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Trial registered on ANZCTR


Registration number
ACTRN12614000123640
Ethics application status
Approved
Date submitted
21/01/2014
Date registered
3/02/2014
Date last updated
22/06/2022
Date data sharing statement initially provided
25/09/2019
Date results provided
22/06/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A clinical trial of Tocilizumab in participants with asthma
Scientific title
A double-blind, placebo-controlled, randomised study to evaluate the safety and efficacy of a single intravenous dose of Tocilizumab for the treatment of allergen-induced asthma
Secondary ID [1] 283941 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 290965 0
Condition category
Condition code
Respiratory 291309 291309 0 0
Asthma
Inflammatory and Immune System 291393 291393 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a double-blind, placebo-controlled trial to evaluate the efficacy of a drug (tocilizumab) that blocks the interleukin-6 receptor for the treatment of allergen-induced asthma. Individuals with stable, mild to moderate allergic asthma, with a history of episodic wheeze and shortness of breath, will be eligible for enrolment. The study is divided into 2 parts.
Part 1: Baseline (visit 1-4)
1. Participants who meet all entry criteria and provide informed consent will then be screened with a history, physical examination, spirometry, and routine laboratory tests.
2. Their atopic status will be documented by skin testing against common airborne allergens.
3. Their rs4129267 Single Nucleotide Polymorphism (SNP) genotype will be determined
4. If they continue to meet entry criteria, an allergen challenge will be performed to confirm the presence of an early and late phase response.
5. Histamine challenge test and sputum differentials will be performed before and after allergen challenges.
6. To enter into Part 2 of the study, participants must have:
-Documented early and late asthmatic response to inhaled incremental allergen challenge;
- rs4129267 genotype TT or CT; and
- Allergic sensitisation to house dust mite

Visit 1 : Baseline screening: Obtain informed consent. Subjects screened with a history, physical examination, spirometry and routine laboratory tests.
Visits 2 to 4 : Baseline allergen challenge: Perform Histamine challenge, allergen inhalation test and sputum induction to assess eligibility for entry into Part 2

Part 2: Treatment and Follow-up (visit 5-10)
1. Participants will be randomised to receive the drug tocilizumab 8mg/kg or placebo by a single dose intravenous infusion.
2. Spirometry, vital signs, asthma symptomatology, histamine challenge, sputum differentials will be evaluated 6 days after drug/placebo.
3. 24 hours later, an allergen inhalation challenge test is performed, with spirometry measured until 7 hours post-challenge. Sputum will also be induced at 7 hours following the allergen challenge.
4. Histamine challenge and sputum induction will be performed again 24 hours after allergen challenge.
5. Any AEs and asthma symptoms will be evaluated at each clinic visit.
6. A physical examination, spirometry and laboratory tests will performed at the termination visit, 28 days after drug/placebo.

Visit 5 : Study drug infusion: Tocilizumab or placebo given as intravenous infusion.
Visits 6 to 8 : Post-treatment allergen challenge: Perform Histamine challenge, allergen inhalation test and sputum induction.
Visit 9 : Follow-Up Visit: Spirometry, vital signs, asthma symptomatology and laboratory tests.
Visit 10 : Termination: Physical examination, spirometry, vital signs and laboratory tests

Participants will be compensated to help retention rates and adherence to the protocol's requirements.
Intervention code [1] 288636 0
Treatment: Drugs
Intervention code [2] 288637 0
Prevention
Comparator / control treatment
Placebo of Normal Saline 0.9 percent given by intravenous infusion.
Control group
Placebo

Outcomes
Primary outcome [1] 291302 0
1. The primary objective of this study is to evaluate the impact of Tocilizumab (TCZ) on the Late Asthmatic Response (LAR) triggered by allergen inhalation in asthma patients, compared with placebo.
Timepoint [1] 291302 0
As such, the primary efficacy outcome measure is the LAR, taken to be the largest fall in Forced Expiratory Volume in 1 second FEV(1) between 3 hours and 7 hours after allergen inhalation. An allergen inhalation challenge test will be performed at visits 3 (screening) and 7 (after treatment).
Primary outcome [2] 291303 0
2. A primary objective is to evaluate the safety of TCZ in patients with asthma.
Timepoint [2] 291303 0
As such the primary safety outcomes will be measured by the following safety laboratory tests that will be performed at visits 1, 3, 5, 7, 9 and 10 (unless otherwise noted):

-Hematology (all visits)

-Blood biochemistry

-Urinalysis

-Serology (visit 1 only)
Secondary outcome [1] 306466 0
The following secondary outcomes will be measured and compared between drug and placebo:
1. The Early Asthmatic Response (EAR)
Timepoint [1] 306466 0
Measurement of the largest fall in FEV(1) within 2 hours after allergen inhalation. This outcome will be measured at visits 3 (screening) and 7 (after treatment).
Secondary outcome [2] 306467 0
The following secondary outcomes will be measured and compared between drug and placebo:
2. Allergen-induced airway hyperresponsiveness at 24h post allergen.
Timepoint [2] 306467 0
Airway hyperresponsiveness is measured as the histamine dose required to cause a fall in FEV(1) of 20 percent of the baseline value (PC20). A histamine inhalation challenge test will be performed at visits 2 and 4 (screening) and 6 and 8 (after treatment).
Secondary outcome [3] 306468 0
The following secondary outcomes will be measured and compared between drug and placebo:
3. Allergen-induced changes in blood and sputum inflammatory cells and mediators at 7 and 24 hours post allergen, between drug and placebo.
Timepoint [3] 306468 0
Immune/Inflammatory cells and mediators will be measured in blood and sputum samples collected at visits 2 to 4 (screening) and 6 to 8 (after treatment). Exhaled Nitric Oxide levels will also be measured at visits 2 to 4 (screening) and 6 to 8 (after treatment).

