Chronic Hand Eczema
Conditions
Brief summary
The purpose of this research trial was to test different strengths of a new trial medication, delgocitinib cream 1, 3, 8, and 20 mg/g, and to investigate how treatment with delgocitinib cream affects chronic hand eczema. This was judged by a range of assessments that rate the severity and extent of chronic hand eczema and its symptoms, as well as general health status and quality of life.
Interventions
Cream for topical application.
The cream vehicle is similar to the delgocitinib cream except that it does not contain any active ingredient.
Sponsors
LEO Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Age 18 years or above. * Diagnosis of chronic hand eczema defined as hand eczema, which has persisted for more than 3 months or returned twice or more within the last 12 months. * Disease severity graded as mild to severe according to IGA (i.e., IGA ≥2). * Recent history (within 1 year before the screening visit) of inadequate response to topical corticosteroid treatment or topical corticosteroid treatment being medically inadvisable. * Diagnostic patch testing performed within 3 years prior to the screening visit. Key
Exclusion criteria
* Concurrent skin diseases on the hands e.g tinnea manuum. * Active atopic dermatitis in regions other than the hands or psoriasis requiring medical treatment. * Clinically significant infection (e.g., impetiginised hand eczema) on the hands. * Systemic treatment with immunosuppressive drugs, immunomodulating drugs, retinoids, or corticosteroids within 4 weeks prior to baseline. * Psoralen ultraviolet A (PUVA) or ultraviolet B (UVB) therapy on the hands within 4 weeks prior to baseline. * Receipt of live attenuated vaccines 4 weeks prior to baseline. * Cutaneously applied treatment with immunomodulators (e.g., phosphodiesterase-4 (PDE-4) inhibitors, pimecrolimus, tacrolimus) or topical corticosteroids on the hands within 2 weeks prior to baseline. * Use of systemic antibiotics or cutaneously applied antibiotics on the hands within 2 weeks prior to baseline. * Change in systemic antihistamine therapy within 2 weeks prior to baseline i.e., subjects must not start antihistamine treatment or change the current dosage regime within 2 weeks prior to baseline. * Other cutaneously applied therapy on the hands (except for the use of subject's own emollients) within 1 week prior to baseline. * Cutaneously applied treatments in regions other than the hands, which could interfere with clinical trial evaluations or pose a safety concern within 1 week prior to baseline. * Receipt of any marketed or investigational biologic agents within 6 months or 5 half-lives prior to baseline or until cells count returns to normal, whichever is longer. * Clinically significant infection (systemic infection or serious skin infection requiring parenteral treatment) within 4 weeks prior to baseline. * Tuberculosis requiring treatment within 12 months prior to screening and/or subjects with a positive blood test for tuberculosis at screening. * History of any known primary immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test at screening, or the subject taking antiretroviral medications. * Any disorder which is not stable and in the investigator's opinion could affect the safety of the subject, influence the findings of the trial, or impede the subject's ability to complete the trial. * Positive hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb), or hepatitis C virus antibody (anti-HCV) serology at screening. Subjects with positive HBsAb may be randomised provided they are hepatitis B vaccinated and have negative HBsAg and HBcAb.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Investigator's Global Assessment for Chronic Hand Eczema (IGA-CHE) Score of 0 (Clear) or 1 (Almost Clear) With at Least a 2-step Improvement (IGA-CHE Treatment Success) From Baseline to Week 16. | Week 0 to Week 16. | IGA-CHE is an instrument used in clinical trials to rate the severity of subject's global disease stage and is based on a 5-point scale ranging from 0 (clear) to 4 (severe). The multiple comparison procedure - modelling (MCP-Mod) approach was used to guide dose selection. Cochran-Mantel-Haenszel analysis was used to determine the difference in response rates between the active delgocitinib cream doses and delgocitinib cream vehicle. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hand Eczema Severity Index (HECSI) From Baseline to Week 16. | Week 0 to Week 16. | HECSI is an instrument used in clinical trials to rate the severity of 6 clinical signs of hand eczema and the extent of the lesions on each of 5 hand areas by use of standard scales. The total HECSI score is based on a 4-point severity scale ranging from 0 (none/absent) to 3 (severe) and a 5-point scale rating the affected area(s) ranging from 0 (0% affected area) to 4 (76% to 100% affected area). The lowest HECSI score is 0 and the highest possible is 360. A higher HECSI score is indicating more severe hand eczema. The multiple comparison procedure - modelling (MCP-Mod) approach was used to guide dose selection. A mixed model for repeated measurements (MMRM) analysis was used to determine the difference in the continuous endpoint between the active delgocitinib cream doses and delgocitinib cream vehicle. |
| Time to IGA-CHE Treatment Success. | Week 0 to Week 16. | Time to IGA-CHE treatment success response is defined as the time from baseline to first assessment of an IGA-CHE score of 0 (clear) or 1 (almost clear) with at least a 2-step improvement. |
Countries
Denmark, Germany, United States
Participant flow
Recruitment details
258 participants from 26 sites in 3 countries (U.S., Denmark, Germany) were randomised in this trial. The first participant was screened on 28-Nov-2018 and the last participant completed the trial on 20-Apr-2020.
