Trial Outcomes & Findings for Dupilumab for the Treatment of Chronic Inducible Cold Urticaria in Patients Who Remain Symptomatic Despite the Use of H1-antihistamine (LIBERTY-CINDU CUrIADS) (NCT NCT04681729)

NCT ID: NCT04681729

Last Updated: 2025-09-10

Results Overview

The ice cube provocation test is the most frequently used provocation method for cold urticaria (ColdU). A negative ice cube provocation test was defined as the absence of confluent hives/wheal at the entire skin site of exposure after ice cube provocation test. Ice cube was applied on forearm skin for 5 minutes. Provocation test reading time was 10 minutes after removal of ice cube.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 82 participants
• Primary outcome timeframe: Week 24
• Results posted on: 2025-09-10

Participant Flow

Study was conducted at 32 active sites in 5 countries. A total of 123 participants were screened between 10 December 2020 and 22 June 2022, of which 41 were screen failures. Screen failures were mainly due to not meeting eligibility criteria.

A total of 82 participants were randomized in 1:1 ratio to receive the study treatment with dupilumab or placebo. Randomization was stratified by age (adults versus adolescents with body weight [BW] greater than or equal to [>=] 60 kilograms [kg] or >=30 kg and less than [<] 60 kg), country and background H1-antihistamine regular/daily use (Yes/No).

Participant milestones

Measure	Placebo Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 milligrams \[mg\] or 400 mg) subcutaneous (SC) injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection every 2 weeks (q2w) up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Overall Study STARTED	40	42
Overall Study COMPLETED	30	31
Overall Study NOT COMPLETED	10	11

Reasons for withdrawal

Measure	Placebo Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 milligrams \[mg\] or 400 mg) subcutaneous (SC) injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection every 2 weeks (q2w) up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Overall Study Lack of Efficacy	2	2
Overall Study Withdrawal by Subject	8	9

Baseline Characteristics

Dupilumab for the Treatment of Chronic Inducible Cold Urticaria in Patients Who Remain Symptomatic Despite the Use of H1-antihistamine (LIBERTY-CINDU CUrIADS)

Baseline characteristics by cohort

Measure	Placebo n=40 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=42 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.	Total n=82 Participants Total of all reporting groups
Age, Continuous	37.9 years STANDARD_DEVIATION 16.3 • n=5 Participants	33.0 years STANDARD_DEVIATION 13.1 • n=7 Participants	35.4 years STANDARD_DEVIATION 14.9 • n=5 Participants
Sex: Female, Male Female	30 Participants n=5 Participants	33 Participants n=7 Participants	63 Participants n=5 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	9 Participants n=7 Participants	19 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	4 Participants n=5 Participants	6 Participants n=7 Participants	10 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	35 Participants n=5 Participants	35 Participants n=7 Participants	70 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 24

Population: The Intent-to-treat (ITT) population consisted of all randomized participants who had been allocated to a randomized intervention by IRT regardless of whether the treatment kit was used or not and were analyzed according to the intervention group allocated by randomization.

The ice cube provocation test is the most frequently used provocation method for cold urticaria (ColdU). A negative ice cube provocation test was defined as the absence of confluent hives/wheal at the entire skin site of exposure after ice cube provocation test. Ice cube was applied on forearm skin for 5 minutes. Provocation test reading time was 10 minutes after removal of ice cube.

Outcome measures

Measure	Placebo n=40 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=42 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Percentage of Participants With Negative Ice Cube Provocation Test at Week 24	37.5 percentage of participants	40.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: The ITT population consisted of all randomized participants who had been allocated to a randomized intervention by IRT regardless of whether the treatment kit was used or not and were analyzed according to the intervention group allocated by randomization. Only data from the participants analyzed were reported.