Eligibility
Key inclusion criteria
For Part 1 of the study:

1.Male/female volunteers 18-65 years of age.
2.General good health.
3.Mild to moderate, stable, allergic asthma.
4.History of episodic wheeze and shortness of breath.
5.FEV(1) at baseline at least 70percent of the predicted value.
6.Positive skin-prick test to common allergens.
7.Able to comprehend and follow all required study procedures
8.Willing and able to sign an informed consent form.

For Part 2 of the study:

1. Positive histamine challenge test.
2. Positive allergen-induced early and late airway bronchoconstriction.
3. rs4129267 genotype TT or CT
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
General:

1.History or symptoms of clinically significant autoimmune disease;
2.Lung disease other than mild to moderate allergic asthma;
3.Recent history of alcohol dependency;
4.Use of tobacco products of any kind currently or within the previous 12 months, or smoking history greater than 10 pack years;
5.Unwillingness or inability to comply with the study protocol for any other reason;

Previous or concomitant therapy:

6.Use of corticosteroids, immunosuppressives, anticoagulants or any medications that may interact with drug within 28 days prior to treatment randomization;
7.Have chronic use of any other medication for treatment of allergic lung disease other than short- and intermediate-acting Beta2-agonists or ipratropium bromide;
8.Participation in any other investigational drug treatment protocol within the preceding 30 days or 5 half lives of the drug;

Exclusions for general safety:

9.A worsening of asthma or a respiratory tract infection within 6 weeks preceding study entry;
10.History of clinically significant hypotensive episodes or symptoms of fainting, dizziness, or lightheadedness;
11.History or symptoms of cardiovascular disease;
12.History or symptoms of significant neurologic disease;
13.History of serious adverse reaction or hypersensitivity to any drug;
14.Abnormal chest X-ray;
15.Abnormal electrocardiogram;
16.History of clinically significant hematologic abnormality;
17.History of intestinal ulceration or diverticulitis.
18.Clinically significant abnormalities in laboratory test results;
19.Women not using adequate contraception, actively seeking pregnancy, pregnant or lactating or have positive serum pregnancy test at screening or positive urine pregnancy test during the study;
20.History of, or known currently active, recurrent bacterial, viral, fungal, mycobacterial or other infections.
21.Primary or secondary immunodeficiency.
22.Patients with lack of peripheral venous access.
23.Concomitant disease or condition which could interfere with the conduct of the study or pose an unacceptable risk to the subject.
24.Development of severe asthma reaction during the screening allergen challenge that could not be rescued by bronchodilator alone.

Laboratory exclusion criteria (at visits 1 to 4):

25.Serum aspartate transaminase or alanine transaminase greater than 1.5x ULN
26.Absolute neutrophil count less than 2 x 10e9/L
27.Platelet count less than 100 x 10e9/L.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
We will screen existing clinical records from participants of our Asthma Genetics study to identify potential eligible participants according to inclusion and exclusion criteria for Part 1 of this study. If required to meet sample size requirements, we will also advertise in the general community

Potential eligible participants will be approached first by email or postal letter to provide information about this trial. Participants interested in taking part in the trial will then be contacted by phone to confirm interest in participating and assess potential eligibility based on inclusion and exclusion criteria An appointment for clinical visit 1 is made for participants that remain potentially eligible to participate.
Once consent is obtained participants will be screening to determine eligibility.

If eligible the participant will be randomised to one of 2 blinded arms of the study which will receive active drug or placebo.
When a participant enters part 2 of the study, the investigator calls the pharmacy to request the investigational drug kit for this participant.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
We will use a block randomization method to ensure that equal numbers of subjects are allocated to tocilizumab and placebo. We will first randomise tocilizumab or placebo (50:50) to an investigational drug kit (numbered 1 to 16). Then each participant is randomly allocated a drug kit. This procedure is done independently in four blocks with four participants each. The resulting randomisation table will be held by the Sponsor throughout the duration of the study. Based on the randomisation table, two envelopes will be created for each participant and sent to the pharmacy. Both envelopes contain the same information, namely the participant number, the block number, the kit number and the kit content. Envelope 1 will be labelled with the project name, project number, participant number and with “Pharmacy Randomisation code” and “To be opened by trial pharmacist only to prepare the investigational drug”. Envelope 2 will be labelled with the project name, project number, participant number and with “Emergency unblinding envelope” and “To be opened by investigator only in an emergency situation”.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Nil
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
We plan to enrol a sufficient number of participants to result in 16 participants entering part 2 of the study (ie. being administered drug or placebo). With this sample size, and based on the mean (23.5 percent ) and Standard Deviation (3.3 percent) of the maximum percentage fall in FEV1 3 to 7 hours after allergen challenge (LAR) that is expected in the placebo group , this study provides greater than 80percent power to detect a difference in LAR between placebo and drug of at least 5 percent (eg 23.5 percent vs 18.5 percent) for an alpha of 0.05 (two-sided test). This corresponds to a 21 percent (5percent / 23.5percent) change in the LAR.
Primary analysis

