Vaccine Responses in Tralokinumab-Treated Atopic Dermatitis - ECZTRA 5 (ECZema TRAlokinumab Trial No. 5) (ECZTRA 5)

• ClinicalTrials.gov Identifier: NCT03562377
• Recruitment Status: Completed
• First Posted: June 19, 2018
• Results First Posted: March 5, 2021
• Last Update Posted: March 5, 2021
• Sponsor: LEO Pharma
• Information provided by (Responsible Party): LEO Pharma

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Atopic Dermatitis
• Interventions: Drug: Tralokinumab; Drug: Placebo; Biological: Tdap vaccine; Biological: Meningococcal vaccine
• Enrollment: 215

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Tralokinumab	Placebo
Arm/Group Description	Participants received tralokinumab every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.	Participants received placebo every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.
Period Title: Treatment Period
Started	107 [1]	108 [1]
Safety Analysis Set [2]	107	107
Per Protocol Anaysis Set [3]	88	78
Full Analysis Set [4]	106	108
Completed	100 [5]	89 [5]
Not Completed	7	19
[1] Number of participants assigned to treatment; [2] Defined as all participants randomised to treatment who were exposed to IMP (tralokinumab/placebo).; [3] Excluding participants who did not receive vaccines, violated selected eligiblity criteria, etc.; [4] Defined as all participants randomised to treatment who were exposed to IMP (tralokinumab/placebo); [5] Number of participants attending the Week 16 visit (end of treatment visit)
Period Title: Safety Follow-up Period
Started	75 [1]	75 [1]
Completed	16 [2]	18 [2]
Not Completed	59	57
[1] Last contact after exposure end. Main reason for not entering follow-up: transfer to extension trial; [2] Attended Week 30 visit. Main reason for not attending was transfer to long-term extension trial.

Baseline Characteristics

Arm/Group Title		Tralokinumab	Placebo	Total
Arm/Group Description		Participants received tralokinumab every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.	Participants received placebo every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.	Total of all reporting groups
Overall Number of Baseline Participants		107	108	215
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	107 participants	108 participants	215 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	107 100.0%	108 100.0%	215 100.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	107 participants	108 participants	215 participants
		34.0 (11.2)	34.4 (10.8)	34.2 (11.0)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	107 participants	108 participants	215 participants
	Female	53 49.5%	73 67.6%	126 58.6%
	Male	54 50.5%	35 32.4%	89 41.4%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	107 participants	108 participants	215 participants
	Hispanic or Latino	17 15.9%	19 17.6%	36 16.7%
	Not Hispanic or Latino	90 84.1%	89 82.4%	179 83.3%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	107 participants	108 participants	215 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	16 15.0%	18 16.7%	34 15.8%
	Native Hawaiian or Other Pacific Islander	0 0.0%	2 1.9%	2 0.9%
	Black or African American	25 23.4%	27 25.0%	52 24.2%
	White	62 57.9%	56 51.9%	118 54.9%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	4 3.7%	5 4.6%	9 4.2%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	107 participants	108 participants	215 participants
Canada		34	35	69
United States		73	73	146
Investigator's Global Assessment (IGA) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	107 participants	108 participants	215 participants
	Clear (IGA=0)	0 0.0%	0 0.0%	0 0.0%
	Almost clear (IGA=1)	0 0.0%	0 0.0%	0 0.0%
	Mild disease (IGA=2)	0 0.0%	0 0.0%	0 0.0%
	Moderate disease (IGA=3)	72 67.3%	72 66.7%	144 67.0%
	Severe disease (IGA=4)	34 31.8%	36 33.3%	70 32.6%
	Missing	1 0.9%	0 0.0%	1 0.5%
		[1] Measure Description: The IGA is an instrument used in clinical trials to rate the severity of the subject's global atopic dermatitis and is based on a 5-point scale ranging from 0 (clear) to 4 (severe).
Eczema Area and Severity Index score [1]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	107 participants	108 participants	215 participants
		26.26 (10.79)	26.75 (11.23)	26.51 (11.00)
		[1] Measure Description: The EASI is a validated measure used in clinical practice and clinical trials to assess the severity and extent of AD. The EASI is a composite index with scores ranging from 0 to 72, with higher values indicating more severe and/or more extensive condition.

