TNF-alpha Directed Therapy in Asthma

Asthma Clinical Trial

Official title:

A Randomised, Double Blind, Placebo-controlled, Parallel Group Pilot Study to Determine the Effect of REMICADE on Safety, Efficacy and Biomarkers of Inflammation in Patients With Asthma Receiving Inhaled Corticosteroids

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00278083
• Other study ID #: C0168T42
• Status: Completed
• Phase: Phase 2
• Start date: October 2001
• Est. completion date: April 2004

Study information

• Verified date: September 2023
• Source: Imperial College London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This trial is a randomised, single-center, placebo-controlled, double blind, parallel group study in patients with asthma symptomatic on inhaled steroids.

This trial will examine the efficacy and safety of 5 mg/kg doses of infliximab in patients with inhaled corticosteroid-dependent asthma. The primary objective of this study is to obtain pharmacological evidence for a role of the pro-inflammatory cytokine TNF-alpha in patients with asthma symptomatic on inhaled steroids and to evaluate the safety and tolerability of repeated intravenous administration of infliximab.

Description:

Study Overview This trial is a randomised, single-center, placebo-controlled, double blind, parallel group study in patients with asthma symptomatic on inhaled steroids.

Patient Population Patients eligible for this study will have a diagnosis of moderate asthma defined by the American Thoracic Society criteria for > 1 year. These patients should be taking inhaled steroids at doses equivalent to /= 400 µg and /= 60 to /= 12% increase in FEV1 in comparison to baseline should be shown within 30 minutes after taking 200 µg salbutamol. If airway reversibility cannot be demonstrated during this visit, patients are eligible for re-testing. Reversible airway disease may be demonstrated at any time between screening and start of run-in period. The 2 to 4 week run-in period will start immediately after demonstration of reversible lung disease.

Patients will also have skin tests to a standard battery of bronchial allergens performed at screening. Patients should have both a purified protein derivative (PPD) skin test and a chest radiograph prior to their first infusion. Patients with evidence of either latent or active tuberculosis (TB) will not be enrolled.

Run-in Period Following acceptable screening tests patients will complete a baseline run-in of 2 to 4 weeks duration prior to the study start. During this period patients will be required to keep a symptom diary and to record baseline lung function parameters using an electronic spirometer. As before, patients will be maintained on their normal inhaled steroids in doses equivalent to >/= 400 µg and /= 4 measured during the last 7 days of the baseline run-in period [A symptom scale with scores ranging from 0 (=symptom free) to 3 (=severe symptoms) is used, with 6 questions, and a total maximum daily symptom score of 18, see appendix D)] and/or have a >/= 10% and < 30% diurnal variation in PEFR measured on at least 2 of 7 days during the same period.

Diurnal variation in PEFR is defined from morning and evening PEFR values; in the morning and evening the PEFR is determined on 3 immediately consecutive occasions and the highest value taken. The calculation of diurnal variation is based on:

[(higher (am or pm) PEFR- lower (am or pm) PEFR) / higher (am or pm) PEFR x 100].

In eligible patients, the following pharmacodynamic assessments will be made: breath NO levels (non-nasal) and breath condensates, pulmonary function testing (FEV1, FVC and PEFR), sputum induction for markers of inflammation, and a blood sample collection for the measurement of markers of inflammation.

Study Treatments Patients will be randomised in a 1:1 ratio to treatment with infliximab or placebo, respectively. PRI will provide the randomisation list. At t=0 weeks, patients will either receive 5 mg/kg infliximab (Group I, n=20) or placebo (Group II, n=20). Subsequently, infliximab or placebo will be infused at weeks 2 and 6. Throughout the study period up to week 12, patients will be allowed to use inhaled corticosteroids at a stable dose regimen. Salbutamol, a short-acting beta2-agonist, will be allowed as necessary to relieve symptoms.

During the study, the two treatment groups are defined as:

Group I: Infliximab 5 mg/kg + short-acting beta2-agonist (as needed) + inhaled corticosteroids (equivalent to >/= 400 µg and /= 400 µg and

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: April 2004
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

1. Have a diagnosis of moderate asthma as defined by the American Thoracic Society criteria (NIH, 1997) for > 1 year.

2. Men and women, >/= 18 to </= 60 years of age and within 60-140% of desirable height and weight range established by the 1983 Metropolitan Life Insurance Company standards.

