Clinical trial NCT02012387: Efficacy Study of Omalizumab in Cholinergic Urticaria
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cholinergic Urticaria
Keywords: Cholinergic urticaria
Omalizumab
Lead sponsor: Clinica Universidad de Navarra, Universidad de Navarra
Sponsor class: OTHER
Collaborators: name: Hospital Clinic of Barcelona
name: Hospital Universitari Joan XXIII de Tarragona.
name: Hospital General Universitario Gregorio Marañon
name: Complejo Hospitalario de Navarra
name: Hospital Universitario Central de Asturias
name: Hospital Clínico Universitario Lozano Blesa
name: Hospital Vall d'Hebron
First posted: 2013-12-16
Enrollment: 24
Sex: ALL
Minimum age (years): 14
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Negativization of the exercise challenge test
timeFrame: It will be assessed prior to the study, and subsequently each 4 weeks up to 12 months.
Secondary outcomes:
measure: Chonic Urticaria Quality of life
timeFrame: It will be evaluated up to 48 weeks.
measure: Patients' card
timeFrame: It will be assessed up to 48 weeks.
measure: Treatment drop offs in each sequence
timeFrame: Up to 48 weeks.
Other outcomes:
Locations:
city: Pamplona
country: Spain
facility: Departamento de Alergología. Clínica Universidad de Navarra
state: Navarra
Study officials:
References:
citation: 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.
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. doi: 10.1001/archderm.123.4.462.
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.
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. doi: 10.1034/j.1398-9995.2003.00091.x.
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.
citation: Zuberbier T, Munzberger 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. doi: 10.1159/000246281.
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.
citation: Haas N, Toppe E, Henz BM. Microscopic morphology of different types of urticaria. Arch Dermatol. 1998 Jan;134(1):41-6. doi: 10.1001/archderm.134.1.41.
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.
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. doi: 10.1016/S1081-1206(10)61136-2.
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.
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.
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. doi: 10.1111/j.1398-9995.2005.00833.x.
citation: Gaig P, Olona M, Munoz Lejarazu D, Caballero MT, Dominguez FJ, Echechipia S, Garcia Abujeta JL, Gonzalo MA, Lleonart R, Martinez Cocera C, Rodriguez A, Ferrer M. Epidemiology of urticaria in Spain. J Investig Allergol Clin Immunol. 2004;14(3):214-20.