| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic spontaneous urticaria |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic spontaneous urticaria |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10072757 |
| E.1.2 | Term | Chronic spontaneous urticaria |
| E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate the efficacy of dupilumab in adult and adolescent participants with CSU who remain symptomatic despite the use of H1 antihistamine (Study A: omalizumab naïve; Study B: omalizumab intolerant or incomplete responders) |
|
| E.2.2 | Secondary objectives of the trial |
- To demonstrate the efficacy of dupilumab on urticaria activity composite endpoint and itch or hives, separately, at various timepoints
- To demonstrate the efficacy of dupilumab on angioedema
- To demonstrate the efficacy of dupilumab on urticaria control
- To demonstrate improvement in health-related quality of life and overall disease status and severity
- To evaluate the ability of dupilumab in reducing the proportion of patients who require treatment with oral corticosteroids (OCS)
- To evaluate safety outcome measures
- To evaluate immunogenicity of dupilumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Must be 12 to 80 years of age, at the time of signing the informed consent
- Participants who have a diagnosis of CSU refractory to H1 antihistamines (H1-AH) at the time of randomization defined by
• Diagnosis of CSU>6 months prior to screening visit
• Presence of itch and hives for >6 consecutive weeks at any time prior to screening visit despite the use of H1-AH during this time period
• Using a study defined H1-antihistamine for CSU treatment
• During the 7 days before randomization:
UAS7=>16
ISS7=> 8
• In-clinic UAS> 4 prior to randomization
• Study A: omalizumab naïve, Study B; intolerant or incomplete responder to omalizumab
- Participants must be willing and able to complete a daily symptom eDiary for the duration of the study |
|
| E.4 | Principal exclusion criteria |
Participants are excluded from any of the studies if any of the following criteria apply:
- Weight is less than 30 kg
- Clearly defined underlying etiology for chronic urticarias other than CSU
- Presence of skin morbidities other than CSU that may interfere with the assessment of the study outcomes
- Active atopic dermatitis
- Severe concomitant illness(es) that, in the investigator’s judgment, would adversely affect the patient’s participation in the study
- Active tuberculosis or non-tuberculous mycobacterial infection, or a history of incompletely treated tuberculosis
- Diagnosed active endoparasitic infections; suspected or high risk of endoparasitic infection
- Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks before the screening visit
- Known or suspected immunodeficiency
- Active malignancy or history of malignancy within 5 years before the baseline visit, except completely treated in situ carcinoma of the cervix, completely treated and resolved non-metastatic squamous or basal cell carcinoma of the skin.
- History of systemic hypersensitivity or anaphylaxis to omalizumab or any biologic therapy, including any excipients |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in weekly itch severity score ; Change from baseline in weekly itch severity score (ISS7) at Week 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1 - 2 - Change from baseline in weekly itch severity score (ISS7) at Week 12 and 24 / Change from baseline in weekly hives severity score (HSS7) at Week 12 and Week 24 ; The hives severity score will be recorded daily in the patient eDiary, on a scale of 0 (none) to 3 (severe). The baseline weekly hive score is the sum of the daily hives scores over the 7 days prior to randomization (Day 1 visit), and the weekly ihives score at Weekk12/ Week 24 is the sum of daily hives scores over the 7 days prior to the Week 12/ Week 24 visit.
3 - Time to ISS7 minimally important (MID) (ISS7 ≥5) response ; The itch severity score will be recorded daily in the patient eDiary, on a scale of 0 (none) to 3 (severe).The weekly itch score is the sum of the daily itch scores over 7 days
4 - Proportion of ISS7 MID (≥5 points) responders at Week 12 and Week 24 ; The itch severity score will be recorded daily in the patient eDiary, on a scale of 0 (none) to 3 (severe).The weekly itch score is the sum of the daily itch scores over 7 days.
5 - Change from baseline in ISS7 at all time points (onset of action is assessed by the first p<0.05 that remains significant at subsequent measures until Week 24 ; The itch severity score will be recorded daily in the patient eDiary, on a scale of 0 (none) to 3 (severe).The weekly itch score is the sum of the daily itch scores over 7 days
6 - Change from baseline in UAS7 at Week 12 ; The UAS is a composite eDiary-recorded score with numeric severity intensity ratings on a scale of 0-3 (0=none to 3=intense/severe) for 1) the number of wheals (hives); and 2) the intensity of the itch measured daily. UAS7 is the sum of the daily UAS scores over 7 days.
7 - 8 - Proportion of patients with UAS7 ≤6 at Week 12 and Week 24 / Proportion of patients with UAS7=0 at Week 12 and Week 24 ; The UAS is a composite eDiary-recorded score with numeric severity intensity ratings on a scale of 0-3 (0=none to 3=intense/severe) for 1) the number of wheals (hives); and 2) the intensity of the itch measured daily. UAS7 is the sum of the daily UAS scores over 7 days.
9 - Change from baseline in angioedema activity score over 7 days (AAS7) at Week 12 and Week 24 ; Angioedema activity score (AAS) is recorded once daily in the Diary by the participants. This validated tool assesses episodes of angioedema including their duration, severity and impact on daily functioning and appearance.
10 - Change from baseline in urticaria control test (UCT) at Week 12 and Week 24 ; The urticarial control test (UCT) is instrument that works in all types of chronic urticaria (not only for CSU), and it can also be used in urticaria patients suffering from recurrent angioedema.otal score ranges 0 to 16; higher scores indicate better disease control.
11 - Proportion of well controlled patients (UCT ≥12) at Week 12 and Week 24 ; The urticarial control test (UCT) is instrument that works in all types of chronic urticaria (not only for CSU), and it can also be used in urticaria patients suffering from recurrent angioedema.otal score ranges 0 to 16; higher scores indicate better disease control. Scores ≥12 are consistent with well-controlled disease.
12 - Change from baseline in health-related quality-of-life as measured by Dermatology Life Quality Index (DLQI) in patients 16 years old and above, and in Children’s Dermatology Life Quality Index (CDLQI) in patients 12 to 16 years old at Week 12 and Week 24 ; The Dermatology Life Quality Index (DLQI) is a 10-item dermatology-specific health-related quality of life measure. Overall scoring ranges from 0 to 30, with a high score indicative of a poor HRQOL.
The Children’s Dermatology Quality Life Quality Index (CDLQI) is a validated questionnaire designed to measure the impact of skin disease on children’s HRQOL. Overall scoring ranges from 0 to 30. The higher the score, the greater the impact is on the child’s HRQOL.
13 - Change from baseline in Patient Global Impression of Severity (PGIS) of CSU at Week 12 and Week 24; The Patient Global Impression of Severity (PGISā¦) is a one-item questionnaire that asks participants to provide the overall self-assessment of their participant’ disease severity on a 4-point scale for the past week.
14 - Patient Global Assessment of Change (PGIC) of CSU at Week 12 and Week 24; The Patient Global Impression of Change (PGIC) is a one-item questionnaire that asks the participant to provide the overall self-assessment of change in their CSU on a 7-point scale, compared to just before participant started taking the study treatment
15 - Proportion and time to event of patients receiving OCS for CSU during the planned treatment period ;
16 - Safety; Percentage of participants experiencing treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs)
Immunogenicity; Incidence of treatment-emergent ADA against dupilumab over time |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1, 2 : Baseline to Week 12 and Week 24
3 : Baseline over time until Week 24
4 : Week 12 and Week 24
5 : Baseline to Week 24
6 : Baseline to Week 12
7, 8 : Week 12 and Week 24
9, 10 : Baseline to Week 12 and Week 24
11 : Week 12 and Week 24
12, 13 : Baseline to Week 12 and Week 24
14 : Week 12 and Week 24
15 : Baseline over time to Week 24
16 : Baseline to Week 24 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Canada |
| China |
| France |
| Germany |
| Hungary |
| Japan |
| Russian Federation |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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