Outcome Measures

1. Primary Outcome

Title	Positive Anti-tetanus Response at Week 16
Description	The antibody response to Tdap vaccine will be assessed by measuring serum anti-tetanus IgG by an immunoassay. A positive response is defined as a 3-fold IgG increase compared to Week 12 if IgG ≤1.0 IU/mL at Week 12; or IgG ≥2.5 IU/mL if IgG >1.0 IU/mL at Week 12.
Time Frame	Week 12 to Week 16

Outcome Measure Data

Analysis Population Description

The per protocol analysis set was used for the primary analysis, excluding participants who did not provide vaccine response data at Week 12 (1 participant in the tralokinumab group and 2 participants in the placebo group).

Arm/Group Title	Tralokinumab	Placebo
Arm/Group Description:	Participants received tralokinumab every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.	Participants received placebo every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.
Overall Number of Participants Analyzed	87	76
Measure Type: Count of Participants; Unit of Measure: Participants
	80 92.0%	73 96.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tralokinumab, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority
	Comments	The difference in response rates was calculated using the Mantel-Haenszel estimate of the risk difference stratified by baseline disease severity together with the 2-sided 95% CI. Non-inferiority of tralokinumab was demonstrated if the lower limit of the 95% CI was greater than -25%. Power calculation assumed 160 subjects in the per protocol analysis set, providing 98% power to establish non-inferiority, assuming response rates of 80% in both treatment groups and a non-inferiority margin of -25%
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mantel Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-4.1
	Confidence Interval	(2-Sided) 95%; -11.3 to 3.1
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Positive Anti-meningococcal Response at Week 16
Description	The antibody response to meningococcal vaccine will be assessed by measuring serum anti-meningococcal IgG by an immunoassay. A positive response is defined as IgG ≥3.0 µg/mL with at least a 3-fold increase compared to Week 12.
Time Frame	Week 12 to Week 16

Outcome Measure Data

Analysis Population Description

The per protocol analysis set was used for the primary analysis, excluding participants who did not provide vaccine response data at Week 12 (2 participants in each treatment group).

Arm/Group Title	Tralokinumab	Placebo
Arm/Group Description:	Participants received tralokinumab every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.	Participants received placebo every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.
Overall Number of Participants Analyzed	86	76
Measure Type: Count of Participants; Unit of Measure: Participants
	74 86.0%	64 84.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tralokinumab, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority
	Comments	The difference in response rates was calculated using the Mantel-Haenszel estimate of the risk difference stratified by baseline disease severity together with the 2-sided 95% CI. Non-inferiority of tralokinumab was demonstrated if the lower limit of the 95% CI was greater than -25%. Power calculation assumed 160 subjects in the per protocol analysis set, providing 98% power to establish non-inferiority, assuming response rates of 80% in both treatment groups and a non-inferiority margin of -25%
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mantel Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 95%; -9.2 to 12.8
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Participants With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 16
Description	The IGA is an instrument used in clinical trials to rate the severity of the subject's global atopic dermatitis and is based on a 5-point scale ranging from 0 (clear) to 4 (severe).
Time Frame	Week 0 to Week 16

Outcome Measure Data

Analysis Population Description

The analysis of the secondary outcome measures was done for the full analysis set, i.e. all subjects who were randomised and exposed to IMP (tralokinumab/placebo). 1 subject in the tralokinumab group was randomised in error and not exposed to IMP and therefore excluded from the full analysis set.

