the treatment group, n1/N1 number of patients with grade/number of patients with assessment at visit, q2w every 2 weeks, q4w every 4 weeks, TCS topical corticosteroid, ULN upper limit of normal

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Supplemental Table S5e Proportion of patients with Grades 1–4 increases in creatinine, n1/N1 (%)

(n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Baseline

Grade 1 (Mild): > ULN–1.5 × ULN 0/120 0/120 0/122

Grade 2 (Moderate): > 1.5–3.0 × baseline; > 1.5–3.0 × ULN 0/120 0/120 0/122

Grade 3 (Severe): > 3.0 × baseline; > 3.0–6.0 × ULN 0/120 0/120 0/122

Grade 4 (Potentially life-threatening): > 6.0 × ULN 0/120 0/120 0/122

Week 4

Grade 1 (Mild): > ULN–1.5 × ULN 1/117 (0.9) 0/112 1/119 (0.8)

Grade 2 (Moderate): > 1.5–3.0 × baseline; > 1.5–3.0 × ULN 2/117 (1.7) 2/112 (1.8) 4/119 (3.4)

Week 8

Week 16

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Supplemental Table S5f Proportion of patients with Grades 1–4 increases in potassium, n1/N1 (%)

(n = 120)

Dupilumab

300 mg q4w + TCS (n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Baseline

Grade 1 (Mild): > ULN–5.5 mmol/L 4/120 (3.3) 4/120 (3.3) 5/122 (4.1)

Grade 2 (Moderate): > 5.5–6.0 mmol/L 0/120 0/120 1/122 (0.8)

Grade 3 (Severe): > 6.0–7.0 mmol/L 0/120 0/120 0/122

Grade 4 (Potentially life-threatening): > 7.0 mmol/L 0/120 0/120 0/122

Week 4

Grade 1 (Mild): > ULN–5.5 mmol/L 1/117 (0.9) 4/111 (3.6) 0/119

Grade 2 (Moderate): > 5.5–6.0 mmol/L 0/117 0/111 0/119

Week 8

Grade 1 (Mild): > ULN–5.5 mmol/L 6/114 (5.3) 5/116 (4.3) 4/114 (3.5)

Grade 2 (Moderate): > 5.5–6.0 mmol/L 0/114 1/116 (0.9) 0/114

Grade 3 (Severe): > 6.0–7.0 mmol/L 2/114 (1.8) 0/116 0/114

Week 16

Grade 1 (Mild): > ULN–5.5 mmol/L 0/115 2/114 (1.8) 2/120 (1.7)

Grade 2 (Moderate): > 5.5–6.0 mmol/L 0/115 0/114 0/120

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Supplemental Table S6 Summary statistics for urinalysis laboratory parameters

Dupilumab

300 mg q4w + TCS (n = 120)

Dupilumab

100/200 mg q2w + TCS (n = 122)

Specific gravity NR (all ages)

All: 1.002–1.035

Median (Q1, Q3), n1

BL 1.024 (1.019, 1.028), 120 1.023 (1.017, 1.026), 120 1.023 (1.017, 1.027), 122 4 1.025 (1.018, 1.028), 117 1.021 (1.016, 1.027), 116 1.023 (1.0145, 1.028), 120 16 1.024 (1.017, 1.028), 116 1.023 (1.017, 1.027), 117 1.021 (1.014, 1.027), 120 Mean change from

baseline (± SD), n1

4 0.0004 (0.00857), 117 −0.0009 (0.00851), 116 −0.0008 (0.00793), 120 16 0.0002 (0.00914), 116 0 (0.00799), 117 −0.0015 (0.00949), 120 pH

NR (all ages)

All: 5.0–8.0 Median (Q1, Q3), n1

BL 6 (5, 7), 120 6 (5, 7), 120 6 (5, 7), 122

4 6 (5, 7), 117 6 (5, 6), 116 6 (5, 6.5), 120

16 6 (5, 7), 116 6 (5, 7), 117 6 (5, 6), 120

4 −0.1 (1.02), 117 −0.2 (1.04), 116 −0.1 (0.89), 120

16 0 (1.06), 116 −0.1 (0.99), 117 −0.1 (0.97), 120

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Supplemental Fig. S1 Absolute platelet counts

Normal range: Age 1–6 years: male, 197–382 × 10⁹/L; female, 213–363 × 10⁹/L; Age 7–12 years: male, 175–311 × 10⁹/L; female, 130–314 × 10⁹/L.

White horizontal lines indicate medians. X depicts mean values. Top and bottom of each box represents Q3 and Q2, respectively. Upper and lower vertical bars represent Q4 and Q1, respectively; horizontal segments on each end of the vertical bars represent minimum and maximum values

n total number of patients in the treatment group, n1 number of patients with a value for absolute count at visit, Q1 quartile 1, Q2 quartile 2, Q3 quartile 3, Q4 quartile 4, q2w every 2 weeks, q4w every 4 weeks, TCS topical corticosteroid

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Supplemental Fig. S2 Platelet counts in the patient who had Grade 3 thrombocytopenia

Horizontal dashed line represents the upper limit of Grade 3 thrombocytopenia (range, 25 × 10⁹/L to < 50 × 10⁹/L) q4w every 4 weeks, TCS topical corticosteroid

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Supplemental Fig. S3 Eosinophil counts in individual patients with Grade 3 eosinophilia

Horizontal dashed line represents the lower limit of grade 3 (range, > 5.00 × 10⁹/L) Medical history and TEAEs of type 2 inflammatory disorders:

• Patient 1: History — asthma, allergic rhinitis, food allergy, and other allergies; TEAEs — moderate eosinophilia and mild allergic rhinitis

• Patient 2: History — asthma, allergic rhinitis, and other allergies

• Patient 3: History — asthma, allergic rhinitis, food allergy, and other allergies

• Patient 4: History — asthma and food allergies

• Patient 5: History — asthma, allergic rhinitis, chronic rhinosinusitis, and food allergy; TEAEs — mild asthma and mild urticaria