Pre-assignment details
305 participants were screened for this trial. Of these, 47 participants (15.4%) were screening failures. The main reason for screening failure was failure to meet eligibility criteria (11.8%). The eligibility criterion that was most frequently not met was exclusion criterion 21 (positive HBsAg, HBsAb, HBcAb, or antiHCV serology at screening \[3.3%\]).
Participants by arm
| Arm | Count |
|---|---|
| Delgocitinib Cream 1 mg/g Delgocitinib cream applied twice daily for 16 weeks.
Delgocitinib cream: Cream for topical application. | 52 |
| Delgocitinib Cream 3 mg/g Delgocitinib cream applied twice daily for 16 weeks.
Delgocitinib cream: Cream for topical application. | 51 |
| Delgocitinib Cream 8 mg/g Delgocitinib cream applied twice daily for 16 weeks.
Delgocitinib cream: Cream for topical application. | 52 |
| Delgocitinib Cream 20 mg/g Delgocitinib cream applied twice daily for 16 weeks.
Delgocitinib cream: Cream for topical application. | 53 |
| Delgocitinib Cream Vehicle Delgocitinib cream vehicle applied twice daily for 16 weeks.
Delgocitinib cream vehicle: The cream vehicle is similar to the delgocitinib cream except that it does not contain any active ingredient. | 50 |
| Total | 258 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 6 | 0 | 1 | 3 |
| Overall Study | Lack of Efficacy | 1 | 3 | 4 | 0 | 4 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 1 | 1 |
| Overall Study | Other personal reasons | 0 | 0 | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 4 | 3 | 5 | 5 |
Baseline characteristics
| Characteristic | Delgocitinib Cream 3 mg/g | Total | Delgocitinib Cream Vehicle | Delgocitinib Cream 20 mg/g | Delgocitinib Cream 1 mg/g | Delgocitinib Cream 8 mg/g |
|---|---|---|---|---|---|---|
| Age, Continuous | 46.1 years STANDARD_DEVIATION 14.6 | 46.0 years STANDARD_DEVIATION 14.5 | 47.8 years STANDARD_DEVIATION 16.2 | 43.9 years STANDARD_DEVIATION 15.1 | 44.3 years STANDARD_DEVIATION 13.6 | 47.9 years STANDARD_DEVIATION 12.9 |
| Baseline HECSI score | 52.4 units on a scale STANDARD_DEVIATION 35.9 | 55.9 units on a scale STANDARD_DEVIATION 42.8 | 52.7 units on a scale STANDARD_DEVIATION 34.9 | 65.7 units on a scale STANDARD_DEVIATION 58.3 | 59.0 units on a scale STANDARD_DEVIATION 48 | 49.5 units on a scale STANDARD_DEVIATION 29.3 |
| Baseline IGA-CHE score 0 - Clear | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Baseline IGA-CHE score 1 - Almost clear | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Baseline IGA-CHE score 2 - Mild | 13 Participants | 61 Participants | 12 Participants | 12 Participants | 13 Participants | 11 Participants |
| Baseline IGA-CHE score 3 - Moderate | 29 Participants | 145 Participants | 27 Participants | 31 Participants | 29 Participants | 29 Participants |
| Baseline IGA-CHE score 4 - Severe | 9 Participants | 52 Participants | 11 Participants | 10 Participants | 10 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 9 Participants | 3 Participants | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 51 Participants | 249 Participants | 47 Participants | 52 Participants | 49 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 51 Participants | 254 Participants | 50 Participants | 52 Participants | 51 Participants | 50 Participants |
| Region of Enrollment Denmark | 7 participants | 58 participants | 16 participants | 11 participants | 12 participants | 12 participants |
| Region of Enrollment Germany | 40 participants | 179 participants | 30 participants | 37 participants | 36 participants | 36 participants |
| Region of Enrollment United States | 4 participants | 21 participants | 4 participants | 5 participants | 4 participants | 4 participants |
| Sex: Female, Male Female | 28 Participants | 158 Participants | 27 Participants | 34 Participants | 37 Participants | 32 Participants |
| Sex: Female, Male Male | 23 Participants | 100 Participants | 23 Participants | 19 Participants | 15 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 52 | 0 / 51 | 0 / 52 | 0 / 53 | 0 / 50 |
