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Long-Term Effects of Sublingual Grass Therapy

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ClinicalTrials.gov Identifier: NCT01335139
Recruitment Status : Completed
First Posted : April 14, 2011
Last Update Posted : June 2, 2017
Sponsor:
Collaborators:
Immune Tolerance Network (ITN)
Imperial College London
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE April 8, 2011
First Posted Date  ICMJE April 14, 2011
Last Update Posted Date June 2, 2017
Study Start Date  ICMJE March 2011
Actual Primary Completion Date February 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 31, 2017)
Nasal Response to Allergen Challenge [ Time Frame: 3 years ]
Defined as the average of the Total Nasal Symptom Score (TNSS) area under the curve (AUC) measured at 0 to 1 hours and the AUC measured at 1 to 10 hours after allergen challenge. The primary outcome consists of the comparison of SLIT + SCIT placebo versus SLIT placebo + SCIT placebo.
Original Primary Outcome Measures  ICMJE
 (submitted: April 12, 2011)
Nasal Response to Allergen Challenge [ Time Frame: 3 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 31, 2017)
  • Skin Late Phase Response (LPR) to Intradermal Testing [ Time Frame: Baseline (Time 0) and 1,-2, and -3 years ]
    Recorded as the mean diameter of the swelling measured at the specified time points after allergen challenge at 1, 2, and 3 years. The analysis of this outcome will compare the mean diameter of the swelling at 1, 2, and 3 years separately, adjusting for baseline diameter using ANCOVA at the 0.05 level of significance.
  • Skin Early Phase Response (EPR) to Intradermal Testing [ Time Frame: Baseline (Time 0) and 1, -2, and -3 years ]
    Recorded as the mean diameter of the swelling measured at the specified time points after allergen challenge at 1, 2, and 3 years. The analysis of this outcome will compare the mean diameter of the swelling at 1, 2, and 3 years separately, adjusting for baseline diameter using ANCOVA at the 0.05 level of significance.
  • Nasal LPR [ Time Frame: Baseline (Time 0) and 1, -2, and -3 years ]
    Defined as the TNSS AUC over the specified time periods after allergen challenge at 1, 2, and 3 years. The analysis of these this outcome will compare the mean TNSS AUC at 1, 2, and 3 years separately, adjusting for baseline LPR using ANCOVA at the 0.05 level of significance.
  • Nasal EPR [ Time Frame: Baseline (Time 0) and 1, -2, and -3 years ]
    Defined as the TNSS AUC over the specified time periods after allergen challenge at 1, 2, and 3 years. The analysis of these this outcome will compare the mean TNSS AUC at 1, 2, and 3 years separately, adjusting for baseline EPR using ANCOVA at the 0.05 level of significance.
  • Peak Total Nasal Symptom Score (TNSS) EPR [ Time Frame: Baseline (Time 0) and 1, -2, and -3 years ]
    Maximum TNSS score measured between 0 and 1 hour after challenge.
  • Peak Nasal Inspiratory Flow (PNIF) LPR [ Time Frame: Baseline (Time 0) and 1, -2, and -3 years ]
    Defined as PNIF AUC over the specified time periods after allergen challenge at 1, 2 and 3 years. The analyses for this outcome will compare the mean PNIF AUC at 1, 2, and 3 years separately, adjusting for baseline PNIF using ANCOVA at the 0.05 level of significance.
  • Peak Nasal Inspiratory Flow (PNIF) LPR Area Under the Curve (AUC) [ Time Frame: Baseline (Time 0) and 1, -2, and -3 years ]
    Defined as PNIF AUC over the specified time periods after allergen challenge at 1, 2 and 3 years. The analyses for this outcome will compare the mean PNIF AUC at 1, 2, and 3 years separately, adjusting for baseline PNIF using ANCOVA at the 0.05 level of significance.
