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
29
Supplemental Table S5a Proportion of patients with Grades 1–4 increases in ALP, n1/N1 (%)
Time
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
Grade 1 (Mild): > ULN–2.5 × ULN if baseline was normal;
2.0–2.5 × ULN if baseline was abnormal 4/117 (3.4) 2/111 (1.8) 1/117 (0.9)
Grade 2 (Moderate): > 2.5–5.0 × ULN if baseline was normal;
> 2.5 –5.0 × baseline if baseline was abnormal 0/117 0/111 0/117
Grade 3 (Severe): > 5.0–20.0 × ULN if baseline was normal;
> 5.0–20.0 × baseline if baseline was abnormal 0/117 0/111 0/117
Grade 4 (Potentially life-threatening): > 20.0 × ULN if baseline
was normal; > 20.0 × baseline if baseline was abnormal 0/117 0/111 0/117
Week 8
Grade 1 (Mild): > ULN–2.5 × ULN if baseline was normal;
2.0–2.5 × ULN if baseline was abnormal 0/113 3/115 (2.6) 2/115 (1.7)
Grade 2 (Moderate): > 2.5–5.0 × ULN if baseline was normal;
> 2.5 –5.0 × baseline if baseline was abnormal 0/113 0/115 0/115
Grade 3 (Severe): > 5.0–20.0 × ULN if baseline was normal;
> 5.0–20.0 × baseline if baseline was abnormal 0/113 0/115 0/115
Grade 4 (Potentially life-threatening): > 20.0 × ULN if baseline
was normal; > 20.0 × baseline if baseline was abnormal 0/113 0/115 0/115
Week 16
Grade 1 (Mild): > ULN–2.5 × ULN if baseline was normal;
2.0–2.5 × ULN if baseline was abnormal 4/114 (3.5) 5/113 (4.4) 7/120 (5.8)
Grade 2 (Moderate): > 2.5–5.0 × ULN if baseline was normal;
> 2.5–5.0 × baseline if baseline was abnormal 0/114 0/113 0/120
Grade 3 (Severe): > 5.0–20.0 × ULN if baseline was normal;
> 5.0–20.0 × baseline if baseline was abnormal 0/114 0/113 0/120
Grade 4 (Potentially life-threatening): > 20.0 × ULN if baseline
was normal; > 20.0 × baseline if baseline was abnormal 0/114 0/113 0/120
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]
30
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
31
Supplemental Table S5b Proportion of patients with Grades 1–4 increases in bilirubin, n1/N1 (%)
Time
Grade 1 (Mild): > ULN–1.5 × ULN if baseline was normal;
1.0–1.5 × baseline if baseline was abnormal 0/120 0/120 0/122
Grade 2 (Moderate): > 1.5–3.0 × ULN if baseline was normal;
>1.5–3.0 × baseline if baseline was abnormal 0/120 0/120 0/122
Grade 3 (Severe): > 3.0–10.0 × ULN if baseline was normal;
> 3.0–10.0 × 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
Grade 1 (Mild): > ULN–1.5 × ULN if baseline was normal;
1.0–1.5 × baseline if baseline was abnormal 0/117 0/111 0/118
Grade 2 (Moderate): > 1.5–3.0 × ULN if baseline was normal;
> 1.5–3.0 × baseline if baseline was abnormal 0/117 1/111 (0.9) 0/118
Grade 3 (Severe): > 3.0–10.0 × ULN if baseline was normal;
> 3.0–10.0 × baseline if baseline was abnormal 0/117 0/111 0/118
Grade 4 (Potentially life-threatening): > 10.0 × ULN if baseline was
normal; > 10.0 × baseline if baseline was abnormal 0/117 0/111 0/118
Week 8
Grade 1 (Mild): > ULN–1.5 × ULN if baseline was normal;
1.0–1.5 × baseline if baseline was abnormal 0/113 1/114 (0.9) 1/113 (0.9)
Grade 2 (Moderate): > 1.5–3.0 × ULN if baseline was normal;
> 1.5–3.0 × baseline if baseline was abnormal 0/113 0/114 0/113
Grade 3 (Severe): > 3.0–10.0 × ULN if baseline was normal;
> 3.0–10.0 × baseline if baseline was abnormal 0/113 0/114 0/113
