Atopic Dermatitis
Conditions
Brief summary
The purpose of this trial is to test if treatment with the trial drug, tralokinumab, can affect the body's immune response to vaccines. The trial will also evaluate the efficacy of tralokinumab when it is given concomitantly with vaccines. The trial includes a screening period of 2 to 6 weeks, a treatment period of 16 weeks (Weeks 0 to 16), and a 14-week off-treatment follow-up period for the assessment of safety (Weeks 16 to 30). Eligible subjects may transfer to an open-label, long-term trial at Week 16 or later.
Detailed description
Subjects with atopic dermatitis (AD) will be treated with either tralokinumab or dummy treatment (placebo) for 16 weeks. All subjects will receive 2 vaccines at Week 12. The vaccines are: 1. Tetanus (lockjaw), diphtheria (infection of the nose and throat), and pertussis (whooping cough) vaccine. This combination vaccine is also known as the Tdap vaccine and is used to prevent these 3 diseases. 2. Meningococcal vaccine. This vaccine is used to prevent meningococcal diseases (infection of the brain and spinal cord) and blood poisoning. The primary objective of the trial is to demonstrate non-inferiority of tralokinumab versus placebo with respect to immune responses to concomitantly administered vaccines. The secondary objective is to evaluate efficacy of tralokinumab concomitantly administered with vaccines.
Interventions
DRUGTralokinumab
Tralokinumab is a human recombinant monoclonal antibody of the IgG4 subclass that specifically binds to human IL-13 and blocks interaction with the IL-13 receptors. It is presented as a liquid formulation for subcutaneous administration.
DRUGPlacebo
Placebo contains the same excipients in the same concentration only lacking tralokinumab.
BIOLOGICALTdap vaccine
Tetanus (lockjaw), diphtheria (infection of the nose and throat), and pertussis (whooping cough) vaccine. All subjects will receive 1 dose at Week 12.
BIOLOGICALMeningococcal vaccine
This vaccine is used to prevent meningococcal diseases (infection of the brain and spinal cord) and blood poisoning. All subjects will receive 1 dose at Week 12.
Sponsors
LEO Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Neither the subject nor any of the investigator or LEO staff who are involved in the treatment or clinical evaluation and monitoring of the subjects will be aware of the treatment received. The packaging and labelling of tralokinumab/placebo will contain no evidence of their identity. Since tralokinumab and placebo are visually distinct and not matched for viscosity, they will be handled and administered by a qualified, unblinded healthcare professional at the trial site who will not be involved in the management of trial subjects.
Eligibility
Sex/Gender
ALL
Age
18 Years to 54 Years
Healthy volunteers
No
Inclusion criteria
* Age 18 to 54 years * Diagnosis of AD as defined by Hanifin and Rajka (1980) criteria for AD * History of AD for ≥1 year * Subjects who have a recent history of inadequate response to treatment with topical medications or for whom topical treatments are otherwise medically inadvisable * AD involvement of ≥10% body surface area at screening and baseline * An EASI score of ≥12 at screening and 16 at baseline * An IGA score of ≥3 at screening and at baseline * Subjects must have applied a stable dose of emollient twice daily (or more, as needed) for at least 14 days before randomisation
Exclusion criteria
* Subjects for whom administration of the meningococcal vaccine provided in this trial is contraindicated or medically inadvisable, according to local label of the vaccine * Subjects for whom administration of the tetanus, diphtheria, and pertussis vaccine provided in this trial is contraindicated or medically inadvisable, according to local label of the vaccine * Active dermatologic conditions that may confound the diagnosis of AD or would interfere with assessment of treatment * Use of tanning beds or phototherapy within 6 weeks prior to randomization * Treatment with systemic immunosuppressive/immunomodulating medications and/or systemic corticosteroids within 4 weeks prior to randomization * Treatment with the topical medications topical corticosteroids (TCS), topical calcineurin inhibitor (TCI) or phosphodiesterase 4 (PDE-4) inhibitor within 2 weeks prior to randomization * Receipt of any vaccine (except influenza virus vaccines) within 3 months prior to screening, any meningococcal vaccine within 1 year prior to screening, or any tetanus-, diphtheria-, or pertussis-containing vaccine within 5 years prior to screening * Receipt of any marketed (i.e. immunoglobulin, anti-IgE) or investigational biologic agent, including dupilumab * History of any active skin infection within 1 week prior to randomization * History of a clinically significant infection (systemic infection or serious skin infection requiring parenteral treatment) within 4 weeks prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Positive Anti-tetanus Response at Week 16 | Week 12 to Week 16 | 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. |
| Positive Anti-meningococcal Response at Week 16 | Week 12 to Week 16 | The antibody response to meningococcal vaccine will be assessed by measuring serum anti-meningococcal IgG by an immunoassay. A positive response is defined as at least a 3-fold increase compared to Week 12. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 16 | Week 0 to Week 16 | 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). |
| Participants Achieving at Least 75% Reduction in Eczema Area and Severity Index (EASI) at Week 16. | Week 0 to Week 16 | 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. |
| Number of AEs. | Week 0 to Week 16 | 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. |
| Presence of Anti-drug Antibodies (ADA). | Week 0 to Week 16 | 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. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tralokinumab Participants received tralokinumab every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12. | 107 |
| Placebo Participants received placebo every 2 weeks for 16 weeks, and the Tdap and meningococcal vaccines at Week 12. | 108 |
| Total | 215 |
Baseline characteristics
| Characteristic | Placebo | Tralokinumab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 108 Participants | 107 Participants | 215 Participants |
| Age, Continuous | 34.4 years STANDARD_DEVIATION 10.8 | 34.0 years STANDARD_DEVIATION 11.2 | 34.2 years STANDARD_DEVIATION 11 |
| Eczema Area and Severity Index score | 26.75 units on a scale STANDARD_DEVIATION 11.23 | 26.26 units on a scale STANDARD_DEVIATION 10.79 | 26.51 units on a scale STANDARD_DEVIATION 11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants | 17 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 89 Participants | 90 Participants | 179 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Investigator's Global Assessment (IGA) Almost clear (IGA=1) | 0 Participants | 0 Participants | 0 Participants |
| Investigator's Global Assessment (IGA) Clear (IGA=0) | 0 Participants | 0 Participants | 0 Participants |
| Investigator's Global Assessment (IGA) Mild disease (IGA=2) | 0 Participants | 0 Participants | 0 Participants |
| Investigator's Global Assessment (IGA) Missing | 0 Participants | 1 Participants | 1 Participants |
| Investigator's Global Assessment (IGA) Moderate disease (IGA=3) | 72 Participants | 72 Participants | 144 Participants |
| Investigator's Global Assessment (IGA) Severe disease (IGA=4) | 36 Participants | 34 Participants | 70 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 18 Participants | 16 Participants | 34 Participants |
| Race (NIH/OMB) Black or African American | 27 Participants | 25 Participants | 52 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) White | 56 Participants | 62 Participants | 118 Participants |
| Region of Enrollment Canada | 35 participants | 34 participants | 69 participants |
| Region of Enrollment United States | 73 participants | 73 participants | 146 participants |
| Sex: Female, Male Female | 73 Participants | 53 Participants | 126 Participants |
| Sex: Female, Male Male | 35 Participants | 54 Participants | 89 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 107 | 0 / 107 |
| other Total, other adverse events | 27 / 107 | 25 / 107 |
| serious Total, serious adverse events | 3 / 107 | 3 / 107 |
Outcome results
Primary
Positive Anti-meningococcal Response at Week 16
The antibody response to meningococcal vaccine will be assessed by measuring serum anti-meningococcal IgG by an immunoassay. A positive response is defined as at least a 3-fold increase compared to Week 12.
Time frame: Week 12 to Week 16
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tralokinumab | Positive Anti-meningococcal Response at Week 16 | 74 Participants |
| Placebo | Positive Anti-meningococcal Response at Week 16 | 64 Participants |
95% CI: [-9.2, 12.8]Mantel Haenszel
Primary
Positive Anti-tetanus Response at Week 16
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tralokinumab | Positive Anti-tetanus Response at Week 16 | 80 Participants |
| Placebo | Positive Anti-tetanus Response at Week 16 | 73 Participants |
95% CI: [-11.3, 3.1]Mantel Haenszel
Secondary
Number of AEs.
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Tralokinumab | Number of AEs. | 112 AEs |
| Placebo | Number of AEs. | 133 AEs |
Secondary
Participants Achieving at Least 75% Reduction in Eczema Area and Severity Index (EASI) at Week 16.
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tralokinumab | Participants Achieving at Least 75% Reduction in Eczema Area and Severity Index (EASI) at Week 16. | 52 Participants |
| Placebo | Participants Achieving at Least 75% Reduction in Eczema Area and Severity Index (EASI) at Week 16. | 39 Participants |
p-value: 0.05795% CI: [-0.2, 25.7]Cochran-Mantel-Haenszel
Secondary
Participants With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 16
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tralokinumab | Participants With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 16 | 33 Participants |
| Placebo | Participants With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 16 | 21 Participants |
p-value: 0.04995% CI: [0.2, 22.6]Cochran-Mantel-Haenszel
Secondary
Presence of Anti-drug Antibodies (ADA).
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
Population: All subjects in the safety analysis set were included.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tralokinumab | Presence of Anti-drug Antibodies (ADA). | Positive | 2 Participants |
| Tralokinumab | Presence of Anti-drug Antibodies (ADA). | Perishing | 1 Participants |
| Tralokinumab | Presence of Anti-drug Antibodies (ADA). | Negative | 103 Participants |
| Tralokinumab | Presence of Anti-drug Antibodies (ADA). | No post-baseline ADA assessment | 1 Participants |
| Placebo | Presence of Anti-drug Antibodies (ADA). | No post-baseline ADA assessment | 4 Participants |
| Placebo | Presence of Anti-drug Antibodies (ADA). | Positive | 4 Participants |
| Placebo | Presence of Anti-drug Antibodies (ADA). | Negative | 97 Participants |
| Placebo | Presence of Anti-drug Antibodies (ADA). | Perishing | 2 Participants |