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

• ClinicalTrials.gov Identifier: NCT02237196
• Recruitment Status: Completed
• First Posted: September 11, 2014
• Results First Posted: May 6, 2020
• Last Update Posted: May 6, 2020
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborator: Immune Tolerance Network (ITN)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Cat Allergy; Cat Hypersensitivity	Biological: AMG 157; Biological: Cat Immunotherapy; Biological: Cat Immunotherapy Placebo; Biological: AMG 157 Placebo	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 121 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Anti-TSLP (AMG 157) Plus Antigen-Specific Immunotherapy for Induction of Tolerance in Individuals With Cat Allergy (ITN057AD)
• Actual Study Start Date: March 3, 2015
• Actual Primary Completion Date: March 4, 2019
• Actual Study Completion Date: March 4, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: AMG 157+Cat Immunotherapy; AMG 157 will be administered every four weeks. Cat immunotherapy will be administered weekly.	Biological: AMG 157; 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.; Other Name: MEDI9929/AMG 157; Biological: Cat Immunotherapy; A standardized allergen extract licensed in the United States for allergen immunotherapy, and is formulated as a long-acting suspension for subcutaneous injection; Other Name: Cat Allergen Extract
Active Comparator: AMG 157 Placebo+Cat Immunotherapy; Placebo for AMG 157 of similar appearance will be administered every four weeks. Cat immunotherapy will be administered weekly.	Biological: Cat Immunotherapy; A standardized allergen extract licensed in the United States for allergen immunotherapy, and is formulated as a long-acting suspension for subcutaneous injection; Other Name: Cat Allergen Extract; Biological: AMG 157 Placebo; Placebo for AMG 157 administered intravenously; Other Name: Placebo for AMG157
Experimental: AMG 157+Cat Immunotherapy Placebo; AMG 157 will be administered every four weeks. Placebo for Cat immunotherapy will be administered weekly.	Biological: AMG 157; 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.; Other Name: MEDI9929/AMG 157; Biological: Cat Immunotherapy Placebo; Placebo for allergen-specific immunotherapy administered subcutaneously; Other Name: Placebo for Cat Immunotherapy
Placebo Comparator: Placebo-Placebo; Placebo for AMG 157 will be administered every four weeks. Placebo for cat immunotherapy will be administered weekly.	Biological: Cat Immunotherapy Placebo; Placebo for allergen-specific immunotherapy administered subcutaneously; Other Name: Placebo for Cat Immunotherapy; Biological: AMG 157 Placebo; Placebo for AMG 157 administered intravenously; Other Name: Placebo for AMG157

Outcome Measures

Primary Outcome Measures :

1. Total Nasal Symptom Score (TNSS) Area Under the Curve (AUC) [ Time Frame: 0 to 1 hour of the NAC at Week 104 ]
   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.

Secondary Outcome Measures :

1. Skin Prick Test Endpoint Titration [ Time Frame: 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 ]
   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.
2. Skin Early Phase Response (EPR) to Intradermal Testing [ Time Frame: 15 minutes after Time 0 of the intradermal test at: Baseline (Week 0) and Weeks 26, 52, and 104 ]
   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.
3. Skin Late Phase Response (LPR) to Intradermal Testing [ Time Frame: 6 hours status post cat allergen challenge at: Baseline (Time 0) and Weeks 26, 52 and 104 ]
   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.
4. Peak Total Nasal Symptom Score (TNSS): Early Phase Response (EPR) [ Time Frame: 0 to 1 hour of the NAC at: Baseline (Week 0) and Weeks 26, 52, 78 and 104 ]
   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.
5. Total Nasal Symptom Score (TNSS) Early Phase Response (EPR) [ Time Frame: 0 to 1 hour of the NAC at: Baseline (Week 0) and Weeks 26, 52, 78 and 104 ]
   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.
6. Total Nasal Symptom Score (TNSS) Late Phase Response (LPR) [ Time Frame: Hours 5 to 6 of the NAC at: Baseline (Week 0) and Weeks 26, 52, and 104 ]
   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.
7. Peak Nasal Inspiratory Flow (PNIF) Early Phase Response (EPR) Area Under the Curve (AUC) [ Time Frame: 0 to 1 hour of the NAC at: Baseline (Week 0) and Weeks 26, 52 and 104 ]
   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.
8. Peak Nasal Inspiratory Flow (PNIF) Late Phase Response (LPR) Area Under Curve AUC [ Time Frame: Hours 5 to 6 of the NAC at: Baseline (Week 0) and Weeks 26, 52, 78, and 104 ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, California

University of California, Los Angeles

Los Angeles, California, United States, 90025

United States, Colorado

National Jewish Health

Denver, Colorado, United States, 80206

United States, Illinois

Northwestern University

Chicago, Illinois, United States, 60611

University of Chicago

Chicago, Illinois, United States, 60637

United States, Maryland

Johns Hopkins Asthma & Allergy Center

Baltimore, Maryland, United States, 21231

United States, North Carolina

University of North Carolina, Chapel Hill

Chapel Hill, North Carolina, United States, 27599

United States, Oklahoma

Vital Prospects Clinical Research Institute, P.C.

Tulsa, Oklahoma, United States, 74136

United States, Washington

ASTHMA Inc. Clinical Research Center

Seattle, Washington, United States, 98115

United States, Wisconsin

University Wisconsin, Madison

Madison, Wisconsin, United States, 53792

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Immune Tolerance Network (ITN)

Investigators

• Study Chair: Jonathan Corren, MD; University of California, Los Angeles

  Study Documents (Full-Text)

Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):

Study Protocol  [PDF] August 14, 2017

Statistical Analysis Plan  [PDF] March 29, 2019

More Information

Additional Information:

National Institute of Allergy and Infectious Diseases (NIAID) 

Division of Allergy, Immunology, and Transplantation (DAIT) 

Immune Tolerance Network (ITN) Website 

World Allergy Organization (WAO) Subcutaneous Immunotherapy Systemic Reaction Grading System 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Corren J, Larson D, Altman MC, Segnitz RM, Avila PC, Greenberger PA, Baroody F, Moss MH, Nelson H, Burbank AJ, Hernandez ML, Peden D, Saini S, Tilles S, Hussain I, Whitehouse D, Qin T, Villarreal M, Sever M, Wheatley LM, Nepom GT, Sanda S; Immune Tolerance Network ITN057AD CATNIP Study Team. Effects of combination treatment with tezepelumab and allergen immunotherapy on nasal responses to allergen: A randomized controlled trial. J Allergy Clin Immunol. 2023 Jan;151(1):192-201. doi: 10.1016/j.jaci.2022.08.029. Epub 2022 Oct 9.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT02237196
• Other Study ID Numbers: DAIT ITN057AD; CATNIP ( Other Identifier: Immune Tolerance Network )
• First Posted: September 11, 2014
• Results First Posted: May 6, 2020
• Last Update Posted: May 6, 2020
• Last Verified: April 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The plan is to share data in upon completion of the study in: 1.)ImmPort, a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts; and 2.)TrialShare, a clinical trials research portal developed by the Immune Tolerance Network that makes data from the consortium's clinical trials publicly available.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

cat-allergic; cat immunotherapy; anti-thymic stromal lymphopoietin (anti-TSLP)

Additional relevant MeSH terms:

Hypersensitivity; Immune System Diseases; Immunologic Factors; Physiological Effects of Drugs