UCT is validated patient reported outcome (PRO) questionnaire used for assessing urticaria control. UCT has been developed and validated with participants Chronic Spontaneous Urticaria (CSU) and Chronic inducible urticaria (CIndU). It comprised of 4 items: severity of physical symptoms of urticaria (itch, hives and/or swelling); quality of life (QoL) impairment; frequency of treatment being not sufficient to control urticaria; overall urticarial control. Each item was rated on a 5-point Likert scale ranged from 0 (high disease activity) to 4 (low disease activity). The UCT total score was calculated as sum of all 4 individual item scores,ranged from 0 to 16. Higher scores indicated low disease activity, complete disease control, and vice-versa. Least square (LS) mean and standard error (SE) were analyzed using Analysis of covariance (ANCOVA) model with corresponding Baseline value, intervention group, region and background H1-antihistamine regular/daily use (Yes or No) as covariates.

Outcome measures

Measure	Placebo n=30 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=32 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Change From Baseline in Urticaria Control Test (UCT) Scale Scores at Week 24	3.75 score on a scale Standard Error 0.89	4.36 score on a scale Standard Error 0.80

SECONDARY outcome

Timeframe: Week 24

Population: The ITT population consisted of all randomized participants who had been allocated to a randomized intervention by IRT regardless of whether the treatment kit was used or not and were analyzed according to the intervention group allocated by randomization.

The UCT is a validated PRO questionnaire used for assessing urticaria control. The questionnaire has been developed and validated with participants with CSU and CIndU. It comprised of 4 items: severity of physical symptoms of urticaria (itch, hives and/or swelling); QoL impairment; frequency of treatment being not sufficient to control urticaria; overall urticarial control. Each item was rated on a 5-point Likert scale ranging from 0 to 4, with low score indicating high disease activity and low disease control, and vice-versa. The UCT total score was calculated as sum of all 4 individual item scores, which ranged from 0 to 16. Higher scores indicated low disease activity and complete disease control, and vice-versa. A score of >=12 on the scale indicates well-controlled urticaria. Percentage of participants with UCT score >=12 (i.e., well controlled urticaria) at Week 24 are reported in this endpoint.

Outcome measures

Measure	Placebo n=40 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=42 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Percentage of Participants With Urticaria Control Test Score >=12 at Week 24	27.5 percentage of participants	33.3 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: The ITT population consisted of all randomized participants who had been allocated to a randomized intervention by IRT regardless of whether the treatment kit was used or not and were analyzed according to the intervention group allocated by randomization.

The UCT is a validated PRO questionnaire used for assessing urticaria control. The questionnaire has been developed and validated with participants with CSU and CIndU. It comprised of 4 items: severity of physical symptoms of urticaria (itch, hives and/or swelling); QoL impairment; frequency of treatment being not sufficient to control urticaria; overall urticarial control. Each item was rated on a 5-point Likert scale ranging from 0 (high disease activity) to 4 (low disease activity), with low score indicating high disease activity and low disease control, and vice-versa. The UCT total score was calculated as sum of all 4 individual item scores, which ranged from 0 to 16. Higher scores indicated low disease activity and complete disease control, and vice-versa.

Outcome measures

Measure	Placebo n=40 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=42 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Percentage of Participants With an Improvement of >=3 Points From Baseline in Urticaria Control Test Score at Week 24	30.0 percentage of participants	45.2 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 12 and Week 24

Population: The ITT population consisted of all randomized participants who had been allocated to a randomized intervention by IRT regardless of whether the treatment kit was used or not and were analyzed according to the intervention group allocated by randomization. Here, only participants with available data for each specified category were reported.

Wheal intensity Likert scale (ranging from 0 to 5) is a clinician-reported endpoint completed at the study visit, 10 minutes after removal of the ice cube from the participants' arm. The scale comprised of a single item assessing the intensity of participants' cutaneous reaction rated as follows: 0 = no wheals; 1 = numerous small, non-coalescent wheals; 2 = a large, regular, slightly edematous, coalescent wheal; 3 = a large and moderately edematous wheal; 4 = a large, regular, and significantly edematous wheal without pseudopodia; and 5 = a large, very edematous wheal with pseudopodia. Higher score indicated greater severity. LS mean and SE were analyzed using ANCOVA model with the corresponding Baseline value, intervention group, region and background H1-antihistamine regular/daily use (Yes or No) as covariates.

Outcome measures

Measure	Placebo n=40 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=42 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Change From Baseline in Local Wheal Intensity Likert Scale Score at Weeks 12 and 24 Week 12	-1.49 score on a scale Standard Error 0.23	-1.19 score on a scale Standard Error 0.23
Change From Baseline in Local Wheal Intensity Likert Scale Score at Weeks 12 and 24 Week 24	-1.52 score on a scale Standard Error 0.28	-1.55 score on a scale Standard Error 0.27

SECONDARY outcome

Timeframe: Baseline, Week 12 and Week 24

Population: The ITT population consisted of all randomized participants who had been allocated to a randomized intervention by IRT regardless of whether the treatment kit was used or not and were analyzed according to the intervention group allocated by randomization. Here, only participants with available data for each specified category were reported.

Local itch (pruritus) severity was assessed using the peak pruritus numerical rating scale (NRS). Peak pruritus NRS is a PRO comprised of a single item rated on a scale ranged from 0 ("No itch") to 10 ("Worst itch imaginable"), where higher scores indicated worse itch. Participants were asked to rate the intensity of their worst local site itch (pruritus) 10 minutes after removal of the ice cube. LS mean and SE were analyzed using ANCOVA model with the corresponding Baseline value, intervention group, region and background H1-antihistamine regular/daily use (Yes or No) as covariates.

Outcome measures

Measure	Placebo n=40 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=42 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Change From Baseline in Local Itch Severity Scale Score at Weeks 12 and 24 Week 12	-2.12 score on a scale Standard Error 0.58	-2.52 score on a scale Standard Error 0.59
Change From Baseline in Local Itch Severity Scale Score at Weeks 12 and 24 Week 24	-2.18 score on a scale Standard Error 0.63	-2.43 score on a scale Standard Error 0.62

SECONDARY outcome

Timeframe: Baseline, Week 12 and Week 24

Population: The ITT population consisted of all randomized participants who had been allocated to a randomized intervention by IRT regardless of whether the treatment kit was used or not and were analyzed according to the intervention group allocated by randomization. Here, only participants with available data for each specified category were reported.

Local skin burning sensation was assessed using peak burning sensation NRS which is a PRO comprised of a single item rated on a scale ranged from 0 ("No burning sensation") to 10 ("Worst imaginable burning sensation"). Higher score indicated worst burning sensation. Participants were asked to rate the intensity of the worst local site burning sensation of their skin 10 minutes after the removal of the ice cube. LS mean and SE were analyzed using ANCOVA model with the corresponding Baseline value, intervention group, region and background H1-antihistamine regular/daily use (Yes or No) as covariates.

Outcome measures

Measure	Placebo n=40 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=42 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Change From Baseline in Local Skin Burning Sensation Scale Score at Weeks 12 and 24 Week 12	-1.60 score on a scale Standard Error 0.60	-2.43 score on a scale Standard Error 0.61
Change From Baseline in Local Skin Burning Sensation Scale Score at Weeks 12 and 24 Week 24	-1.76 score on a scale Standard Error 0.69	-2.04 score on a scale Standard Error 0.68

SECONDARY outcome

Timeframe: Baseline, Week 12 and Week 24

Population: The ITT population consisted of all randomized participants who had been allocated to a randomized intervention by IRT regardless of whether the treatment kit was used or not and were analyzed according to the intervention group allocated by randomization. Here, only participants with available data for each specified category were reported.

Local pain severity was assessed using peak pain NRS. The peak pain NRS is a PRO comprised of a single item rated on a scale ranged from 0 ("No pain") to 10 ("Worst imaginable pain"). Higher score indicated worst pain. Participants were asked to rate the intensity of their worst local site pain 10 minutes after removal of the ice cube. LS mean and SE was analyzed using ANCOVA model with the corresponding Baseline value, intervention group, region and background H1-antihistamine regular/daily use (Yes or No) as covariates.