1. Our primary efficacy outcome is the largest fall in FEV(1) recorded between 3 hours and 7 hours after allergen inhalation (visit 7), ie LAR. The LAR will be compared between the TCZ and placebo groups using a two-sided t-test. Only participants entering part 2 of the trial will be included in the analysis.

2. Comparison of safety outcomes between TCZ and placebo groups.

Secondary analyses

1. Comparison of EAR (measured at visit 7) between TCZ and placebo groups: analysis as per the primary outcome above.

2. Comparison of baseline (visit 6) and allergen-induced (visit 8) airway hyperresponsiveness between TCZ and placebo groups: analyses as per the primary outcome above.

3. Comparison of baseline (visit 6) and post allergen-challenge (visit 8) levels of immune/inflammatory cells and mediators between TCZ and placebo groups: analyses as per the primary outcome above.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/05/2014
Actual
15/10/2014
Date of last participant enrolment
Anticipated
30/07/2016
Actual
10/07/2017
Date of last data collection
Anticipated
Actual
19/07/2017
Sample size
Target
16
Accrual to date
Final
5
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 3561 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 5395 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 9366 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 12847 0
4006 - Herston

Funding & Sponsors
Funding source category [1] 288583 0
Government body
Name [1] 288583 0
Smart Future Fellowship
Department of Employment, Economic Development and Innovation
State of Queensland
Country [1] 288583 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
QIMR Berghofer Medical Research Institute
Address
300 Herston Road, Herston, Brisbane, QLD, 4006
Country
Australia
Secondary sponsor category [1] 287292 0
None
Name [1] 287292 0
Address [1] 287292 0
Country [1] 287292 0
Other collaborator category [1] 277773 0
Individual
Name [1] 277773 0
Professor John Upham
Address [1] 277773 0
Level 5, Translational Research Institute (TRI)
37 Kent Street, Woolloongabba QLD 4102
Country [1] 277773 0
Australia
Other collaborator category [2] 278392 0
Individual
Name [2] 278392 0
Dr Paul Griffin
Address [2] 278392 0
Q-Pharm
QIMR Berghofer
300 Herston Rd
Herston 4006
Country [2] 278392 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290446 0
QIMR Berghofer Medical Research Institute Human Research Ethics Committee (HREC)
Ethics committee address [1] 290446 0
Ethics committee country [1] 290446 0
Australia
Date submitted for ethics approval [1] 290446 0
12/11/2013
Approval date [1] 290446 0
06/06/2014
Ethics approval number [1] 290446 0
P2025
Ethics committee name [2] 290447 0
Metro South Human Research Ethics Committee
Ethics committee address [2] 290447 0
Ethics committee country [2] 290447 0
Australia
Date submitted for ethics approval [2] 290447 0
16/01/2014
Approval date [2] 290447 0
29/04/2014
Ethics approval number [2] 290447 0
HREC/14/QPAH/22

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 45730 0
Dr Manuel Ferreira
Address 45730 0
QIMR Berghofer Medical Research Institute
300 Herston Rd
Herston QLD 4006
Country 45730 0
Australia
Phone 45730 0
+61 7 3845 3552
Fax 45730 0
+61 7 3362 0101
Email 45730 0
manuel.ferreira@qimrberghofer.edu.au
Contact person for public queries
Name 45731 0
Lisa Bain
Address 45731 0
QIMR Berghofer Medical Research Institute
300 Herston Rd
Herston QLD 4006
Country 45731 0
Australia
Phone 45731 0
+61 7 3362 3153
Fax 45731 0
+61 7 3362 0101
Email 45731 0
lisa.bain@qimrberghofer.edu.au
Contact person for scientific queries
Name 45732 0
Manuel Ferreira
Address 45732 0
QIMR Berghofer Medical Research Institute
300 Herston Rd
Herston QLD 4006
Country 45732 0
Australia
Phone 45732 0
+61 7 3845 3552
Fax 45732 0
+61 7 3362 0101
Email 45732 0
manuel.ferreira@qimrberghofer.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEffects of interleukin-6 receptor blockade on allergen-induced airway responses in mild asthmatics.2019https://dx.doi.org/10.1002/cti2.1044
EmbaseCytokines at the Interplay Between Asthma and Atherosclerosis?.2020https://dx.doi.org/10.3389/fphar.2020.00166
N.B. These documents automatically identified may not have been verified by the study sponsor.