Anti-TSLP (AMG 157) Plus Antigen-Specific Immunotherapy for Induction of Tolerance in Individuals With Cat Allergy

Study Overview
=================
Brief Summary
-----------------
This trial will test whether a novel therapeutic approach, cat immunotherapy combined with an investigational new drug called MEDI9929/AMG 157 (an anti-TSLP [thymic stromal lymphopoietin] antibody being co-developed by Amgen and MedImmune) can lead to lasting tolerance to cat allergen.The objective of the study is to determine whether one year of immunotherapy combined with MEDI9929/AMG 157 can induce tolerance to cat allergen.

Detailed Description
-----------------
This study will implement the concept referred to as allergen-plus, which aims to enhance the disease-modifying mechanisms of allergen-specific immunotherapy by combining it with other anti-inflammatory or immune-modulating agents. Thymic stromal lymphopoietin (TSLP) is a cytokine which appears to be instrumental in both initiating and maintaining allergic sensitivity to antigens, and Immune Tolerance Network (ITN) investigators hypothesize that blocking TSLP during the administration of cat immunotherapy will induce durable immune changes that lead to tolerance. CATNIP will be conducted at multiple sites in the US and enroll cat-allergic adults who will be randomized to four possible treatment groups: immunotherapy plus MEDI9929/AMG 157, immunotherapy plus placebo, placebo plus MEDI9929/AMG 157, or two corresponding placebos. This study is specifically enrolling cat allergic individuals who do not live with cats in order to limit exposure to the allergen outside of the study. Treatment will be given for about one year, followed by one year off therapy.

Official Title
-----------------
Anti-TSLP (AMG 157) Plus Antigen-Specific Immunotherapy for Induction of Tolerance in Individuals With Cat Allergy (ITN057AD)