Outcome measures

Measure	Placebo n=40 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=42 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Change From Baseline in Local Pain Severity Scale Score at Weeks 12 and 24 Week 12	-1.82 score on a scale Standard Error 0.54	-2.14 score on a scale Standard Error 0.55
Change From Baseline in Local Pain Severity Scale Score at Weeks 12 and 24 Week 24	-1.60 score on a scale Standard Error 0.58	-2.28 score on a scale Standard Error 0.57

SECONDARY outcome

Timeframe: Week 12

Population: The ITT population consisted of all randomized participants who had been allocated to a randomized intervention by IRT regardless of whether the treatment kit was used or not and were analyzed according to the intervention group allocated by randomization.

The ice cube provocation test is the most frequently used provocation method for ColdU. A negative ice cube provocation test was defined as the absence of confluent hives/wheal at the entire skin site of exposure after ice cube provocation test. Ice cube was applied on forearm skin for 5 minutes. Provocation test reading time was 10 minutes after removal of ice cube.

Outcome measures

Measure	Placebo n=40 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=42 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Percentage of Participants With Negative Ice Cube Provocation Test at Week 12	35.0 percentage of participants	31.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: The ITT population consisted of all randomized participants who had been allocated to a randomized intervention by IRT regardless of whether the treatment kit was used or not and were analyzed according to the intervention group allocated by randomization. Only data from the participants analyzed were reported.

Cold Urticaria Activity Score (ColdUAS) is disease-specific PRO questionnaire designed to determine cold urticaria disease activity. Intended for participants with cold urticaria aged 12 years old and above; developed and comprehensively tested with adults and adolescent participants with cold urticaria. Disease activity assessment was based on daily documentation of cold-induced skin reactions (wheals and swelling), skin sensations (itching, burning, pain or feeling hot), avoidance behavior and trigger exposure, and overall symptoms severity. Skin reaction, skin sensations, exposition to cold temperatures that usually cause ColdU symptoms and overall symptom severity were rated on a 4-point scale ranged from 0 (less severe) to 4 (more severe), where higher score indicated more signs and symptoms. LS mean and SE were analyzed using ANCOVA model with corresponding Baseline value, intervention group, region and background H1-antihistamine regular/daily use (Yes/No) as covariates.

Outcome measures

Measure	Placebo n=29 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=24 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Change From Baseline in Cold Urticaria Signs and Symptoms Severity Scale Score at Week 24	-1.04 score on a scale Standard Error 0.23	-1.28 score on a scale Standard Error 0.22

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: The ITT population consisted of all randomized participants who had been allocated to a randomized intervention by IRT regardless of whether the treatment kit was used or not and were analyzed according to the intervention group allocated by randomization. Only data from the participants analyzed were reported.

ColdUAS: disease-specific PRO questionnaire to determine cold urticaria disease activity in adults and adolescents with cold urticaria. For change from Baseline in percentage of cold urticaria sign and symptom-free days, responses to ColdUAS question (Q) 1 (rating severity of signs: wheals and swelling) and ColdUAS, Q2 (rating severity of symptoms: itch, burning, pain, or feeling hot) on days exposed to cold (ColdUAS Q3 responded Yes) were used. Within 14-day interval before each visit the number of sign and symptom-free days (ColdUAS Q1=0 and Q2=0) on days exposed to cold (ColdUAS Q3 greater than >0) was counted and divided by total number of days exposed to cold in this interval. Percentage of cold urticaria sign and symptom free days = sign and symptom free days/cold exposure days in 14 days window*100. LS mean and SE by ANCOVA model with the corresponding Baseline value, intervention group, region and background H1-antihistamines regular/daily use (Yes/No) as covariates.

Outcome measures

Measure	Placebo n=29 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=24 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Change From Baseline in Percentage of Cold Urticaria Sign and Symptom-Free Days at Week 24	15.66 percentage of days Standard Error 7.49	27.82 percentage of days Standard Error 7.26

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: The ITT population consisted of all randomized participants who had been allocated to a randomized intervention by IRT regardless of whether the treatment kit was used or not and were analyzed according to the intervention group allocated by randomization. Only data from the participants analyzed were reported.