  • Peak Nasal Inspiratory Flow (PNIF) EPR Area Under the Curve (AUC) [ Time Frame: Baseline (Time 0) and 1, -2, and -3 years ]
    Defined as PNIF AUC over the specified time periods after allergen challenge at 1, 2 and 3 years. The analyses for this outcome will compare the mean PNIF AUC at 1, 2, and 3 years separately, adjusting for baseline PNIF using ANCOVA at the 0.05 level of significance. AUC measured hourly between 1 and 10 hours after challenge.
  • Skin Prick Test Endpoint Titration [ Time Frame: Baseline (Time 0) and 1, -2, and -3 years ]
    Assessed as the mean wheal diameters (mm) in response to skin prick tests in duplicate with 1000 SQ, 10,000 SQ and 100,000 SQ units of grass pollen allergen.
  • Use of Rescue Medications During the Pollen Season [ Time Frame: 1, -2, and -3 years ]
    A composite rescue medication score will be derived using a pre-defined scoring algorithm.
  • Mini Rhinoconjunctivitis Quality-of-Life Questionnaire Score [ Time Frame: 1, -2, and -3 years ]
    Mini Rhinoconjunctivitis Quality-of-Life Questionnaire (MiniRQLQ) scores will be collected pre-, peak-, and post-pollen season at 1, 2, and 3 years.
  • Hay Fever Severity Score [ Time Frame: 1, 2 and 3 years ]
    Measured at the end of each pollen season at 1, -2, and -3 years.
  • Weekly Visual Analog Symptom (VAS) Scores [ Time Frame: 1, -2, and -3 years ]
    Weekly Visual Analogue Scale scores will be summarized descriptively by group and year.
  • EXPLORATORY: Mechanistic Assessments of Local Immune Responses [ Time Frame: 1, 2, and 3 years ]
    Measured in the nasal mucosa before and after nasal allergen challenge. Nasal secretions will be assayed for inflammatory mediators and local antibodies.
  • EXPLORATORY: Mechanistic Assessments of Peripheral Blood Subsets [ Time Frame: 1, 2, and 3 years ]
    Peripheral blood mononuclear cells (PBMCs) samples will be analyzed.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 12, 2011)
  • Skin late phase response [ Time Frame: 1,2, and 3 years ]
  • Skin early phase response [ Time Frame: 1, 2, and 3 years ]
  • Nasal late phase response [ Time Frame: 1, 2, and 3 years ]
  • Nasal early phase response [ Time Frame: 1, 2, and 3 years ]
  • Peak nasal inspiratory flow late phase response [ Time Frame: 1, 2, and 3 years ]
  • Peak nasal inspiratory flow early phase response [ Time Frame: 1, 2, and 3 years ]
  • Skin Prick Test Endpoint Titration [ Time Frame: 1, 2, and 3 years ]
  • Use of Rescue Medications During the Pollen Season [ Time Frame: 1, 2, and 3 years ]
  • Quality-of-life questionnaire score measured pre-, peak-, and post- pollen season [ Time Frame: 1, 2, and 3 years ]
  • Hay fever severity score measured at the end of each pollen season [ Time Frame: 1, 2 and 3 years ]
  • Weekly visual analog symptom scores measured pre-, peak-, and post-pollen season [ Time Frame: 1, 2, and 3 years ]
  • Mechanistic assessments of local immune responses in the nasal mucosa before and after nasal allergen challenge. [ Time Frame: 1, 2, and 3 years ]
  • Mechanistic assessments of peripheral blood subsets before and after therapy. [ Time Frame: 1, 2, and 3 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Long-Term Effects of Sublingual Grass Therapy
Official Title  ICMJE A Randomized, Double-blind, Single-center, Placebo Controlled Study of Sublingual Immunotherapy and Subcutaneous Immunotherapy in Adults With Seasonal Allergic Rhinitis (ITN043AD)
Brief Summary The purpose of this research study is to investigate whether sublingual immunotherapy (SLIT, grass pollen tablets under the tongue) has long term effects in severe hay fever.
Detailed Description