Grade 4 (Potentially life-threatening): > 10.0 × ULN if baseline was
normal; > 10.0 × baseline if baseline was abnormal 0/113 0/114 0/113
Week 16
Grade 1 (Mild): > ULN–1.5 × ULN if baseline was normal;
1.0–1.5 × baseline if baseline was abnormal 0/114 0/113 2/120 (1.7)
Grade 2 (Moderate): > 1.5–3.0 × ULN if baseline was normal;
> 1.5–3.0 × baseline if baseline was abnormal 0/114 0/113 0/120
Grade 3 (Severe): > 3.0–10.0 × ULN if baseline was normal;
> 3.0–10.0 × baseline if baseline was abnormal 0/114 0/113 0/120
Grade 4 (Potentially life-threatening): > 10.0 × ULN if baseline was
normal; > 10.0 × baseline if baseline was abnormal 0/114 0/113 0/120
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]
32
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
33
Supplemental Table S5c Proportion of patients with Grades 1–4 increases in ALT, n1/N1 (%)
Time
Grade 1 (Mild): > ULN–3.0 × ULN if baseline was normal;
1.5–3.0 × baseline if baseline was abnormal 0/120 0/120 0/122
Grade 2 (Moderate): > 3.0–5.0 × ULN if baseline was normal;
> 3.0–5.0 × 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
Grade 1 (Mild): > ULN–3.0 × ULN if baseline was normal;
1.5–3.0 × baseline if baseline was abnormal 5/117 (4.3) 2/113 (1.8) 4/119 (3.4)
Grade 2 (Moderate): > 3.0–5.0 × ULN if baseline was normal;
> 3.0–5.0 × baseline if baseline was abnormal 1/117 (0.9) 0/113 0/119
Grade 3 (Severe): > 5.0–20.0 × ULN if baseline was normal;
> 5.0–20.0 × baseline if baseline was abnormal 0/117 0/113 0/119
Grade 4 (Potentially life-threatening): > 20.0 × ULN if baseline
was normal; > 20.0 × baseline if baseline was abnormal 0/117 0/113 0/119
Week 8
Grade 1 (Mild): > ULN–3.0 × ULN if baseline was normal;
1.5–3.0 × baseline if baseline was abnormal 5/113 (4.4) 4/114 (3.5) 4/114 (3.5)
Grade 2 (Moderate): > 3.0–5.0 × ULN if baseline was normal;
> 3.0–5.0 × baseline if baseline was abnormal 0/113 0/114 0/114
Grade 3 (Severe): > 5.0–20.0 × ULN if baseline was normal;
> 5.0–20.0 × baseline if baseline was abnormal 0/113 0/114 0/114
Grade 4 (Potentially life-threatening): > 20.0 × ULN if baseline
was normal; > 20.0 × baseline if baseline was abnormal 0/113 0/114 0/114
Week 16
Grade 1 (Mild): > ULN–3.0 × ULN if baseline was normal;
1.5–3.0 × baseline if baseline was abnormal 3/114 (2.6) 2/113 (1.8) 3/120 (2.5)
Grade 2 (Moderate): > 3.0–5.0 × ULN if baseline was normal;
> 3.0–5.0 × baseline if baseline was abnormal 0/114 0/113 0/120
Grade 3 (Severe): > 5.0–20.0 × ULN if baseline was normal;
> 5.0–20.0 × baseline if baseline was abnormal 0/114 0/113 0/120
Grade 4 (Potentially life-threatening): > 20.0 × ULN if baseline
was normal; > 20.0 × baseline if baseline was abnormal 0/114 0/113 0/120
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]
34
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
35
Supplemental Table S5d Proportion of patients with Grades 1–4 increases in AST, n1/N1 (%)
Time
Grade 1 (Mild): > ULN–3.0 × ULN if baseline was normal;
1.5–3.0 × baseline if baseline was abnormal 0/120 0/120 0/122
Grade 2 (Moderate): > 3.0–5.0 × ULN if baseline was normal;
> 3.0–5.0 × 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
Grade 1 (Mild): > ULN–3.0 × ULN if baseline was normal;
1.5–3.0 × baseline if baseline was abnormal 3/117 (2.6) 4/112 (3.6) 2/118 (1.7)
