Clinical trial NCT00414141: Efficacy and Safety/Tolerability of Grass MATA MPL
Official title: Efficacy and Safety/Tolerability of Grass MATA MPL, a Randomized, Placebo-Controlled, Double-Blind Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Type I Hypersensitivity
Keywords: Allergy
Allergoid
Specific Immunotherapy
Lead sponsor: Allergy Therapeutics
Sponsor class: INDUSTRY
First posted: 2006-12-21
Enrollment: 1028
Sex: ALL
Minimum age (years): 18
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Grass MATA MPL has been developed by Allergy Therapeutics (UK) Ltd. to provide pre-seasonal specific immunotherapy for patients with proven type I hypersensitivity to cross reacting grass pollens causing rhinitis and/or conjunctivitis with or without mild to moderate asthma bronchiale. The purpose of this study is to compare the efficacy of Grass MATA MPL versus placebo in grass-allergic subjects following 4 subcutaneous injections of study medication administered before the start of the 2007 grass pollen season.

Detailed description: Grass MATA MPL has been developed by Allergy Therapeutics (UK9 Ltd.to provide pre-seasonal specific immunotherapy for patients with proven type I hypersensitivity to cross reacting grass pollens causing rhinitis and/or conjunctivitis with or without mild to moderate asthma bronchiale. Grass MATA MPL is produced as a re-formulation of the Allergy Therapeutics product Pollinex Quattro, which has been used in Europe since 1999 on a 'named patient' basis (with approximately 65,000 treatment courses containing grass pollens).

Grass MATA MPL contains an extract of the 13 grass pollens. This extract is chemically modified with glutaraldehyde to produce the active ingredient, an allergoid. Such modification reduces the reactivity of the extract with IgE antibody. However, a simultaneous reduction in other important immunological properties, such as IgG and T cell reactivity is not seen. The modified extract is adsorbed to L-tyrosine as a depot formulation. MPL®, a purified, detoxified glycolipid derived from the cell walls of Salmonella minnesota, is also included in the current product formulation. This excipient/adjuvant is included to increase the immunogenic effect of the product and to enhance the switch from an allergen-specific TH2 to TH1-like T cell profile.

The current formulation is designed to provide a product that will be efficacious with only 4 injections, in contrast to the longer schedules currently in use with unmodified extracts. The product will also be safer to use than a formulation containing a similar mass of unmodified allergen extract as regards its ability to cause severe local allergic reactions or anaphylaxis, because of its reduced reactivity with IgE antibody. The modification is greater than 75%, so that only a small amount of unmodified allergen is remaining in the product.

The purpose of this study is to compare the efficacy of Grass MATA MPL versus placebo in grass-allergic subjects following 4 subcutaneous injections of study medication administered before the start of the 2007 grass pollen season.

Eligibility criteria: Inclusion Criteria:

* Have given written informed consent;
* Are 18 to 59 years of age;
* Have a history of moderate to severe symptoms of seasonal allergic rhinitis and/or conjunctivitis ascribed to grass pollen exposure that required repeated use of antihistamines, nasal steroids, and/or leukotriene modifiers;
* Have a history of moderate to severe symptoms in the past grass pollen season as determined by a score of ≥ 5 on the Disease Severity Questionnaire;
* Have a positive skin prick test to grass pollen mix \[wheal (longest diameter) ≥ 5 mm greater than the negative control\] and a positive RAST or equivalent test (class ≥ 2) to grass pollen mix;
* Have a positive skin prick test to histamine \[wheal (longest diameter) of ≥ 3 mm greater than the negative control\];
* Have a negative skin prick test to the negative control (redness with wheal ≤ 2 mm is acceptable);
* Have a forced expiratory volume in 1 second (FEV1) ≥ 80% of predicted, with a FEV1/FVC ratio ≥ 70%;
* Women of childbearing potential must be using a medically acceptable method of birth control \[i.e. double barrier method of contraception (e.g., intrauterine device and condom, spermicide and condom), stable hormonal contraceptive for ≥ 90 days prior to the study or if \< 90 days additional use of a double barrier method until 90 days reached, sexual abstinence or have a vasectomized partner until study completion\], and have a negative β-HCG pregnancy test result at Visits 1 and 2;
* Are able to understand and comply with study instructions;
* Demonstrate proper use of electronic diary with at least 85% compliance (i.e., correct entries for symptoms on 6 of 7 days) during the 1-week period between Visit 1 and Visit 2.

