E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
chronic spontaneous urticaria despite H1-antihistamine treatment |
chronische spontane urticaria |
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E.1.1.1 | Medical condition in easily understood language |
Chronic spontaneous urticaria is characterized by the occurence of recurrent wheals, pruritus and or angioedema which can affect the whole body. |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009159 |
E.1.2 | Term | Chronic urticaria |
E.1.2 | System Organ Class | 100000004858 |
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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 |
The primary objective is the evaluation of Dupilumab (600 mg loading dose and subsequent 300 mg regular long term dose) being superior to placebo regarding be the difference in the change in urticaria activity score 7 (UAS7) from baseline to week 16 in adult patients with moderate to severe CSU and with H1-antihistamine resistant alone or in combination with LTRA. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of Dupilumab based on changes of following secondary objectives: Itch score (ISS) complete itch response is defined as 0 or a reduction of ≥ 90% compared to baseline; UCT (Urticaria control test): UCT response is defined as ≥ 12, complete UCT response is defined as 16; CU-Q2oL (Chronic Urticaria Quality of Life questionnaire), mean improvement and responder as defined as rate of patients achieving at least the defined minimal important difference; Angioedema burdened days (if applicable); AAS (Angioedema Activity Score) (if applicable); AE-QoL (Angioedema Quality-of-Life questionnaire) (if applicable); DLQI (Dermatology Quality of Life Index); Time to first recurrence after discontinuation of Dupilumab in comparison to placebo therapy within follow-up period; Need for non-sedating H1-antihistamine and corticosteroids based rescue medication (as specified under 6.5.5); Investigator’s Global Assessment of efficacy; Patient´s Global Assessment of efficacy
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient is informed about study procedures and medications and has given written informed consent before any assessment. 2. Patient is able to communicate with the investigator, understands and complies with the requirements of the study. 3. Male or Female 4. Patient is 18-75 years of age 5. Patient is diagnosed with moderate to severe CSU and refractory to standard of care treatment at the time of randomization, as defined by the following: • The presence of itch, hives and recurrent angioedema for ≥ 6 consecutive weeks at any time prior to enrollment despite current use of H1 antihistamine • UAS7 score ≥ 16, 7 days prior to randomization (Day 1) • CSU diagnosis for 6 months 6. Willing and able to complete a daily symptom Diary for the duration of the study and adhere to the study visit schedules. 7. Patients must not have more than one missing Diary entry in the 7 days prior to randomization. Re-screening may be considered. 8. Women of childbearing potential have to agree to use an acceptable form of contraception (as determined by the site investigator) and have to continue its use for the duration of the study. |
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E.4 | Principal exclusion criteria |
1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer; or longer if required by local regulations, and for any other limitation of participation in an investigational trial based on local regulations. 2. History of hypersensitivity to any of the study drugs (Dupilumab, rescue medication) or to drugs of similar chemical classes. 3. Patients whose urticaria is solely due to inducible urticaria 4. Other diseases with symptoms of urticaria or angioedema, including urticarial vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa), and hereditary or acquired angioedema (e.g., due to C1 inhibitor deficiency) 5. Any other skin disease associated with chronic itching that might confound the study evaluations and results (e.g. atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, etc.) 6. 7. Patients who have received concomitant prohibited medication within the last 3 months prior to screening: • Anti-IgE therapy (e.g. omalizumab) • Routine (daily or every other day during 5 or more consecutive days) doses of systemic corticosteroids or other immunosupressants • Intravenous immunoglobulins • Biological therapy • Systemic immunosuppressants • Live/attenuated vaccines 8. Other investigational drugUse of prohibited treatment detailed in protocol (see under 6.5.8 Table 3) 9. History of anaphylaxis 10. Presence of hypereosinophilic diseases (blood eosinophils >1500 cells/mm3 at the latest available test). 11. Presence of clinically significant cardiovascular, bronchial, neurological, psychiatric, metabolic or other pathological conditions that could interfere with the interpretation of the study results and or compromise the safety of the patients. 12. Medical examination or laboratory findings that suggest the possibility of decompensation of co-existing conditions for the duration of the study. Any items that are cause for uncertainty must be reviewed with the Medical Monitor. 13. Inability to comply with study and follow-up procedures. 14. History of malignancy of any organ system (other than localized basal cell carcinoma or actinic keratosis or Bowen disease: carcinoma in situ of skin; carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been removed), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. 15. Evidence of severe renal dysfunction at screening 14. Patient considered potentially unreliable or where it is envisaged the patient may not consistently attend scheduled study visits. 15. History or evidence of ongoing drug or alcohol abuse, within the last 6 months prior to randomization. 16. Patient unable to complete a patient diary or complete questionnaires on paper. 17. Any other condition or prior/current treatment, which in the opinion of the investigator renders the patient ineligible for the study schedule. 18. Study personnel or first-degree relatives of investigator(s) must not be included in the study. 19. Subjects who live in detention on court order or on regulatory action as per local and national law (see §40 subsection 1 sentence 3 no. 4 Arzneimittelgesetz) 20. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. 21. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are using effective methods of contraception during the duration of the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
difference in the change of UAS7 at week 16 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
When all of the planned patients have completed the Week 16 visit (or discontinued prior to that). |
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E.5.2 | Secondary end point(s) |
To evaluate the efficacy of Dupilumab based on changes of following secondary objectives: Itch score (ISS) complete itch response is defined as 0 or a reduction of ≥ 90% compared to baseline; UCT (Urticaria control test): UCT response is defined as ≥ 12, complete UCT response is defined as 16; CU-Q2oL (Chronic Urticaria Quality of Life questionnaire), mean improvement and responder as defined as rate of patients achieving at least the defined minimal important difference; Angioedema burdened days (if applicable); AAS (Angioedema Activity Score) (if applicable); AE-QoL (Angioedema Quality-of-Life questionnaire) (if applicable); DLQI (Dermatology Quality of Life Index); Time to first recurrence after discontinuation of Dupilumab in comparison to placebo therapy within follow-up period; Need for non-sedating H1-antihistamine and corticosteroids based rescue medication (as specified under 6.5.5); Investigator’s Global Assessment of efficacy; Patient´s Global Assessment of efficacy
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The Continuous secondary efficacy endpoints will be analyzed analogous to the primary endpoint, as a mean difference from baseline (visit 1) to week 16 (visit 9) and other time points. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
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 | 2 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
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
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Before study start a CRO representative will review the protocol and CRFs with the investigators and their staff. During the study, the field monitor will visit the site regularly to check the completeness of patient records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study drug is being stored, dispensed, and accounted for according to specifications. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |