Anti-inflammatory Effects of Tiotropium in Patients With Stable COPD (ANTIOFLAM)

July 19, 2022 updated by: Huib A.M. Kerstjens, University Medical Center Groningen

Anti-inflammatory Effects of Tiotropium in Patients With Stable COPD- A Multicenter Randomized Controlled Double-blind Study

This study aims to assess the anti-inflammatory effects after 6 weeks treatment with tiotropium compared to placebo in patients with stable COPD

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Rationale: Acetylcholine is the primary parasympathetic neurotransmitter in the airways, and induces bronchoconstriction. Since the cholinergic tone appears to be the major reversible component of obstruction, muscarinic receptor antagonism and bronchodilation represent the primary goal of anticholinergic therapy in patients with chronic obstructive pulmonary disease (COPD). Long-acting anticholinergic therapy is central in GOLD stage B-D, because of improvements in lung function, quality of life, and especially reduction of exacerbations. The elicited reduction in exacerbations with the long-acting muscarinic antagonist (LAMA) tiotropium appears larger than that of the long-acting beta agonist (LABA) salmeterol even when the bronchodilation is similar. In asthma too, it has been shown that the addition of the tiotropium to inhaled corticosteroids (ICS)+LABA combination therapy reduces the number of severe exacerbations. These effects on exacerbation frequency suggest that tiotropium might exert anti-inflammatory effects in the airways next to bronchodilatory effects. There are multiple animal and in vivo studies to indeed suggest an anti-inflammatory effect of anticholinergics.

Such an anti-inflammatory effect of anticholinergic intervention could be clinically relevant; however it has not been previously demonstrated in patients with COPD.

The investigators hypothesize that tiotropium bromide reduces the ongoing inflammation in patients with COPD compared to placebo. The investigators expect a decrease of TNF-alpha mRNA in sputum after treatment with tiotropium bromide.

Objective: This research proposal aims to assess the anti-inflammatory effects after 6 weeks treatment with tiotropium compared to placebo in patients with stable COPD.

Study design: This will be a multicenter parallel design randomized controlled double-blinded study.

Study population: A total of 50 COPD patients with stable disease status will be included and followed for two consecutive visits.

Intervention: COPD patients will be randomized to the treatment group (tiotropium respimat 5 ug) or to the placebo group.

Main study parameters/endpoints: A decrease of TNF-alpha mRNA in induced sputum will be the main parameter for assessing the anti-inflammatory effects of 6 week treatment with tiotropium in patients with stable COPD. Additionally, changes in sputum cell differentials and other cytokine parameters (protein, mRNA,LTB4), blood cell differentials, CRP, and cytokine parameters, health related quality of life (CCQ, CAT) will be assessed as well as changes in post-bronchdilator FEV1.

Study Type

Interventional

Enrollment (Anticipated)

50

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

      • Groningen, Netherlands, 9713 GZ
        • Recruiting
        • University Medical Center
        • Contact:
        • Contact:
      • Leeuwarden, Netherlands, 8934 AD
        • Recruiting
        • Medical centrum Leeuwarden
        • Contact:
        • Contact:
          • Wouter van Geffen, Dr, MD
          • Phone Number: 003158- 2866190

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • • Men or women, age >= 40 years.

    • A diagnosis of COPD according to the criteria of the GOLD organization
    • Post-bronchodilator FEV1 / FVC ratio < 70% (ERS equations) and post-bronchodilator FEV1 < 80%pred.
    • A smoking history of > 10 pack years.
    • post-bronchodilator FEV1 > 1.5 Litres and ability to produce sputum after hypertonic saline induction.
    • No upper or lower respiratory tract infection in the last 4 weeks necessitating antibiotic treatment or consisting of quite probable viral etiology.
    • Being in a stable phase of COPD, as judged by the investigator. No courses of systemic steroids or antibiotics for respiratory problems last 4 weeks
    • The participant needs to be able to understand the Dutch language
    • Signed and dated informed consent obtained before any study related procedures (including withdrawal of concomitant medication) are conducted.

Exclusion Criteria:

  • • Treatment with immune-modulating agents for any disease, including leuktriene receptor antagonists,

    • Treatment with long-acting anticholinergics <4 weeks before the start of the study.
    • Treatment with corticosteroids <4 weeks before the start of the study.
    • Targeted lung denervation therapy in the past.
    • Concomitant diagnosis of asthma.
    • Any significant other pulmonary disease or disorder (e.g. known alpha1-antitrypsine deficiency, significant bronchiectasis), as judged by the investigator.
    • Narrow angle glaucoma.
    • Azithromycine maintenance treatment.
    • Active malignant disease (at least 5 years malignant disease-free)
    • Other significant disease or disorder (like cardiovascular, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic (including diagnosed diabetes), malignant, psychiatric, major physical impairment), which, in the opinion of the investigators may either put the patient at risk because of participation in the study, or may influence the results of the study, or the patient's ability to participate in the study.
    • Females of childbearing potential without an efficient contraception unless they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH >40 mIU/mL or the use of one or more of the following acceptable methods of contraception:

      1. Surgical sterilization (e.g. bilateral tubal ligation, hysterectomy).
      2. Hormonal contraception (implantable, patch, oral, injectable).
      3. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/cream/suppository.
      4. Continuous abstinence.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Tiotropium respimat
Tiotropium respimat 2.5mcg two actuations once daily
Participants will be double-blind randomized for Tiotropium or Placebo treatment for 6 weeks
Placebo Comparator: Placebo respimat
Placebo respimat two actuations once daily
Participants will be double-blind randomized for Tiotropium or Placebo treatment for 6 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in concentration of TNF-alpha (mRNA level) in induced sputum
Time Frame: 6 week treatment duration
To assess whether 6 weeks treatment with tiotropium elicts anti-inflammatory effects compared to placebo in patients with stable COPD, as measured by a change in TNF-alpha mRNA level in induced sputum
6 week treatment duration

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in concentration of sputum cell differentials in induced sputum
Time Frame: 6 week treatment duration
To assess whether 6 weeks treatment with tiotropium elicts anti-inflammatory effects compared to placebo in patients with stable COPD, as measured by a change in sputum cell differentials (% of total cells) in induced sputum
6 week treatment duration
Change in concentration of LTB4 level in induced sputum
Time Frame: 6 week treatment duration
To assess whether 6 weeks treatment with tiotropium elicts anti-inflammatory effects compared to placebo in patients with stable COPD, as measured by a change in LTB4 level (pg/ml) in induced sputum
6 week treatment duration
Change in concentration of cytokine protein level in induced sputum
Time Frame: 6 week treatment duration
To assess whether 6 weeks treatment with tiotropium elicts anti-inflammatory effects compared to placebo in patients with stable COPD, as measured by a change in cytokine protein levels (IL-8,IL-6,MCP-1, TNF-a, MIP-1beta,TGF-beta,MPO, ECP; pg/ml) in induced sputum
6 week treatment duration
Change in concentration of cytokine mRNA level in induced sputum
Time Frame: 6 week treatment duration
To assess whether 6 weeks treatment with tiotropium elicts anti-inflammatory effects compared to placebo in patients with stable COPD, as measured by a change in cytokine mRNA levels of IL-8,IL-6,MCP-1, TNF-a, MIP-1beta,TGF-beta,MPO, ECP in induced sputum
6 week treatment duration
Change in concentration of cell differentials + CRP in blood serum
Time Frame: 6 week treatment duration
To assess whether 6 weeks treatment with tiotropium elicts anti-inflammatory effects compared to placebo in patients with stable COPD, as measured by a change in cell differentials (10^9/L) +CRP (mg/L) in blood serum
6 week treatment duration
Change in concentration cytokine protein level in blood serum
Time Frame: 6 week treatment duration
To assess whether 6 weeks treatment with tiotropium elicts anti-inflammatory effects compared to placebo in patients with stable COPD, as measured by a change in cytokine protein levels (IL-6,TNF-a,siCAM; pg/ml) in blood serum
6 week treatment duration
Change in health related quality of life (CCQ, CAT questionnaires)
Time Frame: 6 week treatment duration
To assess whether 6 weeks treatment with tiotropium elicts anti-inflammatory effects compared to placebo in patients with stable COPD, as measured by a changein health related quality of life (CCQ and CAT questionnaires)
6 week treatment duration

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Differences in gene expression measured in sputum samples
Time Frame: 6 week treatment duration
RNA-sequencing of sputum samples
6 week treatment duration

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Collaborators

Investigators

  • Principal Investigator: Wouter van Geffen, MD PhD, Medical centrum Leeuwarden, Department of pulmonology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 19, 2019

Primary Completion (Anticipated)

December 1, 2022

Study Completion (Anticipated)

December 31, 2022

Study Registration Dates

First Submitted

August 14, 2019

First Submitted That Met QC Criteria

August 16, 2019

First Posted (Actual)

August 19, 2019

Study Record Updates

Last Update Posted (Actual)

July 20, 2022

Last Update Submitted That Met QC Criteria

July 19, 2022

Last Verified

July 1, 2022

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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