Exclusion Criteria:

* Are pregnant or lactating
* Have asthma requiring the daily use of controller medication;
* Had an emergency room visit or admission for asthma in the 12 months prior to Visit 1;
* Have the presence of secondary alteration at the affected organ (i.e., emphysema, bronchiectasis, nasal polyps, chronic sinusitis);
* Have auto-immune disease (e.g., liver, kidney, thyroid, nervous system);
* Have acute or subacute (historic) atopic dermatitis, chronic dermatitis, urticaria factitia, and/or urticaria due to physical/chemical influence or any other skin conditions which might interfere with the interpretation of the skin prick test results;
* Have a history or presence of diabetes (both insulin dependent and non-dependent), cancer or concomitant illness (e.g., cardiac, metabolic, renal, hepatic, gastrointestinal, dermatologic, venereal, hematologic, neurologic, or psychiatric diseases or disorders) that, in the opinion of the Investigator, would pose a safety risk or compromise the interpretation of efficacy for this grass immunotherapy;
* Have a history of angioedema;
* Have manifest pulmonary or cardiac insufficiency;
* Have current malignant disease;
* Have disorders of tyrosine metabolism (i.e., alcaptonuria, tyrosinemia);
* Have an acute or chronic infection;
* Have any clinically significant abnormal laboratory value (as determined by the Investigator) at Visit 1;
* Perennial Allergens: Have a positive skin prick test \[wheal (longest diameter) ≥ 3mm greater than the negative control\] at Visit 1 to: house dust mites (Dermatophagoides pteronyssinus and Dermatophagoides farinae), molds (Cladosporium cladosporioides, Alternaria alternata, Penicillium chrysogenum, and Aspergillus fumigatus), or epithelia (cat, dog, and horse). In these cases, a careful history is to be taken and if moderate or severe symptoms are reported when exposed to the aforementioned allergens, the subject is to be excluded. Exception: the source of the allergen (cat, dog, horse) can be avoided for the entire study. Subjects with mild or no symptoms when exposed to the aforementioned allergens during the 3 years prior to Visit 1 will be allowed to enroll. Mild symptoms are defined as: sign/symptom clearly present, but minimal awareness; easily tolerated;
* Only for the USA and Canada:Autumn/Winter Flowering Plant Allergens: Have a positive skin prick test \[wheal (longest diameter) ≥ 3mm greater than the negative control\] at Visit 1 to: ragweed (Ambrosia sp.) or mountain cedar/mountain juniper (Juniperus ashei). In these cases, a careful history is to be taken and if moderate to severe symptoms are reported when exposed to the aforementioned allergens the subject is to be excluded. Exception: one or both of the listed allergens must not be tested if they are not common to the Investigator's region or, if common to the region, the treatment phase of the study can be initiated at least 30 days after the end of the allergen(s) season. Subjects with mild or no symptoms when exposed to the aforementioned allergens during the 3 years prior to Visit 1 will be allowed to enroll. Mild symptoms are defined as: sign/symptom clearly present, but minimal awareness, easily tolerated;
* Springtime Flowering Plant Allergens: Applies only to subjects living in geographic areas where springtime flowering plant season and grass season overlap and/or when treatment phase cannot be completed at least 30 days prior to the start of the springtime flowering plant season. Otherwise, no testing of the following allergens is necessary; Have a positive skin prick test \[wheal (longest diameter) ≥ 3mm greater than the negative control\] at Visit 1 to: birch (Betula sp.), oak (Quercus sp.), sycamore/plane (Platanus sp.), beech (Fagus sp.), ash (Fraxinus sp.), or poplar (Populus sp.). In these cases, a careful history is to be taken and if moderate to severe symptoms are reported when exposed to the aforementioned allergens the subject is to be excluded. Subjects with mild or no symptoms when exposed to the aforementioned allergens during the 3 years prior to Visit 1 will be allowed to enroll. Mild symptoms are defined as: sign/symptom clearly present, but minimal awareness, easily tolerated;
* Only for the USA and Canada:Summertime Flowering Plant Allergens: Have a positive skin prick test \[wheal (longest diameter) ≥ 3mm greater than the negative control\] at Visit 1 to: Bermuda grass (Cynodon dactylon). In these cases, a careful history is to be taken and if moderate to severe symptoms are reported when exposed to the aforementioned allergens the subject is to be excluded. Exception: the listed allergen must not be tested if it is not common to the Investigator's region. Subjects with mild or no symptoms when exposed to the aforementioned allergens during the 3 years prior to Visit 1 will be allowed to enroll. Mild symptoms are defined as: sign/symptom clearly present, but minimal awareness; easily tolerated;
* Have inadequate washout period prior to screening (Visit 1). The following washout periods prior to Visit 1 are acceptable:

