Efficacy Study of Omalizumab in Cholinergic Urticaria

Cholinergic Urticaria Clinical Trial

— CUN-OMAL-UCOL  

Official title:

Multicenter Randomized, Double-blind, Placebo-controlled Parallel Clinical Trial to Assess Efficacy and Safety of Omalizumab (Xolair®) in a New Indication: Cholinergic Urticarial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02012387
• Other study ID #: CUN-OMAL-UCOL
• Status: Completed
• Phase: Phase 2
• Start date: January 2014
• Est. completion date: June 2017

Study information

• Verified date: April 2017
• Source: Clinica Universidad de Navarra, Universidad de Navarra
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To demonstrate the efficacy and safety of Omalizumab in a new indication, that is cholinergic urticaria.

Description:

Physical urticarias, such as delayed pressure, cholinergic, dermatographism and cold urticaria, are highly disabling conditions[1]. Cholinergic urticaria occurs due to an active (e.g. exercise) or passive (e.g. hot bath) increase in core body temperature, causing itching and small hives with flare reaction on the trunk and limps that fade away upon cooling of the body[2].

As it is the case of chronic urticaria, physical urticarias have a great impact on patients' quality of life[3, 4]. However, these types of urticarias cause even more alteration on quality of life because of the limitations they cause in daily life activities, sports practicing[5] or work performance.

In spite of the high morbidity of this disease and the impact on quality of life, there is no available treatment. Antihistamines that usually control other types of urticaria could only partially alleviate cholinergic urticaria. There is only one paper[6] that shows efficacy doubling the dose of cetirizine above the recommended dosage on the Summary of Product Characteristics (off-label dosage). The poor response to antihistamine is justified by the minimal role of histamine in its physiopathology and only after employing very high doses[7].

The etiology and pathogenesis of hive formation remains unknown, though it is recognized that mast cells are clearly involved[8]. On the other hand, it seems that desensitization or tolerance could be induced in cholinergic urticaria[9]. Thus as it is the case of drug desensitization, Immunoglobulin E (IgE) receptor must also play a role in the development of this physical urticaria[10].

In the past years, the monoclonal humanized anti-IgE antibody (Omalizumab) was shown to be effective in control cholinergic urticaria[11] not respondent to conventional therapies at maximum or off-label doses. A negative response was also reported for cholinergic urticaria[12].

Our rationale for this approach in this type of urticaria is that Omalizumab exerts an inhibitory action on mast cell activation, as is the case of desensitization.

For that purpose, we will perform a multicenter, randomized, double-blind, placebo-controlled parallel clinical trial. We will include 24 patients including both female and male patients (age 14 years or older), non-respondent to antihistamines.

Efficacy will be evaluated through the negativization of the European Academy of Allergy and Clinical Immunology (EAACI), European Dermatology Forum (EDF) and urticaria network e.V (UNEV) standardized exercise challenge test, Visual Analog Scale (VAS), Chronic Urticaria Quality of Life validated questionnaire[13], patients' card of symptoms and use of rescue medication. Additional measures of efficacy will also be: the number of dropouts in each treatment group; the leave days due of urticaria and Emergency Department visits. Finally, safety will be assessed by means of recording and evaluation of adverse reactions during treatment.

As we previously stated, Omalizumab is not indicated for physical or other types of urticaria. The only indication is for treatment of moderate-to-severe allergic asthma. The hypothesis we are working on is that the monoclonal anti-IgE antibody Omalizumab could be as well effective in controlling physical urticaria symptoms in patients non-respondent to conventional therapy. We hypothesize that Omalizumab is able to revert the basophil or mast cell activation present in those urticaria types.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: June 2017
• Est. primary completion date: September 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 14 Years and older

Eligibility

Inclusion Criteria:

Adult female and male patients (age 14 years or older). Diagnosis of cholinergic urticaria trough clinical history and positive challenge test.

Non-respondent to supra therapeutic doses of antihistamines (defined as 2x the maximal dose included in the drug labeling) Written informed consent.

Exclusion Criteria:

Pruritus related to dermatitis or other skin condition. Any systemic disease that hampers follow up or interpretation of data. Omalizumab treatment within the previous 12 months. Any exclusion criteria included in the drug labeling. Any other conditions that do not allow the accomplishment of the clinical trial requisites, such as the abuse of drugs or alcohol.

Related Conditions & MeSH terms

• Cholinergic Urticaria
• Urticaria

Intervention

Biological:
• Active
Two injections will be administered every four weeks for four months, we will administer 4 doses within 16 weeks
• Placebo
Two injections will be administered every four weeks for four months, we will administer 4 doses within 16 weeks
• Open labeled
Two injections will be administered every four weeks for 8 months, we will administer 4 doses within 32 weeks

Locations

Country	Name	City	State
Spain	Departamento de Alergología. Clínica Universidad de Navarra	Pamplona	Navarra

Sponsors (8)

Lead Sponsor	Collaborator
Clinica Universidad de Navarra, Universidad de Navarra	Complejo Hospitalario de Navarra, Hospital Clinic of Barcelona, Hospital Clínico Universitario Lozano Blesa, Hospital General Universitario Gregorio Marañon, Hospital Universitari Joan XXIII de Tarragona., Hospital Universitario Central de Asturias, Hospital Vall d'Hebron

Country where clinical trial is conducted

Spain, 

References & Publications (14)

Abajian M, Mlynek A, Maurer M. Physical urticaria. Curr Allergy Asthma Rep. 2012 Aug;12(4):281-7. doi: 10.1007/s11882-012-0269-0. Review. — View Citation

Baiardini I, Giardini A, Pasquali M, Dignetti P, Guerra L, Specchia C, Braido F, Majani G, Canonica GW. Quality of life and patients' satisfaction in chronic urticaria and respiratory allergy. Allergy. 2003 Jul;58(7):621-3. — View Citation

Baiardini I, Pasquali M, Braido F, Fumagalli F, Guerra L, Compalati E, Braga M, Lombardi C, Fassio O, Canonica GW. A new tool to evaluate the impact of chronic urticaria on quality of life: chronic urticaria quality of life questionnaire (CU-QoL). Allergy. 2005 Aug;60(8):1073-8. — View Citation

Gaig P, Olona M, Muñoz Lejarazu D, Caballero MT, Domínguez FJ, Echechipia S, García Abujeta JL, Gonzalo MA, Lleonart R, Martínez Cócera C, Rodríguez A, Ferrer M. Epidemiology of urticaria in Spain. J Investig Allergol Clin Immunol. 2004;14(3):214-20. — View Citation

Haas N, Toppe E, Henz BM. Microscopic morphology of different types of urticaria. Arch Dermatol. 1998 Jan;134(1):41-6. — View Citation

Hirschmann JV, Lawlor F, English JS, Louback JB, Winkelmann RK, Greaves MW. Cholinergic urticaria. A clinical and histologic study. Arch Dermatol. 1987 Apr;123(4):462-7. — View Citation

Kozaru T, Fukunaga A, Taguchi K, Ogura K, Nagano T, Oka M, Horikawa T, Nishigori C. Rapid desensitization with autologous sweat in cholinergic urticaria. Allergol Int. 2011 Sep;60(3):277-81. doi: 10.2332/allergolint.10-OA-0269. Epub 2011 Feb 25. — View Citation

Metz M, Altrichter S, Ardelean E, Kessler B, Krause K, Magerl M, Siebenhaar F, Weller K, Zuberbier T, Maurer M. Anti-immunoglobulin E treatment of patients with recalcitrant physical urticaria. Int Arch Allergy Immunol. 2011;154(2):177-80. doi: 10.1159/000320233. Epub 2010 Aug 24. — View Citation

Morales AR, Shah N, Castells M. Antigen-IgE desensitization in signal transducer and activator of transcription 6-deficient mast cells by suboptimal doses of antigen. Ann Allergy Asthma Immunol. 2005 May;94(5):575-80. — View Citation

Nakamizo S, Egawa G, Miyachi Y, Kabashima K. Cholinergic urticaria: pathogenesis-based categorization and its treatment options. J Eur Acad Dermatol Venereol. 2012 Jan;26(1):114-6. doi: 10.1111/j.1468-3083.2011.04017.x. Epub 2011 Mar 4. Review. — View Citation

O'Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The impact of chronic urticaria on the quality of life. Br J Dermatol. 1997 Feb;136(2):197-201. — View Citation

Sabroe RA. Failure of omalizumab in cholinergic urticaria. Clin Exp Dermatol. 2010 Jun;35(4):e127-9. doi: 10.1111/j.1365-2230.2009.03748.x. Epub 2009 Nov 19. — View Citation

Tlougan BE, Mancini AJ, Mandell JA, Cohen DE, Sanchez MR. Skin conditions in figure skaters, ice-hockey players and speed skaters: part II - cold-induced, infectious and inflammatory dermatoses. Sports Med. 2011 Nov 1;41(11):967-84. doi: 10.2165/11592190-000000000-00000. Review. — View Citation

Zuberbier T, Münzberger C, Haustein U, Trippas E, Burtin B, Mariz SD, Henz BM. Double-blind crossover study of high-dose cetirizine in cholinergic urticaria. Dermatology. 1996;193(4):324-7. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Negativization of the exercise challenge test	a. Our primary endpoint will be the negativization of the exercise challenge test: We will perform the exercise challenge test following the European Guidelines[14] for cholinergic urticaria. According with such guidelines, all centers will follow the same center standardized protocol. The patient will exercise in treadmill or running to the point of sweating and following for 15 more minutes, wearing warm clothing in a warm room. The test will be considered positive if exercise challenge leads to the typical rash over 10 minutes.	It will be assessed prior to the study, and subsequently each 4 weeks up to 12 months.
Secondary	Chonic Urticaria Quality of life	Quality of Life: QoL will be evaluated through the Spanish validated version of Chronic Urticaria quality of life (CU-Q2oL)	It will be evaluated up to 48 weeks.
Secondary	Patients' card	Use of medication, VAS, daily symptoms, emergency visits, days off work.	It will be assessed up to 48 weeks.
Secondary	Treatment drop offs in each sequence		Up to 48 weeks.