Discoid Lupus Erythematosus
Conditions
Brief summary
This was a double-blind, multi-centre, randomised, vehicle-controlled, within-subject phase 2a trial. The trial was designed to establish the efficacy and safety of delgocitinib cream in the treatment of adult subjects with discoid lupus erythematosus (DLE).
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)
Intervention model description
This was a phase 2a, within-subject trial design, where all subjects were treated with active treatment on one DLE target lesion and vehicle treatment on another DLE target lesion.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Histopathological findings (current or previous) consistent with clinical diagnosis of DLE. * Unequivocal clinical diagnosis of 2 active DLE target lesions that were \<6 months old and amenable for clinical evaluation. This included lesions located on the scalp if they fulfilled all lesion-specific eligibility criteria. * Target lesion IGA score of at least moderate severity (≥3) at screening and baseline. * Target lesion erythema score ≥2 at screening and baseline. Main
Exclusion criteria
* Target lesion dyspigmentation score of 2 at screening or baseline. * Target lesion scarring/atrophy score of 2 at screening or baseline. * Target lesion scarring alopecia score of \>0 in scalp lesions at screening or baseline. * Medical history of systemic lupus erythematosus (SLE) with clinically significant organ involvement (American College of Rheumatology SLE classification criteria no. 6 to 9) including SLE-related pleuritis or pericarditis (by clinical evaluation and electrocardiogram), and neurologic, renal, and/or other major SLE-related organ system involvement. SLE joint involvement was acceptable. * Subjects with unstable or significant SLE disease activity findings that would, by its progressive nature and/or severity, interfere with the trial evaluation, completion, and/or procedures per the investigator's discretion. * Other skin conditions at screening or baseline that would interfere with the evaluation of DLE. * Immunosuppressive/immunomodulating therapy with e.g. methotrexate, cyclosporine, azathioprine, retinoids (both topical and systemic), or dapsone within 4 weeks prior to baseline. * Systemic prednisolone \>7.5 mg/day or changed dose within 4 weeks prior to baseline (nasal and inhaled corticosteroids were allowed). * Treatment with the following medications: * Oral antimalarial treatment with hydroxychloroquine \>6.5 mg/kg body weight/day, or chloroquine \>4 mg/kg body weight/day, or changed dose within 12 weeks prior to baseline. * Quinacrine combined with either hydroxychloroquine or chloroquine within 12 weeks prior to baseline. * Drugs known to interact with antimalarials (e.g. digoxin, cimetidine) within 12 weeks prior to baseline. * Treatment with topical corticosteroids, calcineurin inhibitors, and phosphodiesterase-4 (PDE-4) inhibitors within 2 weeks prior to baseline. * Use of systemic antibiotics or cutaneously applied antibiotics on the target lesions within 2 weeks prior to baseline. * Ultraviolet (UV) therapy within 2 weeks prior to baseline. * Any procedure impairing the skin barrier (e.g. incision) within 2 cm from the border of any of the target lesions within 4 weeks prior to baseline. * Receipt of live (attenuated) vaccines within 4 weeks prior to baseline. * Treatment with any marketed biological therapy or investigational biologic agents: * Any cell-depleting agents including but not limited to rituximab: within 6 months prior to baseline, or until lymphocyte count returned to normal, whichever was longer. * Other biologics: within 3 months or 5 half-lives, whichever was longer, prior to baseline. * Unstable or fluctuating use of tobacco within 1 month prior to screening which, in the opinion of the investigator, could affect the natural course of the disease and thus affect the evaluation of the treatment. * History of any active skin infection within 1 week prior to baseline. * Clinically significant infection within 4 weeks prior to baseline which, in the opinion of the investigator, could compromise the safety of the subject in the trial, interfere with evaluation of the IMP, or reduce the subject's ability to participate in the trial. Clinically significant infections are defined as: * A systemic infection. * A serious skin infection requiring parenteral (intravenous or intramuscular) antibiotics, antiviral, or antifungal medication. * Tuberculosis requiring treatment within 12 months prior to screening and/or subjects with a positive blood test for tuberculosis at screening. Subjects with high risk of latent tuberculosis (e.g. prior residence in or travel to countries with high prevalence of tuberculosis, close contact with a person with active tuberculosis, or a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed) must have been tested at screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Target Lesions With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 6. | Week 6 | The IGA is an instrument used in clinical trials to rate the severity of the subject's global disease and is based on a 5-point scale ranging from 0 (clear) to 4 (severe). In this trial, the IGA was a lesion-specific assessment and was evaluated separately for each of the 2 target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With AEs up to Week 6. | Week 0 to Week 6 | Number of subjects with AEs from baseline to Week 6 |
| Number of Lesion-specific, Treatment-related AEs up to Week 6. | Week 0 to Week 6 | The number of lesion-specific, treatment-related AEs per target lesion will be compared for active and vehicle treatment. Lesion-specific AEs are defined as lesional/perilesional AEs (i.e. AE location within the treatment area and/or ≤2 cm from the border of a target lesion). |
| Number of Lesions With ≥2-point Reduction in IGA Score at Week 6 Compared to Baseline. | Week 0 to Week 6 | The IGA is an instrument used in clinical trials to rate the severity of the subject's global disease and is based on a 5-point scale ranging from 0 (clear) to 4 (severe). In this trial, the IGA was a lesion-specific assessment and was evaluated separately for each of the 2 target lesions. |
| Number of Adverse Events (AEs) up to Week 6. | Week 0 to Week 6 | Number of AEs from baseline to Week 6 |
| Erythema Score at Week 6. | Week 6 | The erythema score is lesion-specific and based on the CLASI and the RCLASI which are validated scoring systems to assess disease activity and damage in patients with cutaneous lupus erythematosus. The severity of the erythema is scored on a 4-point scale ranging from 0 to 3. The severity is scored from low to high with 0=absent and 3=dark red, purple/violaceous/crusted/haemorrhagic. |
| Total Skin Disease Activity Score (Sum of Scores for Erythema, Scaling/Hyperkeratosis, and Oedema/Infiltration) at Week 6. | Week 6 | The skin disease activity scores are based on the CLASI and the RCLASI which are validated scoring systems to assess disease activity and damage in patients with cutaneous lupus erythematosus. The total skin disease activity score is defined as the sum of the scores for 3 clinical signs (erythema, scaling/hyperkeratosis, oedema/infiltration) for each target lesion. For the total score and the individual clinical signs, higher scores indicate more severe symptoms. Erythema is scored on a 4-point scale ranging from 0 (absent) to 3 (dark red, purple/violaceous/crusted/haemorrhagic). Hyperkeratosis/scaling is scored on a 3-point scale from 0 (absent) to 2 (verrucous hyperkeratosis). Oedema/infiltration is scored on a 3-point scale from 0 (absent) to 2 (palpable and visible). The total skin disease activity score can therefore range from 0 to 7. |
| Number of Lesions With ≥2-point Reduction in Erythema Score at Week 6 Compared to Baseline. | Week 0 to Week 6 | The erythema score is lesion-specific and based on the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the Revised CLASI (RCLASI) which are validated scoring systems to assess disease activity and damage in patients with cutaneous lupus erythematosus. The severity of the erythema is scored on a 4-point scale ranging from 0 to 3. The severity is scored from low to high with 0=absent and 3=dark red, purple/violaceous/crusted/haemorrhagic. |
Countries
Denmark, France, Germany, United States
Participant flow
Recruitment details
37 subjects screened. 27 subjects randomised. 26 subjects completed.
Pre-assignment details
A screening visit took place 7 to 28 days before the first application of investigational medicinal product (IMP). To be eligible for participation in the trial each subject had to have at least 2 discoid lupus erythematosus (DLE) target lesions with active disease (referred to as lesions 1 and 2) fulfilling the inclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| All Randomised Subjects Randomised subjects received delgocitinib cream 20 mg/g on one DLE target lesion and delgocitinib cream vehicle on another DLE target lesion twice daily for 6 weeks.
Delgocitinib cream 20 mg/g: Cream for topical application.
Delgocitinib cream vehicle: The cream vehicle is similar to the delgocitinib cream except that it does not contain any active ingredient. | 27 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | All Randomised Subjects |
|---|---|
| Age, Continuous | 45.7 years STANDARD_DEVIATION 13.4 |
| Baseline erythema score of lesions to be treated with delgocitinib cream Erythema score 2 | 37.0 percentage of lesions |
| Baseline erythema score of lesions to be treated with delgocitinib cream Erythema score 3 | 63.0 percentage of lesions |
| Baseline erythema score of lesions to be treated with vehicle Erythema score 2 | 48.1 percentage of lesions |
| Baseline erythema score of lesions to be treated with vehicle Erythema score 3 | 51.9 percentage of lesions |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Investigator's Global Assessment (IGA) of lesions to be treated with delgocitinib cream IGA score 3 (moderate) | 88.9 percentage of lesions |
| Investigator's Global Assessment (IGA) of lesions to be treated with delgocitinib cream IGA score 4 (severe) | 11.1 percentage of lesions |
| Investigator's Global Assessment (IGA) of lesions to be treated with vehicle IGA score 3 (moderate) | 88.9 percentage of lesions |
| Investigator's Global Assessment (IGA) of lesions to be treated with vehicle IGA score 4 (severe) | 11.1 percentage of lesions |
| Race/Ethnicity, Customized Race Black or African American | 2 Participants |
| Race/Ethnicity, Customized Race Other | 4 Participants |
| Race/Ethnicity, Customized Race Unknown or Not Reported | 1 Participants |
| Race/Ethnicity, Customized Race White | 20 Participants |
| Region of Enrollment Denmark | 1 participants |
| Region of Enrollment France | 5 participants |
| Region of Enrollment Germany | 17 participants |
| Region of Enrollment United States | 4 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 12 Participants |
| Total skin disease activity score of lesions to be treated with delgocitinib cream | 5.0 scores on a scale |
| Total skin disease activity score of lesions to be treated with vehicle | 5.0 scores on a scale |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 27 |
| other Total, other adverse events | 10 / 27 |
| serious Total, serious adverse events | 0 / 27 |
Outcome results
Primary
Target Lesions With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 6.
The IGA is an instrument used in clinical trials to rate the severity of the subject's global disease and is based on a 5-point scale ranging from 0 (clear) to 4 (severe). In this trial, the IGA was a lesion-specific assessment and was evaluated separately for each of the 2 target lesions.
Time frame: Week 6
Population: Per protocol (PP) analysis set. 5 subjects were excluded from the per protocol (PP) analysis set as the primary endpoint data were compromised. The PP analysis set hence comprised 22 (81.5%) subjects. Data at Week 8 was excluded from the PP analysis set for 2 subjects, as they used prohibited concomitant medication in the safety follow-up period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Delgocitinib Cream 20 mg/g | Target Lesions With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 6. | 3 lesions |
| Delgocitinib Cream Vehicle | Target Lesions With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 6. | 6 lesions |
p-value: 0.453195% CI: [-0.37, 0.09]McNemar
Secondary
Erythema Score at Week 6.
The erythema score is lesion-specific and based on the CLASI and the RCLASI which are validated scoring systems to assess disease activity and damage in patients with cutaneous lupus erythematosus. The severity of the erythema is scored on a 4-point scale ranging from 0 to 3. The severity is scored from low to high with 0=absent and 3=dark red, purple/violaceous/crusted/haemorrhagic.
Time frame: Week 6
Population: Per protocol (PP) analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Delgocitinib Cream 20 mg/g | Erythema Score at Week 6. | 1.5 scores on a scale |
| Delgocitinib Cream Vehicle | Erythema Score at Week 6. | 1.5 scores on a scale |
p-value: 0.5797Wilcoxon signed rank test
Secondary
Number of Adverse Events (AEs) up to Week 6.
Number of AEs from baseline to Week 6
Time frame: Week 0 to Week 6
Population: Safety analysis set. All 27 subjects were exposed to IMP. All subjects were treated with delgocitinib cream on one target lesion and with vehicle on another target lesion, and except for lesion-specific AEs, it was therefore not possible to distinguish between AEs related to delgocitinib cream or vehicle treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Delgocitinib Cream 20 mg/g | Number of Adverse Events (AEs) up to Week 6. | 8 AEs |
Secondary
Number of Lesion-specific, Treatment-related AEs up to Week 6.
The number of lesion-specific, treatment-related AEs per target lesion will be compared for active and vehicle treatment. Lesion-specific AEs are defined as lesional/perilesional AEs (i.e. AE location within the treatment area and/or ≤2 cm from the border of a target lesion).
Time frame: Week 0 to Week 6
Population: Safety analysis set. All 27 subjects were exposed to IMP. All subjects were treated with delgocitinib cream on one target lesion and with vehicle on another target lesion. It was therefore only possible to distinguish between AEs related to delgocitinib cream or vehicle treatment for the lesion-specific AEs.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Delgocitinib Cream 20 mg/g | Number of Lesion-specific, Treatment-related AEs up to Week 6. | 2 AEs |
| Delgocitinib Cream Vehicle | Number of Lesion-specific, Treatment-related AEs up to Week 6. | 0 AEs |
p-value: 0.595% CI: [-0.02, 0.17]McNemar
Secondary
Number of Lesions With ≥2-point Reduction in Erythema Score at Week 6 Compared to Baseline.
The erythema score is lesion-specific and based on the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the Revised CLASI (RCLASI) which are validated scoring systems to assess disease activity and damage in patients with cutaneous lupus erythematosus. The severity of the erythema is scored on a 4-point scale ranging from 0 to 3. The severity is scored from low to high with 0=absent and 3=dark red, purple/violaceous/crusted/haemorrhagic.
Time frame: Week 0 to Week 6
Population: Per protocol (PP) analysis set. 5 subjects were excluded from the per protocol (PP) analysis set as the primary endpoint data were compromised. The PP analysis set hence comprised 22 (81.5%) subjects. Data at Week 8 was excluded from the PP analysis set for 2 subjects, as they used prohibited concomitant medication in the safety follow-up period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Delgocitinib Cream 20 mg/g | Number of Lesions With ≥2-point Reduction in Erythema Score at Week 6 Compared to Baseline. | 5 lesions |
| Delgocitinib Cream Vehicle | Number of Lesions With ≥2-point Reduction in Erythema Score at Week 6 Compared to Baseline. | 5 lesions |
p-value: 195% CI: [-0.22, 0.22]McNemar
Secondary
Number of Lesions With ≥2-point Reduction in IGA Score at Week 6 Compared to Baseline.
The IGA is an instrument used in clinical trials to rate the severity of the subject's global disease and is based on a 5-point scale ranging from 0 (clear) to 4 (severe). In this trial, the IGA was a lesion-specific assessment and was evaluated separately for each of the 2 target lesions.
Time frame: Week 0 to Week 6
Population: Per protocol (PP) analysis set. 5 subjects were excluded from the per protocol (PP) analysis set as the primary endpoint data were compromised. The PP analysis set hence comprised 22 (81.5%) subjects. Data at Week 8 was excluded from the PP analysis set for 2 subjects, as they used prohibited concomitant medication in the safety follow-up period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Delgocitinib Cream 20 mg/g | Number of Lesions With ≥2-point Reduction in IGA Score at Week 6 Compared to Baseline. | 3 lesions |
| Delgocitinib Cream Vehicle | Number of Lesions With ≥2-point Reduction in IGA Score at Week 6 Compared to Baseline. | 6 lesions |
p-value: 0.453195% CI: [-0.37, 0.09]McNemar
Secondary
Number of Subjects With AEs up to Week 6.
Number of subjects with AEs from baseline to Week 6
Time frame: Week 0 to Week 6
Population: Safety analysis set. All 27 subjects were exposed to IMP. All subjects were treated with delgocitinib cream on one target lesion and with vehicle on another target lesion, and except for lesion-specific AEs, it was therefore not possible to distinguish between AEs related to delgocitinib cream or vehicle treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Delgocitinib Cream 20 mg/g | Number of Subjects With AEs up to Week 6. | 8 Participants |
Secondary
Total Skin Disease Activity Score (Sum of Scores for Erythema, Scaling/Hyperkeratosis, and Oedema/Infiltration) at Week 6.
The skin disease activity scores are based on the CLASI and the RCLASI which are validated scoring systems to assess disease activity and damage in patients with cutaneous lupus erythematosus. The total skin disease activity score is defined as the sum of the scores for 3 clinical signs (erythema, scaling/hyperkeratosis, oedema/infiltration) for each target lesion. For the total score and the individual clinical signs, higher scores indicate more severe symptoms. Erythema is scored on a 4-point scale ranging from 0 (absent) to 3 (dark red, purple/violaceous/crusted/haemorrhagic). Hyperkeratosis/scaling is scored on a 3-point scale from 0 (absent) to 2 (verrucous hyperkeratosis). Oedema/infiltration is scored on a 3-point scale from 0 (absent) to 2 (palpable and visible). The total skin disease activity score can therefore range from 0 to 7.
Time frame: Week 6
Population: Per protocol (PP) analysis set. 5 subjects were excluded from the per protocol (PP) analysis set as the primary endpoint data were compromised. The PP analysis set hence comprised 22 (81.5%) subjects. Data at Week 8 was excluded from the PP analysis set for 2 subjects, as they used prohibited concomitant medication in the safety follow-up period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Delgocitinib Cream 20 mg/g | Total Skin Disease Activity Score (Sum of Scores for Erythema, Scaling/Hyperkeratosis, and Oedema/Infiltration) at Week 6. | 2.5 scores on a scale |
| Delgocitinib Cream Vehicle | Total Skin Disease Activity Score (Sum of Scores for Erythema, Scaling/Hyperkeratosis, and Oedema/Infiltration) at Week 6. | 2.5 scores on a scale |
Comparison: Total skin disease activity score is the sum of the scores for erythema, scaling/hyperkeratosis, and oedema/infiltration. Total skin disease activity score ranges from 0 to 7 with lower score indicating better state.p-value: 0.7862Wilcoxon signed rank test