| other Total, other adverse events | 20 / 52 | 25 / 51 | 25 / 52 | 26 / 53 | 24 / 50 |
| serious Total, serious adverse events | 0 / 52 | 2 / 51 | 1 / 52 | 0 / 53 | 0 / 50 |
Outcome results
Primary
Investigator's Global Assessment for Chronic Hand Eczema (IGA-CHE) Score of 0 (Clear) or 1 (Almost Clear) With at Least a 2-step Improvement (IGA-CHE Treatment Success) From Baseline to Week 16.
IGA-CHE is an instrument used in clinical trials to rate the severity of subject's global disease stage and is based on a 5-point scale ranging from 0 (clear) to 4 (severe). The multiple comparison procedure - modelling (MCP-Mod) approach was used to guide dose selection. Cochran-Mantel-Haenszel analysis was used to determine the difference in response rates between the active delgocitinib cream doses and delgocitinib cream vehicle.
Time frame: Week 0 to Week 16.
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Delgocitinib Cream 1 mg/g | Investigator's Global Assessment for Chronic Hand Eczema (IGA-CHE) Score of 0 (Clear) or 1 (Almost Clear) With at Least a 2-step Improvement (IGA-CHE Treatment Success) From Baseline to Week 16. | 11 Participants |
| Delgocitinib Cream 3 mg/g | Investigator's Global Assessment for Chronic Hand Eczema (IGA-CHE) Score of 0 (Clear) or 1 (Almost Clear) With at Least a 2-step Improvement (IGA-CHE Treatment Success) From Baseline to Week 16. | 4 Participants |
| Delgocitinib Cream 8 mg/g | Investigator's Global Assessment for Chronic Hand Eczema (IGA-CHE) Score of 0 (Clear) or 1 (Almost Clear) With at Least a 2-step Improvement (IGA-CHE Treatment Success) From Baseline to Week 16. | 19 Participants |
| Delgocitinib Cream 20 mg/g | Investigator's Global Assessment for Chronic Hand Eczema (IGA-CHE) Score of 0 (Clear) or 1 (Almost Clear) With at Least a 2-step Improvement (IGA-CHE Treatment Success) From Baseline to Week 16. | 20 Participants |
| Delgocitinib Cream Vehicle | Investigator's Global Assessment for Chronic Hand Eczema (IGA-CHE) Score of 0 (Clear) or 1 (Almost Clear) With at Least a 2-step Improvement (IGA-CHE Treatment Success) From Baseline to Week 16. | 4 Participants |
Comparison: The primary endpoint was evaluated by determining if there was a dose-response relationship between the IGA-CHE response rate at Week 16 and the dose administered, using the Multiple Comparison Procedure - Modelling (MCP-Mod) methodology. Several candidate parametric models were assumed and multiple comparison techniques were used to choose the model(s) most likely to represent the true underlying dose-response curve.p-value: <0.001Multiple contrast test
Comparison: The difference in response rates between the active delgocitinib cream doses and delgocitinib cream vehicle was analysed separately for each of the active dose groups using the Cochran-Mantel-Haenszel test stratified by region and disease severity (baseline IGA-CHE score). The null hypothesis of no difference in response rates between the delgocitinib cream active doses and delgocitinib cream vehicle was tested against the 2-sided alternative that there is a difference.p-value: >0.0595% CI: [0.34, 26.24]Cochran-Mantel-Haenszel
Comparison: The difference in response rates between the active delgocitinib cream doses and delgocitinib cream vehicle was analysed separately for each of the active dose groups using the Cochran-Mantel-Haenszel test stratified by region and disease severity (baseline IGA-CHE score). The null hypothesis of no difference in response rates between the delgocitinib cream active doses and delgocitinib cream vehicle was tested against the 2-sided alternative that there is a difference.p-value: >0.0595% CI: [-10.44, 10.39]Cochran-Mantel-Haenszel
Comparison: The difference in response rates between the active delgocitinib cream doses and delgocitinib cream vehicle was analysed separately for each of the active dose groups using the Cochran-Mantel-Haenszel test stratified by region and disease severity (baseline IGA-CHE score). The null hypothesis of no difference in response rates between the delgocitinib cream active doses and delgocitinib cream vehicle was tested against the 2-sided alternative that there is a difference.p-value: <0.00195% CI: [13.8, 42.64]Cochran-Mantel-Haenszel
