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

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ClinicalTrials.gov Identifier: NCT04061161
Recruitment Status : Recruiting
First Posted : August 19, 2019
Last Update Posted : September 26, 2019
Sponsor:
Collaborator:
Boehringer Ingelheim
Information provided by (Responsible Party):
Huib A.M. Kerstjens, University Medical Center Groningen

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

Condition or disease Intervention/treatment Phase
COPD Drug: Tiotropium Bromide Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This will be a multicenter parallel design randomized placebo controlled double-blinded study.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind
Primary Purpose: Treatment
Official Title: Anti-inflammatory Effects of Tiotropium in Patients With Stable COPD- A Multicenter Randomized Controlled Double-blind Study
Actual Study Start Date : August 19, 2019
Estimated Primary Completion Date : December 1, 2020
Estimated Study Completion Date : December 1, 2020

Resource links provided by the National Library of Medicine


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

Placebo Comparator: Placebo respimat
Placebo respimat two actuations once daily
Drug: Tiotropium Bromide
Participants will be double-blind randomized for Tiotropium or Placebo treatment for 6 weeks




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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. 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

  7. 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)


Other Outcome Measures:
  1. Differences in gene expression measured in sputum samples [ Time Frame: 6 week treatment duration ]
    RNA-sequencing of sputum samples



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04061161


Contacts
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Contact: Benedikt Ditz, MD +31625649905 l.b.ditz@umcg.nl
Contact: Huib A.M. Kerstjens, MD PhD +31503612080 h.a.m.kerstjens@umcg.nl

Locations
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Netherlands
University Medical Center Recruiting
Groningen, Netherlands, 9713 GZ
Contact: Benedikt Ditz, MD    0037625649905    l.b.ditz@umcg.nl   
Contact: Huib Kerstjens, Prof, Dr, MD    0031 50 361 0280    h.a.m.kerstjens@umcg.nl   
Medical centrum Leeuwarden Recruiting
Leeuwarden, Netherlands, 8934 AD
Contact: Petra Hirmann    003158-2866427    Petra.Hirmann@ZNB.NL   
Contact: Wouter van Geffen, Dr, MD    003158- 2866190      
Sponsors and Collaborators
University Medical Center Groningen
Boehringer Ingelheim
Investigators
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Principal Investigator: Wouter van Geffen, MD PhD Medical centrum Leeuwarden, Department of pulmonology
Publications:

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Responsible Party: Huib A.M. Kerstjens, Full professor pulmonology; Head of department of Pulmonology and Tuberculosis; Principal Investigator, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT04061161    
Other Study ID Numbers: 2018-002173-22
First Posted: August 19, 2019    Key Record Dates
Last Update Posted: September 26, 2019
Last Verified: September 2019

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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
Keywords provided by Huib A.M. Kerstjens, University Medical Center Groningen:
Tiotropium
Anti-inflammatory effects
TNF-alpha mRNA in induced sputum
Additional relevant MeSH terms:
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Bromides
Tiotropium Bromide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Parasympatholytics
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anticonvulsants