3. Non-smoker for at least 1 year and less than a 10 pack year history of smoking.

4. Screening values for haematology, biochemistry and urinalysis should be within clinically acceptable limits for this patient group.

5. Chest radiograph at screening must show no evidence of malignancy, infection, or fibrosis. The chest radiographs should also show no apical scarring, cavitary lesions, or calcified granulomas, as evidence of past tuberculosis infections.

6. Serological assays for hepatitis B and C must be negative for active infection.

Exclusion Criteria:

1. Are pregnant, nursing, or planning a pregnancy within 12 months of enrolment.

2. Diagnosis of chronic obstructive pulmonary disease, cystic fibrosis or other significant respiratory disorder (excluding asthma).

3. Exacerbation of asthma symptoms requiring hospitalisation within the previous 12 weeks.

4. History of clinically significant seasonal allergies will require that the patient is studied outside the allergy season.

5. Have been previously treated with infliximab or any other therapeutic agent targeted at reducing TNF.

6. Have been treated with any anti-CD-4 antibody.

7. Have been treated with any investigational drug within the previous 3 months or within 5 half-lives, whichever is greater.

8. Have previously used cyclophosphamide, nitrogen mustard, chlorambucil, or other alkylating agents.

9. Have a history of any clinically significant adverse reaction to murine or chimeric proteins, including but not limited to allergic reactions.

11. Have had a serious infection during the previous 2 months. 12. Have a chronic or recurrent infectious disease 13. Have a history of opportunistic infections 14. Have current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or cerebral disease.

15. Have a history of lymphoproliferative disease, including lymphoma 16. Currently have any known malignancy or have a history of malignancy within the previous 5 years.

17. Have had substance abuse (drug or alcohol) problem within the previous 10 years.

18. Use of restricted respiratory medication prior to screening within the following time periods: 1) oral or systemic steroids, 1 month; 2) immunosuppressant therapy, 3 months.

19. Have a history of chronic cough, haemoptysis, weight loss, or pyrexia considered suggestive of possible current tuberculosis infection.

20. Patients with current active tuberculosis (TB) or atypical mycobacterial infection or a previous history of these infections.

21. Be considered at high risk for tuberculosis according to US Centers for Disease Control and Prevention (CDC) criteria, 22. A tuberculin (purified protein derivative, PPD) intradermal skin test > 10mm induration.

23. Have demyelinating disease (multiple sclerosis), autoimmune conditions such as systemic lupus.

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• Study drug administration

Procedure:
• Tuberculin intradermal skin test

• Lung function test for FEV1

• Asthma symptom scores diary

• Quality of life diary

• Breath nitric oxide

• Breath condensate

• Sputum induction

• Blood sampling

• Urinalysis

Locations

Country	Name	City	State
United Kingdom	NHLI Clinical Studies Unit	London

Sponsors (1)

Lead Sponsor	Collaborator
Imperial College London

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline (prior to visit 4: days -7 to -1) to week 8 (prior to visit 8: days 49-56) in mean morning PEFR from clinical diaries:
Primary	The morning PEFR for a 7 day period (week 7 to 8) will be compared to the 7 day period prior to first administration (days -7 to -1).
Secondary	1. Evening PEFR
Secondary	2. FEV1 from clinical diaries and on study visits
Secondary	3. Diurnal variation in PEFR
Secondary	4. Symptoms score
Secondary	5. Short-acting beta2-agonist usage = rescue salbutamol
Secondary	6. Exacerbation's and episode-free days
Secondary	7. Quality of life (St. George's Respiratory Questionnaire)
Secondary	8. Exhaled breath NO and breath condensates
Secondary	9. Sputum levels of IL-8, TNF-alpha and eotaxin (in supernatant) and differential white cell count
Secondary	10. Peripheral blood eosinophil count, and total IgE
Secondary	11. Expression of mRNA related to inflammation in peripheral blood