This is a randomized, double-blind, single-center, placebo-controlled, three-arm study comparing SLIT with placebo and SCIT with placebo. The main comparison will be between SLIT and placebo.

Individuals with severe grass pollen hay fever, with or without associated seasonal asthma, will be recruited during the pollen season of March through September 2011. Eligible participants will be randomized to one of the following three treatment arms administered in a double-blind (masked), double-dummy fashion in a 1:1:1 ratio:

  • SLIT + SCIT placebo
  • SCIT + SLIT placebo
  • SLIT placebo + SCIT placebo

Participants will receive treatment over a 2-year period followed by a 1-year blinded (masked) withdrawal phase. Participants will be provided with anti-allergic rescue medications (antihistamine, topical intranasal corticosteroids, and short-acting beta agonists) throughout the study. Clinical endpoint assessments will be performed at prior to initiating their assigned treatment, after 1 and 2 years of treatment, and after the 1-year withdrawal period at 3 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Rhinitis, Allergic, Seasonal
Intervention  ICMJE
  • Biological: Sublingual immunotherapy (SLIT)
    Participants randomized to receive sublingual allergen tablet immunotherapy with placebo injections.
    Other Name: Grazax®
  • Biological: Subcutaneous immunotherapy (SCIT)
    Participants randomized to receive subcutaneous injection immunotherapy with placebo tablets. Subcutaneous immunotherapy was included as a positive control.
    Other Name: Alutard SQ Grass Pollen®
  • Other: Placebo
    Participants randomized to double-placebo tablets and injections. This group was included as a negative control.
Study Arms  ICMJE
  • Experimental: SCIT + Placebo
    Subcutaneous immunotherapy (SCIT) + sublingual immunotherapy (SLIT) placebo
    Interventions:
    • Biological: Subcutaneous immunotherapy (SCIT)
    • Other: Placebo
  • Experimental: SLIT + Placebo
    Sublingual immunotherapy (SLIT) + subcutaneous immunotherapy (SCIT) placebo
    Interventions:
    • Biological: Sublingual immunotherapy (SLIT)
    • Other: Placebo
  • Placebo Comparator: Placebo + Placebo
    Sublingual immunotherapy (SLIT) placebo + subcutaneous immunotherapy (SCIT) placebo
    Intervention: Other: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 10, 2017)
106
Original Estimated Enrollment  ICMJE
 (submitted: April 12, 2011)
90
Actual Study Completion Date  ICMJE February 2015
Actual Primary Completion Date February 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • A clinical history of grass pollen-induced allergic rhinoconjunctivitis for at least 2 years with peak symptoms in May, June, or July;
  • A clinical history of moderate to severe rhinoconjunctivitis symptoms interfering with usual daily activities or with sleep as defined according to the Allergic Rhinitis and its Impact on Asthma (ARIA) classification of rhinitis;
  • A clinical history of rhinoconjunctivitis for at least 2 years requiring treatment with either antihistamines or nasal corticosteroids during the grass pollen season;
  • Positive skin prick test response, defined as wheal diameter greater than or equal to 3 mm, to Phleum pratense (e.g., Timothy grass);
  • Positive specific IgE, defined as greater than or equal to IgE class 2 (0.7 kU/L), against Phleum pratense;
  • A positive response to nasal allergen challenge with Phleum pretense, defined as an increase in TNSS greater than or equal to 7 points above baseline;
  • For women of childbearing age, a willingness to use an effective form of contraception for the duration of the trial; and
  • The ability to give informed consent and comply with study procedures.

Exclusion Criteria:

  • Prebronchodilator forced expiratory volume at 1 second (FEV1) less than 70% of predicted value at either screening or baseline visit;
  • A clinical history of moderate to severe allergic rhinitis, according to the ARIA classification, due to tree pollen near or overlapping the grass pollen season;
  • A clinical history of persistent asthma and/or requiring regular inhaled corticosteroids for > 4 weeks per year outside of the grass pollen season;
  • A clinical history of moderate- severe allergic rhinitis, according to the ARIA classification, caused by an allergen to which the participant is regularly exposed;
  • History of emergency visit or hospital admission for asthma in the previous 12 months;
  • History of chronic obstructive pulmonary disease;
  • History of significant recurrent acute sinusitis, defined as 2 episodes per year for the last 2 years, all of which required antibiotic treatment;
  • History of chronic sinusitis, defined as a sinus symptoms lasting greater than 12 weeks that includes 2 or more major factors or 1 major factor and 2 minor factors. Major factors are defined as facial pain or pressure, nasal obstruction or blockage, nasal discharge or purulence or discolored postnasal discharge, purulence in nasal cavity, or impaired or loss of smell. Minor factors are defined as headache, fever, halitosis, fatigue, dental pain, cough, and ear pain, pressure, or fullness.
  • At randomization, current symptoms of, or treatment for, upper respiratory tract infection, acute sinusitis, acute otitis media, or other relevant infectious process; serous otitis media is not an exclusion criterion. Participants may be re-evaluated for eligibility after symptoms resolve.
  • Any tobacco smoking within the last 6 months or a history of ≥ 10 pack years;
  • Previous treatment by immunotherapy with grass pollen allergen within the previous 5 years.
  • Any history of grade 4 anaphylaxis due to any cause as defined by the World Allergy Organization (WAO) grading criteria for immunotherapy;
  • History of bleeding disorders or treatment with anticoagulation therapy;
  • History of anti-IgE monoclonal antibody treatment;
  • Ongoing systemic immunosuppressive treatment;
  • History of intolerance to the study therapy, rescue medications, or their excipients;
  • For women of childbearing age a positive serum or urine pregnancy test with sensitivity of less than 50 mIU/mL within 72 hours before the start of study therapy;
  • The use of any investigational drug within 30 days of the screening visit; or
  • The presence of any medical condition that the investigator deems incompatible with participation in the trial.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01335139
Other Study ID Numbers  ICMJE DAIT ITN043AD
2010-023536-16 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Participant level data and additional relevant materials are available to the public in TrialShare, the Immune Tolerance Network (ITN) Clinical Trials Research Portal. ITN TrialShare makes data from the consortium's clinical trials publicly available.
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE
  • Immune Tolerance Network (ITN)
  • Imperial College London
Investigators  ICMJE
Study Chair: Stephen Durham, MD Imperial College London
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP