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COPDPhase 4ANTIOFLAMNCT04061161

Anti-inflammatory Effects of Tiotropium in Patients with Stable COPD

A Phase 4 study testing Tiotropium Bromide in people with COPD, run by University Medical Center Groningen at 2 sites in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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

Who is it for?
Ages 40 years and older
Conditions the study is for
COPD
What is being tested?
Tiotropium Bromide
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
37 participants
Where
2 sitesNetherlands
Study dates
19 Aug 2019to 31 Dec 2023
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 40 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • • 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.
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  • 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.

Who cannot join

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

Trial locations and contacts

2 sites in 1 country.

Netherlands2 sites

  • University Medical Center

    Groningen, 9713 GZ

  • Medical centrum Leeuwarden

    Leeuwarden, 8934 AD

Other trials in Netherlands

About this study

Official title: 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

Read the 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.

Conditions
COPD
Being tested
Tiotropium Bromide
Keywords
Tiotropium, Anti-inflammatory effects, TNF-alpha mRNA in induced sputum
Medical subject headings
Pulmonary Disease, Chronic Obstructive

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Tiotropium BromideDrug

    Participants will be double-blind randomized for Tiotropium or Placebo treatment for 6 weeks

Study groups in NCT04061161
Study groupRoleWhat they receive
Tiotropium respimatActive comparatorTiotropium respimat 2.5mcg two actuations once daily
Receives: Drug: Tiotropium Bromide
Placebo respimatPlacebo comparatorPlacebo respimat two actuations once daily
Receives: Drug: Tiotropium Bromide

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in concentration of TNF-alpha (mRNA level) in induced sputum

    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

    Measured: 6 week treatment duration

Secondary outcomes (7)

  1. Change in concentration of sputum cell differentials in induced sputum

    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

    Measured: 6 week treatment duration

  2. Change in concentration of LTB4 level in induced sputum

    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

    Measured: 6 week treatment duration

  3. Change in concentration of cytokine protein level in induced sputum

    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

    Measured: 6 week treatment duration

  4. Change in concentration of cytokine mRNA level in induced sputum

    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

    Measured: 6 week treatment duration

  5. Change in concentration of cell differentials + CRP in blood serum

    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

    Measured: 6 week treatment duration

  6. Change in concentration cytokine protein level in blood serum

    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

    Measured: 6 week treatment duration

  7. Change in health related quality of life (CCQ, CAT questionnaires)

    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)

    Measured: 6 week treatment duration

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Aug 2019
  2. Study start19 Aug 2019
  3. Primary completion31 Dec 2023
  4. Study completion31 Dec 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
This will be a multicenter parallel design randomized placebo controlled double-blinded study.
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
37 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04061161
Sponsor's protocol ID
2018-002173-22
Other IDs
2018
Acronym
ANTIOFLAM
Status last verified
Aug 2023
First submitted
14 Aug 2019
Last updated
25 Sep 2024
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Bathoorn E, Liesker J, Postma D, Koeter G, van Oosterhout AJ, Kerstjens HA. Safety of sputum induction during exacerbations of COPD. Chest. 2007 Feb;131(2):432-8. doi: 10.1378/chest.06-2216.

    PubMed 17296644

  • Brightling CE, Monterio W, Green RH, Parker D, Morgan MD, Wardlaw AJ, Pavord D. Induced sputum and other outcome measures in chronic obstructive pulmonary disease: safety and repeatability. Respir Med. 2001 Dec;95(12):999-1002. doi: 10.1053/rmed.2001.1195.

    PubMed 11778799

  • Gosens R, Zaagsma J, Meurs H, Halayko AJ. Muscarinic receptor signaling in the pathophysiology of asthma and COPD. Respir Res. 2006 May 9;7(1):73. doi: 10.1186/1465-9921-7-73.

    PubMed 16684353

  • Kerstjens HA, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, Sigmund R, Seibold W, Moroni-Zentgraf P, Bateman ED. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012 Sep 27;367(13):1198-207. doi: 10.1056/NEJMoa1208606. Epub 2012 Sep 2.

    PubMed 22938706

  • Kistemaker LE, Bos IS, Menzen MH, Maarsingh H, Meurs H, Gosens R. Combination therapy of tiotropium and ciclesonide attenuates airway inflammation and remodeling in a guinea pig model of chronic asthma. Respir Res. 2016 Feb 4;17:13. doi: 10.1186/s12931-016-0327-6.

    PubMed 26846267

  • Kistemaker LE, Gosens R. Acetylcholine beyond bronchoconstriction: roles in inflammation and remodeling. Trends Pharmacol Sci. 2015 Mar;36(3):164-71. doi: 10.1016/j.tips.2014.11.005. Epub 2014 Dec 13.

    PubMed 25511176

  • Kistemaker LE, Oenema TA, Meurs H, Gosens R. Regulation of airway inflammation and remodeling by muscarinic receptors: perspectives on anticholinergic therapy in asthma and COPD. Life Sci. 2012 Nov 27;91(21-22):1126-33. doi: 10.1016/j.lfs.2012.02.021. Epub 2012 Mar 3.

    PubMed 22406302

  • Perng DW, Tao CW, Su KC, Tsai CC, Liu LY, Lee YC. Anti-inflammatory effects of salmeterol/fluticasone, tiotropium/fluticasone or tiotropium in COPD. Eur Respir J. 2009 Apr;33(4):778-84. doi: 10.1183/09031936.00115308. Epub 2009 Jan 7.

    PubMed 19129278

  • Powrie DJ, Wilkinson TM, Donaldson GC, Jones P, Scrine K, Viel K, Kesten S, Wedzicha JA. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Eur Respir J. 2007 Sep;30(3):472-8. doi: 10.1183/09031936.00023907. Epub 2007 May 15.

    PubMed 17504798

  • Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008 Oct 9;359(15):1543-54. doi: 10.1056/NEJMoa0805800. Epub 2008 Oct 5.

    PubMed 18836213

  • "Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary." Claus F. Vogelmeier, Gerard J. Criner, Fernando J. Martinez, Antonio Anzueto, Peter J. Barnes, Jean Bourbeau, Bartolome R. Celli, Rongchang Chen, Marc Decramer, Leonardo M. Fabbri, Peter Frith, David M.G. Halpin, M. Victorina Lopez Varela, Masaharu Nishimura, Nicolas Roche, Roberto Rodriguez-Roisin, Don D. Sin, Dave Singh, Robert Stockley, Jorgen Vestbo, Jadwiga A. Wedzicha and Alvar Agusti. Eur Respir J 2017; 49: 1700214. Eur Respir J. 2017 Jun 22;49(6):1750214. doi: 10.1183/13993003.50214-2017. Print 2017 Jun. No abstract available.

    PubMed 28642306

  • Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van Molken MP, Beeh KM, Rabe KF, Fabbri LM; POET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011 Mar 24;364(12):1093-1103. doi: 10.1056/NEJMoa1008378.

    PubMed 21428765

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Tiotropium Bromide in people with COPD, run by University Medical Center Groningen at 2 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in concentration of TNF-alpha (mRNA level) in induced sputum (time frame: 6 week treatment duration). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04061161, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Sep 2024.

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