Conditions
-----------------
Cat Allergy, Cat Hypersensitivity

Intervention / Treatment
-----------------
* Biological: AMG 157
* Biological: Cat Immunotherapy
* Biological: Cat Immunotherapy Placebo
* Biological: AMG 157 Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: History of moderate-severe allergic rhinitis caused by cat exposure for at least 2 yrs Skin prick test wheal >/=5 mm to standardized cat extract Immunoglobulin E (IgE) >/=0.7 kU/L (class 2) to cat extract Screening nasal allergen challenge in which: *TNSS is </= 3 after the 0 concentration (vehicle control only) dose, TNSS increase is </=1 from the TNSS prior to allergen administration to the TNSS after the 0 concentration (vehicle control only) dose, TNSS is >/=8 after the highest dose, and Between the first non-zero dose and 10 minutes after the highest dose,either: >/=3 sneezes are counted or >20% drop in PNIF is recorded Body mass index (BMI) between 1 and 32 kg/m^2, inclusive at screening Clinically acceptable physical examination and electrocardiogram (ECG) results (12-lead reporting RR, PR, QRS, QT and QTcF) prior to Day 0 based on the opinion of the investigator Adequate renal function (defined by creatinine clearance >80 mL/min using the Cockcroft Gault equation) For women of childbearing age, a willingness to use a highly effective form of contraception for five months after last dose of study medication. Highly effective methods of birth control include abstinence, vasectomy by the male partner, or a condom with spermicide in combination with either hormonal birth control, IUD or barrier methods used by the woman. For men with female partners of childbearing potential, agreement not to donate sperm and to inform their female partner of their participation in this clinical study and use highly effective methods of birth control for five months after last dose of study medication. Highly effective methods of birth control include abstinence, vasectomy, or a condom with spermicide in combination with either hormonal birth control, Intrauterine device (IUD) or barrier methods used by the woman. The ability to give informed consent and comply with study procedures Exclusion Criteria: Prebronchodilator Forced Expiratory Volume at one second (FEV1) less than 0% of predicted value at screening visit History of moderate or higher Allergic Rhinitis and its Impact on Asthma (ARIA) severity classification for allergic rhinitis in the last year due to allergens other than cat History of asthma meeting the National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3 (EPR3) classification of mild-persistent or worse in the past year, other than with cat exposure, requiring regular inhaled corticosteroids for >4 weeks per year History of serious chronic medical conditions which might interfere with treatment or assessments History of emergency visit or hospital admission for asthma in the previous 12 months History of chronic obstructive pulmonary disease (COPD) History of significant recurrent acute sinusitis, defined as 2 episodes/yr for the last 2 years, all of which required antibiotic treatment History of chronic sinusitis, defined as a sinus symptoms lasting >12 weeks that includes >/=2 major factors or 1 major factor and 2 minor factors. Major factors are defined as facial pain or pressure, nasal obstruction or blockage, purulent 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. History of systemic disease affecting the immune system such as autoimmune diseases, immune complex disease, or immunodeficiency, where, in the opinion of the study physician, participation in the trial would pose a risk or significant effect on the immune system Diabetes (Type I or II) Evidence of any active or suspected bacterial, viral, fungal or parasitic infection(s) within 30 days prior to randomization High risk of parasitic disease as judged by the investigator Positive QuantiFERON(R) tuberculin test UNLESS the potential subject has been treated with appropriate chemoprophylaxis Exposure to an individual with active tuberculosis within six months from randomization Subjects tested positive for HIV antibody, Hep B surface antigen, or Hep C antibody 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. History of malignancy of any type, including basal cell and squamous cell cancers of the skin, within 5 years of enrollment Tobacco smoking (ANY) within the last year or a history of >/=10 pack years Previous immunotherapy treatment with cat allergen within the previous 10 yrs Any history of grade 4 anaphylaxis due to any cause as defined by the CTCAE grading criteria for immunotherapy History of bleeding disorders or treatment with anticoagulation therapy Treatment with omalizumab within 6 months prior to randomization Currently taking any of the following medications: beta blockers; tricyclic antidepressants; monoamine oxidase inhibitors; or 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 <50 mIU/mL within 72 hours before the start of study therapy The use of any investigational drug within 6 months of randomization The presence of any medical condition that the investigator deems incompatible with participation in the trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AMG 157+Cat Immunotherapy<br>AMG 157 will be administered every four weeks. Cat immunotherapy will be administered weekly. | Biological: AMG 157<br>* AMG 157 will be administered once every 4 weeks at dose of 700 mg intravenously. Each AMG 157 dose will be administered at least 1 day before immunotherapy through week 24, then on the same day as immunotherapy thereafter.<br>* Other names: MEDI9929/AMG 157;Biological: Cat Immunotherapy<br>* A standardized allergen extract licensed in the United States for allergen immunotherapy, and is formulated as a long-acting suspension for subcutaneous injection<br>* Other names: Cat Allergen Extract;|
| Active Comparator: AMG 157 Placebo+Cat Immunotherapy<br>Placebo for AMG 157 of similar appearance will be administered every four weeks. Cat immunotherapy will be administered weekly. | Biological: Cat Immunotherapy<br>* A standardized allergen extract licensed in the United States for allergen immunotherapy, and is formulated as a long-acting suspension for subcutaneous injection<br>* Other names: Cat Allergen Extract;Biological: AMG 157 Placebo<br>* Placebo for AMG 157 administered intravenously<br>* Other names: Placebo for AMG157;|