Arm/Group Title	Tralokinumab	Placebo
Arm/Group Description:	Participants received tralokinumab every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.	Participants received placebo every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.
Overall Number of Participants Analyzed	106	108
Measure Type: Count of Participants; Unit of Measure: Participants
	33 31.1%	21 19.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tralokinumab, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.049
	Comments	The p-value was adjusted for multiplicity by a pre-specified testing hierarchy. Subjects with missing data or subjects who received rescue medication prior to Week 16 were considered non-responders in the primary analysis of the primary estimand.
	Method	Cochran-Mantel-Haenszel
	Comments	The difference in response rates was analysed using the Cochran-Mantel-Haenszel test stratified by baseline disease severity (moderate or severe).
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	11.4
	Confidence Interval	(2-Sided) 95%; 0.2 to 22.6
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Participants Achieving at Least 75% Reduction in Eczema Area and Severity Index (EASI) at Week 16.
Description	The EASI is a validated measure used in clinical practice and clinical trials to assess the severity and extent of atopic dermatitis. > The EASI is a composite index with scores ranging from 0 to 72, with higher values indicating more severe and/or more extensive condition.
Time Frame	Week 0 to Week 16

Outcome Measure Data

Analysis Population Description

The analysis of the secondary outcome measures was done for the full analysis set, i.e. all participants who were randomised and exposed to IMP (tralokinumab/placebo). 1 participant in the tralokinumab group was randomised in error and not exposed to IMP and therefore excluded from the full analysis set.

Arm/Group Title	Tralokinumab	Placebo
Arm/Group Description:	Participants received tralokinumab every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.	Participants received placebo every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.
Overall Number of Participants Analyzed	106	108
Measure Type: Count of Participants; Unit of Measure: Participants
	52 49.1%	39 36.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tralokinumab, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.057
	Comments	The p-value was adjusted for multiplicity by a pre-specified testing hierarchy. Subjects with missing data or subjects who received rescue medication prior to Week 16 were considered non-responders in the primary analysis of the primary estimand.
	Method	Cochran-Mantel-Haenszel
	Comments	The difference in response rates was analysed using the Cochran-Mantel-Haenszel test stratified by baseline disease severity (moderate or severe).
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	12.7
	Confidence Interval	(2-Sided) 95%; -0.2 to 25.7
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Number of AEs.
Description	Overall summary of AEs during the treatment period is presented. For list of SAEs and frequent AEs by MedDRA system organ class (SOC) and preferred term (PT) during the entire trial period (including safety follow-up), see Adverse Events Overview section.
Time Frame	Week 0 to Week 16

Outcome Measure Data

Analysis Population Description

The descriptive analysis was performed on the safety analysis set. The safety analysis set was defined as all participants who received at least 1 dose of IMP during the trial. Subjects who received at least 1 dose of tralokinumab were analysed in the tralokinumab group.

Arm/Group Title	Tralokinumab	Placebo
Arm/Group Description:	Participants received tralokinumab every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.	Participants received placebo every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.
Overall Number of Participants Analyzed	107	107
Measure Type: Number; Unit of Measure: AEs
	112	133

6. Secondary Outcome

Title	Presence of Anti-drug Antibodies (ADA).
Description	ADA levels were measured using a validated bioanalytical method. Data were reported in the following categories: positive (presence of ADA at baseline and/or presence of ADA at at least 1 post-baseline assessment), perishing (presence of ADA at baseline and absence of ADA at all post-baseline assessments), negative (absence of ADA at all assessments), no post-baseline ADA assessment.
Time Frame	Week 0 to Week 16

Outcome Measure Data

Analysis Population Description

All subjects in the safety analysis set were included.

Arm/Group Title	Tralokinumab	Placebo
Arm/Group Description:	Participants received tralokinumab every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.	Participants received placebo every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12.
Overall Number of Participants Analyzed	107	107
Measure Type: Count of Participants; Unit of Measure: Participants
Positive	2 1.9%	4 3.7%
Perishing	1 0.9%	2 1.9%
Negative	103 96.3%	97 90.7%
No post-baseline ADA assessment	1 0.9%	4 3.7%

Adverse Events

Time Frame	AEs were collected from time of first trial-related activity after the subject had signed the ICF until completion of the clinical trial (defined as the safety follow up visit at Week 30). Non-serious AEs possibly/probably related to IMP and ongoing at the time of trial completion were followed up for 2 weeks or until final outcome, whichever came first. Serious AEs were followed up until final outcome had been established.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Tralokinumab		Placebo
Arm/Group Description	Tralokinumab		Placebo
All-Cause Mortality
	Tralokinumab		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	1/107 (0.93%)		0/107 (0.00%)
Serious Adverse Events
	Tralokinumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/107 (2.80%)		3/107 (2.80%)
Cardiac disorders
Myocarditis * 1	0/107 (0.00%)	0	1/107 (0.93%)	1
Postural orthostatic tachycardia syndrome * 1	1/107 (0.93%)	1	0/107 (0.00%)	0
Hepatobiliary disorders
Acute hepatic failure * 1	1/107 (0.93%)	1	0/107 (0.00%)	0
Infections and infestations
Device related infection * 1	1/107 (0.93%)	1	0/107 (0.00%)	0
Pneumonia * 1	1/107 (0.93%)	1	0/107 (0.00%)	0
Septic shock * 1	1/107 (0.93%)	1	0/107 (0.00%)	0
Injury, poisoning and procedural complications
Procedural haemorrhage * 1	0/107 (0.00%)	0	1/107 (0.93%)	1
Metabolism and nutrition disorders
Failure to thrive * 1	1/107 (0.93%)	1	0/107 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer metastatic * 1	0/107 (0.00%)	0	1/107 (0.93%)	1
Nervous system disorders
Encephalopathy * 1	1/107 (0.93%)	1	0/107 (0.00%)	0
Status epilepticus * 1	1/107 (0.93%)	1	0/107 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism * 1	1/107 (0.93%)	1	0/107 (0.00%)	0
Respiratory failure * 1	1/107 (0.93%)	1	0/107 (0.00%)	0
Vascular disorders
Shock haemorrhagic * 1	1/107 (0.93%)	1	0/107 (0.00%)	0
1 Term from vocabulary, MedDRA 20.0; * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Tralokinumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/107 (25.23%)		25/107 (23.36%)
Gastrointestinal disorders
Abdominal pain * 1	1/107 (0.93%)	1	3/107 (2.80%)	3
Nausea * 1	1/107 (0.93%)	1	3/107 (2.80%)	3
Immune system disorders
Seasonal allergy * 1	3/107 (2.80%)	4	0/107 (0.00%)	0
Infections and infestations
Upper respiratory tract infection * 1	2/107 (1.87%)	2	5/107 (4.67%)	7
Viral upper respiratory tract infection * 1	10/107 (9.35%)	10	3/107 (2.80%)	4
Nervous system disorders
Headache * 1	3/107 (2.80%)	3	2/107 (1.87%)	2
Skin and subcutaneous tissue disorders
Dermatitis atopic * 1	12/107 (11.21%)	14	13/107 (12.15%)	21
1 Term from vocabulary, MedDRA 20.0; * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

LEO Pharma A/S seeks publication of all phase 3 clinical trials in peer-reviewed journals within 18 months after completion or termination of the clinical trial, regardless of whether the findings are positive or negative. If no publication is submitted by LEO Pharma A/S within these 18 months, the investigator has the right to publish the results from the clinical trial generated by him/herself.

Results Point of Contact

• Name/Title: Disclosure
• Organization: LEO Pharma A/S
• Phone: +45 ext 44945888
• EMail: disclosure@leo-pharma.com

• Responsible Party: LEO Pharma
• ClinicalTrials.gov Identifier: NCT03562377
• Other Study ID Numbers: LP0162-1341
• First Submitted: June 8, 2018
• First Posted: June 19, 2018
• Results First Submitted: January 14, 2021
• Results First Posted: March 5, 2021
• Last Update Posted: March 5, 2021