Comparison: The difference in response rates between the active delgocitinib cream doses and delgocitinib cream vehicle was analysed separately for each of the active dose groups using the Cochran-Mantel-Haenszel test stratified by region and disease severity (baseline IGA-CHE score). The null hypothesis of no difference in response rates between the delgocitinib cream active doses and delgocitinib cream vehicle was tested against the 2-sided alternative that there is a difference.p-value: <0.00195% CI: [14.56, 44.67]Cochran-Mantel-Haenszel
Secondary
Change in Hand Eczema Severity Index (HECSI) From Baseline to Week 16.
HECSI is an instrument used in clinical trials to rate the severity of 6 clinical signs of hand eczema and the extent of the lesions on each of 5 hand areas by use of standard scales. The total HECSI score is based on a 4-point severity scale ranging from 0 (none/absent) to 3 (severe) and a 5-point scale rating the affected area(s) ranging from 0 (0% affected area) to 4 (76% to 100% affected area). The lowest HECSI score is 0 and the highest possible is 360. A higher HECSI score is indicating more severe hand eczema. The multiple comparison procedure - modelling (MCP-Mod) approach was used to guide dose selection. A mixed model for repeated measurements (MMRM) analysis was used to determine the difference in the continuous endpoint between the active delgocitinib cream doses and delgocitinib cream vehicle.
Time frame: Week 0 to Week 16.
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Delgocitinib Cream 1 mg/g | Change in Hand Eczema Severity Index (HECSI) From Baseline to Week 16. | -39.81 score on a scale | Standard Error 3.71 |
| Delgocitinib Cream 3 mg/g | Change in Hand Eczema Severity Index (HECSI) From Baseline to Week 16. | -35.93 score on a scale | Standard Error 3.77 |
| Delgocitinib Cream 8 mg/g | Change in Hand Eczema Severity Index (HECSI) From Baseline to Week 16. | -46.69 score on a scale | Standard Error 3.63 |
| Delgocitinib Cream 20 mg/g | Change in Hand Eczema Severity Index (HECSI) From Baseline to Week 16. | -41.99 score on a scale | Standard Error 3.59 |
| Delgocitinib Cream Vehicle | Change in Hand Eczema Severity Index (HECSI) From Baseline to Week 16. | -26.40 score on a scale | Standard Error 3.8 |
Comparison: The secondary endpoint Change from baseline to Week 16 in HECSI score was evaluated by determining if there was a dose-response relationship between the change from baseline in HECSI score at Week 16 and the dose administered, using the Multiple Comparison Procedure - Modelling (MCP-Mod) methodology. Several candidate parametric models were assumed and multiple comparison techniques were used to choose the model(s) most likely to represent the true underlying dose-response curve.p-value: <0.0001Multiple contrast test
Comparison: Least Square (LS) Means were calculated using a mixed model for repeated measurements on the post-baseline responses up to Week 16 with an unstructured covariance matrix, Kenward-Roger approximation to estimate denominator degrees of freedom, and the mean modelled as follows:~Change from baseline in HECSI~= treatment × visit + baseline HECSI × visit + region + baseline IGA-CHE.~The primary comparison between each active delgocitinib dose and vehicle was at Week 16.p-value: <0.0195% CI: [-22.82, -4.01]Mixed Models Analysis
Comparison: Least Square (LS) Means were calculated using a mixed model for repeated measurements on the post-baseline responses up to Week 16 with an unstructured covariance matrix, Kenward-Roger approximation to estimate denominator degrees of freedom, and the mean modelled as follows:~Change from baseline in HECSI~= treatment × visit + baseline HECSI × visit + region + baseline IGA-CHE.~The primary comparison between each active delgocitinib dose and vehicle was at Week 16.p-value: <0.0595% CI: [-19.04, -0.02]Mixed Models Analysis