  * Oral or parenteral corticosteroids (1 month)
  * Inhaled, ocular or intranasal corticosteroids (1 day)
  * Mast cell stabilizers (7 days)
  * Intranasal or systemic decongestants including cold preparations (1 day)
  * Leukotriene modifiers (7 days)
  * Afrin (oxymetazoline hydrochloride) (14 days)
  * Antihistamines
* Once-daily or twice-daily antihistamines (7 days)
* Short-acting 3 or 4 times a day antihistamines (3 days)
* Hydroxyzine (14 days)

  * H2-blockers (1 day)
  * Other anti-inflammatory, anti-allergy, and any other medications (e.g., anticholinergic agents and tricyclic antidepressants) which, in the opinion of the Investigator, may interfere with the study objectives should be considered on a case-by-case basis
  * Topical skin medications on the forearms (14 days);
* Require use of beta blockers;
* Are unable to receive epinephrine therapy (i.e., use of epinephrine is contraindicated);
* Have a history of anaphylactic reactions to foods, insect venom, exercise, or drugs;
* Have been treated with a preparation containing MPL® within 6 months prior to Visit 1;
* Have diseases with a pathogenesis interfering with the immune response, and who have received medication which could interfere with the results of the study;
* Have a history of allergy, hypersensitivity or intolerance to the excipients of the study medication;
* Have a history of allergy, hypersensitivity or intolerance to study relief medication;
* Have already undergone hyposensitisation therapy with comparable allergen extracts; An exception will be allowed if prior immunotherapy with comparable allergen was successful, symptoms reappeared some time after stopping the immunotherapy, and the immunotherapy was completed ≥ 3 years before Visit 1;
* Have participated in a clinical research trial with a new chemical substance within 4 weeks of Visit 1;
* Are unable or unwilling to cooperate with the Investigator and to comply with the protocol requirements, or not likely to complete the observation periods sufficiently (e.g., 2 weeks holiday abroad during the time of diary recording);
* Have changed residence between geographical regions within the past 3 months