| Experimental: AMG 157+Cat Immunotherapy Placebo<br>AMG 157 will be administered every four weeks. Placebo for Cat immunotherapy will be administered weekly. | Biological: AMG 157<br>* AMG 157 will be administered once every 4 weeks at dose of 700 mg intravenously. Each AMG 157 dose will be administered at least 1 day before immunotherapy through week 24, then on the same day as immunotherapy thereafter.<br>* Other names: MEDI9929/AMG 157;Biological: Cat Immunotherapy Placebo<br>* Placebo for allergen-specific immunotherapy administered subcutaneously<br>* Other names: Placebo for Cat Immunotherapy;|
| Placebo Comparator: Placebo-Placebo<br>Placebo for AMG 157 will be administered every four weeks. Placebo for cat immunotherapy will be administered weekly. | Biological: Cat Immunotherapy Placebo<br>* Placebo for allergen-specific immunotherapy administered subcutaneously<br>* Other names: Placebo for Cat Immunotherapy;Biological: AMG 157 Placebo<br>* Placebo for AMG 157 administered intravenously<br>* Other names: Placebo for AMG157;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Nasal Symptom Score (TNSS) Area Under the Curve (AUC) | TNSS (0-12) is a participant rated score computed as the sum of four subscale scores (0-3) measuring nasal congestion and blockade, rhinorrhea, itching, and sneezing. Participants indicate a score on each subscale of 0, 1, 2, or 3, indicating none, mild, moderate, or severe symptoms, respectively. Higher scores indicate more severe nasal symptoms. The trapezoidal rule was used to calculate the TNSS AUC. The primary outcome compared the mean TNSS AUC from 0 to 1 hour after cat Nasal Allergen Challenge at 104 weeks by treatment group, using a longitudinal repeated measures model in the ITT sample. The model included fixed effects for treatment, time, and treatment by time interaction and included covariates for site, baseline TNSS AUC and Baseline Cat exposure (low vs high). The primary endpoint was assessed at week 104 using a contrast in least squares means between the following groups: AMG 157+Cat Immunotherapy and AMG 157 Placebo+Cat Immunotherapy. | 0 to 1 hour of the NAC at Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skin Prick Test Endpoint Titration | A dilution series of standardized cat allergen extracts were applied in duplicate on the participant's upper back. Wheal size was assessed 15 minutes after application. | 15 minutes after Time 0 of the skin prick titration test at: Baseline (Week 0) and Weeks 1, 4, 12, 26, 52, 78 and 104 | 
| Skin Early Phase Response (EPR) to Intradermal Testing | Concentrations of standardized cat hair extract were applied intradermally to the forearm. Wheal size was measured 15 minutes and 6 hours after application. The Early Phase Response (EPR) is the response measured at 15 minutes after application. | 15 minutes after Time 0 of the intradermal test at: Baseline (Week 0) and Weeks 26, 52, and 104 | 
| Skin Late Phase Response (LPR) to Intradermal Testing | Concentrations of standardized cat hair extract were applied intradermally to the forearm. Wheal size was measured 15 minutes and 6 hours after application. The Late Phase Response (LPR) is the response measured at 6 hours after application. | 6 hours status post cat allergen challenge at: Baseline (Time 0) and Weeks 26, 52 and 104 | 
| Peak Total Nasal Symptom Score (TNSS): Early Phase Response (EPR) | TNSS (0-12) is a participant rated score computed as the sum of four subscale scores (0-3) measuring nasal congestion and blockade, rhinorrhea, itching, and sneezing. Participants indicate a score on each subscale of 0, 1, 2, or 3, indicating none, mild, moderate, or severe symptoms, respectively. Higher scores indicate more severe nasal symptoms. Peak TNSS EPR is the highest value recorded between 0 and 1 hour inclusive. | 0 to 1 hour of the NAC at: Baseline (Week 0) and Weeks 26, 52, 78 and 104 | 
| Total Nasal Symptom Score (TNSS) Early Phase Response (EPR) | TNSS (0-12) is a participant rated score computed as the sum of four subscale scores (0-3) measuring nasal congestion and blockade, rhinorrhea, itching, and sneezing. Participants indicate a score on each subscale of 0, 1, 2, or 3, indicating none, mild, moderate, or severe symptoms, respectively. Higher scores indicate more severe nasal symptoms. The trapezoidal rule was used to calculate the TNSS AUC. The Early Phase Response (EPR) is the TNSS AUC from 0 to 1 hour. | 0 to 1 hour of the NAC at: Baseline (Week 0) and Weeks 26, 52, 78 and 104 | 
| Total Nasal Symptom Score (TNSS) Late Phase Response (LPR) | TNSS (0-12) is a participant rated score computed as the sum of four subscale scores (0-3) measuring nasal congestion and blockade, rhinorrhea, itching, and sneezing. Participants indicate a score on each subscale of 0, 1, 2, or 3, indicating none, mild, moderate, or severe symptoms, respectively. Higher scores indicate more severe nasal symptoms. The trapezoidal rule was used to calculate the TNSS AUC. The Late Phase Response (LPR) is the TNSS AUC from 5 to 6 hours. | Hours 5 to 6 of the NAC at: Baseline (Week 0) and Weeks 26, 52, and 104 | 
| Peak Nasal Inspiratory Flow (PNIF) Early Phase Response (EPR) Area Under the Curve (AUC) | PNIF is defined as the speed of inspiration of air in Liters per minute when breathing in into the lungs through the nose. Lower scores indicate less ability to breathe air into the lungs due to more severe nasal symptoms. The Early Phase Response (EPR) is the PNIF AUC from 0 to 1 hour of the NAC. | 0 to 1 hour of the NAC at: Baseline (Week 0) and Weeks 26, 52 and 104 | 
| Peak Nasal Inspiratory Flow (PNIF) Late Phase Response (LPR) Area Under Curve AUC | PNIF is defined as the speed of inspiration of air in Liters per minute when breathing in into the lungs through the nose. Lower scores indicate less ability to breathe air into the lungs due to more severe nasal symptoms. The Late Phase Response (LPR) is the PNIF AUC from hours 5 to 6 of the NAC. | Hours 5 to 6 of the NAC at: Baseline (Week 0) and Weeks 26, 52, 78, and 104 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cat-allergic, cat immunotherapy, anti-thymic stromal lymphopoietin (anti-TSLP)