Grade 2 (Moderate): > 3.0–5.0 × ULN if baseline was normal;
> 3.0–5.0 × baseline if baseline was abnormal 0/117 0/112 0/118
Grade 3 (Severe): > 5.0–20.0 × ULN if baseline was normal;
> 5.0–20.0 × baseline if baseline was abnormal 0/117 0/112 0/118
Grade 4 (Potentially life-threatening): > 20.0 × ULN if baseline
was normal; > 20.0 × baseline if baseline was abnormal 0/117 0/112 0/118
Week 8
Grade 1 (Mild): > ULN–3.0 × ULN if baseline was normal;
1.5–3.0 × baseline if baseline was abnormal 3/113 (2.7) 1/116 (0.9) 2/114 (1.8)
Grade 2 (Moderate): > 3.0–5.0 × ULN if baseline was normal;
> 3.0–5.0 × baseline if baseline was abnormal 0/113 0/116 0/114
Grade 3 (Severe): > 5.0–20.0 × ULN if baseline was normal;
> 5.0–20.0 × baseline if baseline was abnormal 0/113 0/116 0/114
Grade 4 (Potentially life-threatening): > 20.0 × ULN if baseline
was normal; > 20.0 × baseline if baseline was abnormal 0/113 0/116 0/114
Week 16
Grade 1 (Mild): > ULN–3.0 × ULN if baseline was normal;
1.5–3.0 × baseline if baseline was abnormal 3/114 (2.6) 3/113 (2.7) 0/120
Grade 2 (Moderate): > 3.0–5.0 × ULN if baseline was normal;
> 3.0–5.0 × baseline if baseline was abnormal 0/114 0/113 0/120
Grade 3 (Severe): > 5.0–20.0 × ULN if baseline was normal;
> 5.0–20.0 × baseline if baseline was abnormal 0/114 0/113 0/120
Grade 4 (Potentially life-threatening): > 20.0 × ULN if baseline
was normal; > 20.0 × baseline if baseline was abnormal 0/114 0/113 0/120
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]
36
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
37
Supplemental Table S5e Proportion of patients with Grades 1–4 increases in creatinine, 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): > 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)
Grade 3 (Severe): > 3.0 × baseline; > 3.0–6.0 × ULN 0/117 0/112 0/119
Grade 4 (Potentially life-threatening): > 6.0 × ULN 0/117 0/112 0/119
Week 8
Grade 1 (Mild): > ULN–1.5 × ULN 0/113 0/114 0/113
Grade 2 (Moderate): > 1.5–3.0 × baseline; > 1.5–3.0 × ULN 4/113 (3.5) 5/114 (4.4) 5/113 (4.4)
Grade 3 (Severe): > 3.0 × baseline; > 3.0–6.0 × ULN 0/113 0/114 0/113
Grade 4 (Potentially life-threatening): > 6.0 × ULN 0/113 0/114 0/113
Week 16
Grade 1 (Mild): > ULN–1.5 × ULN 0/114 0/113 0/120
Grade 2 (Moderate): > 1.5–3.0 × baseline; > 1.5–3.0 × ULN 5/114 (4.4) 7/113 (6.2) 2/120 (1.7)
Grade 3 (Severe): > 3.0 × baseline; > 3.0–6.0 × ULN 0/114 0/113 0/120
Grade 4 (Potentially life-threatening): > 6.0 × ULN 0/114 0/113 0/120
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]
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
38
Supplemental Table S5f Proportion of patients with Grades 1–4 increases in potassium, 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): > 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
Grade 3 (Severe): > 6.0–7.0 mmol/L 0/117 0/111 0/119
Grade 4 (Potentially life-threatening): > 7.0 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
Grade 4 (Potentially life-threatening): > 7.0 mmol/L 0/114 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
Grade 3 (Severe): > 6.0–7.0 mmol/L 0/115 0/114 0/120
Grade 4 (Potentially life-threatening): > 7.0 mmol/L 0/115 0/114 0/120
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]
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