Primary outcomes:
measure: Efficacy of Grass MATA MPL versus placebo measured by combined allergy symptom + medication scores during 4 peak weeks of grass season
timeFrame: 9 Months
Secondary outcomes:
measure: Combined symptom + medication scores, Combined symptoms, Individual symptoms, Relief medication use, Specific immunological changes, quality of life, Health Assessments, Days absent from activities
timeFrame: 9 Months
measure: Adverse events, adverse reactions, clinical labs, ECG, and vitals
timeFrame: 9 months
Other outcomes:
Locations:
city: Colorado Springs
country: United States
facility: Asthma & Allergy Associates, PC & Research Center
state: Colorado
city: Denver
country: United States
facility: Colorado Allergy & Asthma Centers, PC
state: Colorado
city: Englewood
country: United States
facility: Colorado Allergy and Asthma Clinic, PC
state: Colorado
city: Waterbury
country: United States
facility: Dr. Dreyfus
state: Connecticut
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Normal
country: United States
facility: Sneeze, Wheeze & Itch Associates
state: Illinois
city: Fort Wayne
country: United States
facility: The Allergy and Asthma Center
state: Indiana
city: Dubuque
country: United States
facility: Medical Associates Clinic
state: Iowa
city: Iowa City
country: United States
facility: Iowa Clinical Research Corporation
state: Iowa
city: Overland Park
country: United States
facility: Kansas City Allergy and Asthma Associates, PA
state: Kansas
city: Boston
country: United States
facility: Brigham & Women's Hospital, Rheumatology & Immunology, Smith Building Rm 626
state: Massachusetts
city: Gardner
country: United States
facility: "The Allergy & Arthritis Family Treatment Centers
state: Massachusetts
city: Springfield
country: United States
facility: McGovern Allergy Associates, PC
state: Massachusetts
city: Ypsilanti
country: United States
facility: Respiratory Medicine Researdh Institute of Michigan, PLC
state: Michigan
city: Minneapolis
country: United States
facility: Clinical Research Institute
state: Minnesota
city: Plymouth
country: United States
facility: Clinical Research Institute
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: St Louis
country: United States
facility: Saint Louis University
state: Missouri
city: Billings
country: United States
facility: Montana Allergy and Asthma 2900 12th Avenue North Suite 302E
state: Montana
city: Missoula
country: United States
facility: Montana Medical Research
state: Montana
city: Omaha
country: United States
facility: Midwest Allegy and Asthma Clinic
state: Nebraska
city: Omaha
country: United States
facility: Creighton University - Allergy & Immunology
state: Nebraska
city: Papillion
country: United States
facility: Nebraska Medical Research Institute
state: Nebraska
city: Marlboro
country: United States
facility: Allergy & Asthma Center
state: New Jersey
city: Skillman
country: United States
facility: Princeton Center for Clinical Research Montgomery Professional Center
state: New Jersey
city: Teaneck
country: United States
facility: The Medical Center at Teaneck
state: New Jersey
city: Verona
country: United States
facility: Allergy Consultants, PA
state: New Jersey
city: Cortland
country: United States
facility: Asthma and Allergy Associates, PC
state: New York
city: Elmira
country: United States
facility: Asthma and Allergy Associates, PC
state: New York
city: Rochester
country: United States
facility: Aair Research Center
state: New York
city: Rockville Center
country: United States
facility: Island Medical Research, PC
state: New York
city: Fargo
country: United States
facility: Allergy & Asthma Care Center
state: North Dakota
city: Fargo
country: United States
facility: Merit Care Health
state: North Dakota
city: Canton
country: United States
facility: Allergy and Respiratory Center
state: Ohio
city: Cincinnati
country: United States
facility: New Horizons Clinical Research
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Perrysburg
country: United States
facility: Clinical Research Source, Inc.
state: Ohio
city: Sylvania
country: United States
facility: Toledo Center for Clinical Research
state: Ohio
city: Eugene
country: United States
facility: Allergy & Asthma Research Group
state: Oregon
city: Lake Oswego
country: United States
facility: Allergy, Asthma and Dermatology Research Center, L.L.C.
state: Oregon
city: Medford
country: United States
facility: Clinical Research Institute of Southern
state: Oregon
city: Portland
country: United States
facility: Allergy Associates Research Center, LLC
state: Oregon
city: Altoona
country: United States
facility: MD Office and Research
state: Pennsylvania
city: Chester
country: United States
facility: Asthma & Allergy Research Assoc Presidents House
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State University Hershey Medical Center, Dept of Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: Allergy and Asthma Research of NJ
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allergy & Clinical Immunology Associates
state: Pennsylvania
city: Johnston
country: United States
facility: Clinical Partners, LLC
state: Rhode Island
city: Providence
country: United States
facility: Allergy Asthma Immunology Clin RI,Ltd
state: Rhode Island
city: Chattanooga
country: United States
facility: Asthma Immunology & Allergy
state: Tennessee
city: Knoxville
country: United States
facility: The Allergy, Asthma, and Sinus Center 801 Weisgarber Road
state: Tennessee
city: Draper
country: United States
facility: Intermountain Clinical Research
state: Utah
city: Murray
country: United States
facility: Allergy Associates of Utah
state: Utah
city: Spanish Fork
country: United States
facility: Clinical Research Specialists of Utah
state: Utah
city: S Burlington
country: United States
facility: Timber Lane Allergy & Asthma Research, LLC
state: Vermont
city: Bellingham
country: United States
facility: Bellingham Asthma And Allergy Associates
state: Washington
city: Everett
country: United States
facility: Physicians Pharmaceutical Study Services
state: Washington
city: Spokane
country: United States
facility: Marycliff Allergy Specialists
state: Washington
city: Spokane
country: United States
facility: Spokane Allergy & Asthma Clinical Research
state: Washington
city: Tacoma
country: United States
facility: Pulmonary Consultants, P.L.L.C.
state: Washington
city: Greenfield
country: United States
facility: Allergy Asthma and Sinus Center
state: Wisconsin
city: Madison
country: United States
facility: Dean Foundation for Health Research & Education, Inc.Med Reseach Dept.
state: Wisconsin
city: Milwaukee
country: United States
facility: Advanced Healthcare Clinical Research Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: West Allis
country: United States
facility: Allergic Diseases, SC
state: Wisconsin
city: Graz
country: Austria
facility: Universitätsklinik für Umweltdermatologie
city: Innsbruck
country: Austria
facility: Universitätsklinik für Dermatologie und Venerologie
city: Vienna
country: Austria
facility: Allgemeines Krankenhaus der Stadt Wien - Universitätsklinik für Dermatologie
city: Vienna
country: Austria
facility: Allergie-Zentrum Wien West
city: Kelowna
country: Canada
facility: Kelowna Allergy and Respiratory Health Clinic
state: British Columbia
city: Hamilton
country: Canada
facility: Hamilton Medical Research Group
state: Ontario
city: Hamilton
country: Canada
facility: McMaster University
state: Ontario
city: Kanata
country: Canada
facility: Kanata Allergy Services Ltd.
state: Ontario
city: Mississauga
country: Canada
facility: Allied Research International
state: Ontario
city: Mississauga
country: Canada
facility: Alpha Medical Research Inc.
state: Ontario
city: Niagara Falls
country: Canada
facility: Niagara Clinical Research
state: Ontario
city: North Bay
country: Canada
facility: Northgate Medical Clinic
state: Ontario
city: Ottawa
country: Canada
facility: Allergy and Asthma Research Centre
state: Ontario
city: Toronto
country: Canada
facility: Filderman R.
state: Ontario
city: Toronto
country: Canada
facility: Knight A.
state: Ontario
city: Toronto
country: Canada
facility: Sussman G.
state: Ontario
city: Toronto
country: Canada
facility: Manna Research
state: Ontario
city: Mirabel
country: Canada
facility: Omnispec Clinical Research
state: Quebec
city: Montreal
country: Canada
facility: The McGill University Health Centre
state: Quebec
city: Sherbrooke
country: Canada
facility: Q&T Research
state: Quebec
city: Quebec
country: Canada
facility: Centre De Recherche Appliquée en Allergie De Québec
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: Brighton
country: United Kingdom
facility: Brighton General Hospital Dept. Respiratory Medicine
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital
city: Dundee
country: United Kingdom
facility: Ninewells Hospital and Medical School
city: Leicester
country: United Kingdom
facility: Glenfield Hospital
city: London
country: United Kingdom
facility: Guys Hospital
city: Manchester
country: United Kingdom
facility: Lung Function - Northwest Lung Center
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
Study officials:
affiliation: Allergy Therapeutics
name: Karl Jürgen Fischer von Weikersthal-Drachenberg, MD
role: STUDY_CHAIR
References:
citation: Frew AJ, DuBuske L, Keith PK, Corrigan CJ, Aberer W, Fischer von Weikersthal-Drachenberg KJ. Assessment of specific immunotherapy efficacy using a novel placebo score-based method. Ann Allergy Asthma Immunol. 2012 Nov;109(5):342-347.e1. doi: 10.1016/j.anai.2012.08.013.