Comparison: Least Square (LS) Means were calculated using a mixed model for repeated measurements on the post-baseline responses up to Week 16 with an unstructured covariance matrix, Kenward-Roger approximation to estimate denominator degrees of freedom, and the mean modelled as follows:~Change from baseline in HECSI~= treatment × visit + baseline HECSI × visit + region + baseline IGA-CHE.~The primary comparison between each active delgocitinib dose and vehicle was at Week 16.p-value: <0.000195% CI: [-29.56, -11.02]Mixed Models Analysis
Comparison: Least Square (LS) Means were calculated using a mixed model for repeated measurements on the post-baseline responses up to Week 16 with an unstructured covariance matrix, Kenward-Roger approximation to estimate denominator degrees of freedom, and the mean modelled as follows:~Change from baseline in HECSI~= treatment × visit + baseline HECSI × visit + region + baseline IGA-CHE.~The primary comparison between each active delgocitinib dose and vehicle was at Week 16.p-value: <0.0195% CI: [-24.82, -6.36]Mixed Models Analysis
Secondary
Time to IGA-CHE Treatment Success.
Time to IGA-CHE treatment success response is defined as the time from baseline to first assessment of an IGA-CHE score of 0 (clear) or 1 (almost clear) with at least a 2-step improvement.
Time frame: Week 0 to Week 16.
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Delgocitinib Cream 1 mg/g | Time to IGA-CHE Treatment Success. | NA days, median |
| Delgocitinib Cream 3 mg/g | Time to IGA-CHE Treatment Success. | NA days, median |
| Delgocitinib Cream 8 mg/g | Time to IGA-CHE Treatment Success. | 82 days, median |
| Delgocitinib Cream 20 mg/g | Time to IGA-CHE Treatment Success. | 98 days, median |
| Delgocitinib Cream Vehicle | Time to IGA-CHE Treatment Success. | NA days, median |
Comparison: Time to IGA-CHE TS was defined as the time from the date of the first IMP application to first assessment of IGA-CHE TS. Subjects without baseline observation were censored at the date of the first IMP application. Subjects with baseline observation not achieving IGA-CHE TS during the treatment period were censored at the date of the last visit with a valid post-baseline assessment on or prior to the date of discontinuation of IMP or initiation of rescue medication, whichever occurred first.p-value: <0.05Log Rank
Comparison: Time to IGA-CHE TS was defined as the time from the date of the first IMP application to first assessment of IGA-CHE TS. Subjects without baseline observation were censored at the date of the first IMP application. Subjects with baseline observation not achieving IGA-CHE TS during the treatment period were censored at the date of the last visit with a valid post-baseline assessment on or prior to the date of discontinuation of IMP or initiation of rescue medication, whichever occurred first.p-value: >0.1Log Rank
Comparison: Time to IGA-CHE TS was defined as the time from the date of the first IMP application to first assessment of IGA-CHE TS. Subjects without baseline observation were censored at the date of the first IMP application. Subjects with baseline observation not achieving IGA-CHE TS during the treatment period were censored at the date of the last visit with a valid post-baseline assessment on or prior to the date of discontinuation of IMP or initiation of rescue medication, whichever occurred first.p-value: <0.0001Log Rank
Comparison: Time to IGA-CHE TS was defined as the time from the date of the first IMP application to first assessment of IGA-CHE TS. Subjects without baseline observation were censored at the date of the first IMP application. Subjects with baseline observation not achieving IGA-CHE TS during the treatment period were censored at the date of the last visit with a valid post-baseline assessment on or prior to the date of discontinuation of IMP or initiation of rescue medication, whichever occurred first.p-value: <0.01Log Rank