DLQI is a PRO developed to measure dermatology-specific HRQoL in adults. It comprises 10 items assessing the impact of skin disease on participant's HRQoL over the previous week. The items cover symptoms, leisure activities, work/school or holiday time, personal relationships including intimate, side effects of treatment, and emotional reactions to having a skin disease. It is a validated questionnaire used in clinical practice and clinical trials. For 9-items; response scale was a 4-point Likert scale ranging from 0 = "Not at all" to 3 = "Very much", where higher score=more impact of QoL, and vice-versa. The remaining 1 item about work/studying was rated on a 3-point Likert scale ranged from 0="Not at all" to 2="A lot". DLQI total score was the sum of score of all the items and ranged from 0 to 30, with a high score indicated poor HRQoL, and vice-versa. LS mean and SE from ANCOVA model.

Outcome measures

Measure	Placebo n=28 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=29 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Change From Baseline in Health-related Quality-of-life (HRQoL) as Measured by Dermatology Life Quality Index (DLQI) Scale Scores at Week 24	-4.70 score on a scale Standard Error 1.08	-4.32 score on a scale Standard Error 1.00

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: The ITT population consisted of all randomized participants who had been allocated to a randomized intervention by IRT regardless of whether the treatment kit was used or not and were analyzed according to the intervention group allocated by randomization. Only data from the participants analyzed were reported.

The ColdU-QoL questionnaire is a disease-specific PRO questionnaire designed to assess the impact of cold urticaria on participant's HRQoL. It has been developed and comprehensively tested with adults and adolescent participants with cold urticaria. The questionnaire contains 19 items, each rated using a 5-point Likert scale ranged from 0 (Not at all / Never) to 4 (Very much / Very often). The total raw score of the ColdU-QoL was transformed to a 0 to 100 score for analysis using the formula: ColdU-QoL total score = Sum of the score of all completed items/Maximum possible sum of the score of all completed items*100. Higher scores indicated higher ColdU-related QoL impairment, and vice-versa. LS mean and SE were analyzed from ANCOVA model with the corresponding Baseline value, intervention group, region and background H1-antihistamine regular/daily use (Yes or No) as covariates.

Outcome measures

Measure	Placebo n=31 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=32 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Change From Baseline in Cold Urticaria Quality of Life (ColdU-QoL) Scale Score at Week 24	-20.12 score on a scale Standard Error 3.81	-20.07 score on a scale Standard Error 3.65

SECONDARY outcome

Timeframe: From first investigational medicinal product (IMP) administration (Day 1) up to Week 24

Population: The ITT population consisted of all randomized participants who had been allocated to a randomized intervention by IRT regardless of whether the treatment kit was used or not and were analyzed according to the intervention group allocated by randomization.

Rescue therapy included additional doses of H1-antihistamines and short course of oral corticosteroids (OCS).

Outcome measures

Measure	Placebo n=40 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=42 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Percentage of Participants Receiving Rescue Therapy for Primary Acquired Chronic Inducible Cold Urticaria OCS	2.5 percentage of participants	0 percentage of participants
Percentage of Participants Receiving Rescue Therapy for Primary Acquired Chronic Inducible Cold Urticaria H1-antihistamines	32.5 percentage of participants	45.2 percentage of participants

SECONDARY outcome

Timeframe: From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36)

Population: The ITT population consisted of all randomized participants who had been allocated to a randomized intervention by IRT regardless of whether the treatment kit was used or not and were analyzed according to the intervention group allocated by randomization.

Percentage of participants with cold exposure triggered urticaria that required hospitalization/emergency medical care visit or treatment with epinephrine are reported in this endpoint.

Outcome measures

Measure	Placebo n=40 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=42 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Percentage of Participants With Cold Exposure Triggered Urticaria That Required Hospitalization/Emergency Medical Care Visit or Treatment With Epinephrine Hospitalization/emergency medical care visit	0 percentage of participants	0 percentage of participants
Percentage of Participants With Cold Exposure Triggered Urticaria That Required Hospitalization/Emergency Medical Care Visit or Treatment With Epinephrine Epinephrine treatment	0 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36)

Population: The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.

An Adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. Serious adverse events (SAEs) was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the treatment-emergent period (from the first IMP administration to the last IMP administration + 14 weeks).

Outcome measures

Measure	Placebo n=39 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=43 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) TEAEs	27 Participants	23 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) TESAEs	0 Participants	1 Participants

SECONDARY outcome

Timeframe: From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36)

Population: The ADA population consisted of all participants who were randomized and received at least 1 dose of IMP and had at least 1 non-missing ADA result after first dose of IMP. Participants were analyzed according to the intervention actually received.

ADA response was categorized as: Treatment-emergent and Treatment-boosted. Treatment-emergent ADAs were defined as a positive response in the ADA assay post-first dose, when baseline results were negative or missing. Treatment-boosted ADAs: defined as an ADA positive response in the assay post first dose that was >=4-fold over baseline titer levels, when Baseline results were positive. Titer values were defined as low titer (< 1,000); moderate (1,000 less than or equal to [<=] titer <=10,000) and high titer (> 10,000).

Outcome measures

Measure	Placebo n=36 Participants Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1- antihistamine.	Dupilumab n=38 Participants Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Number of Participants With Treatment-emergent Antidrug Antibodies (ADA) Response Treatment-emergent ADAs	0 Participants	4 Participants
Number of Participants With Treatment-emergent Antidrug Antibodies (ADA) Response Treatment-boosted ADAs	0 Participants	0 Participants

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 16 other events

Deaths: 0 deaths

Dupilumab

Serious events: 1 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=39 participants at risk Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.	Dupilumab n=43 participants at risk Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
Psychiatric disorders Bipolar Disorder	0.00% 0/39 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.	2.3% 1/43 • Number of events 1 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.

Other adverse events

Measure	Placebo n=39 participants at risk Participants based on their BW \>=60 kg or BW \>=30 kg and \<60 kg received loading dose of placebo (matched to dupilumab 600 mg or 400 mg) SC injection on Day 1, respectively, followed by placebo (matched to dupilumab 300 mg or 200 mg) SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.	Dupilumab n=43 participants at risk Participants based on their BW \>=60 kg or \>=30 kg and \<60 kg received loading dose of dupilumab 600 mg or 400 mg SC injection on Day 1, respectively, followed by dupilumab 300 mg or 200 mg SC injection q2w up to Week 22 along with their established standard of care background therapy with a long-acting non-sedating H1-antihistamine.
General disorders Injection Site Erythema	0.00% 0/39 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.	7.0% 3/43 • Number of events 4 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.
General disorders Injection Site Pain	2.6% 1/39 • Number of events 1 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.	9.3% 4/43 • Number of events 8 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.
General disorders Injection Site Reaction	2.6% 1/39 • Number of events 1 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.	14.0% 6/43 • Number of events 26 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.
General disorders Pyrexia	5.1% 2/39 • Number of events 2 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.	0.00% 0/43 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.
Infections and infestations Covid-19	20.5% 8/39 • Number of events 8 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.	11.6% 5/43 • Number of events 5 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.
Infections and infestations Suspected Covid-19	7.7% 3/39 • Number of events 3 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.	4.7% 2/43 • Number of events 2 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.
Injury, poisoning and procedural complications Accidental Overdose	5.1% 2/39 • Number of events 2 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.	2.3% 1/43 • Number of events 1 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.
Nervous system disorders Headache	5.1% 2/39 • Number of events 3 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.	2.3% 1/43 • Number of events 1 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.
Skin and subcutaneous tissue disorders Eczema Asteatotic	5.1% 2/39 • Number of events 3 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.	0.00% 0/43 • From first IMP administration (Day 1) up to 14 weeks after last IMP administration (i.e., up to Week 36) The Safety population consisted of all participants who were randomized and received at least 1 dose of IMP and were analyzed according to the intervention actually received.

Additional Information

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