CLIMB: The Effect of Chlorhexidine on the Oral and Lung Microbiota in Chronic Obstructive Pulmonary Disease

• Sponsor: University of Minnesota (Other)
• Overall Status: Completed
• CT.gov ID: NCT02252588
• Collaborator: Veterans Medical Research Foundation (Other), Flight Attendant Medical Research Institute (Other)
• Enrollment: 44
• Location: 1
• Arms: 2
• Actual Duration (Months): 64
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

Determine the effect of twice-daily chlorhexidine oral rinse on oral and lung microbiota biomass in subjects with chronic obstructive pulmonary disease (COPD) with chronic bronchitis. Our primary outcome will be to compare the microbiota biomass (number of bacteria as measured by 16S rRNA copy number) of induced sputum and the oral cavity before and after 8 weeks of twice-daily chlorhexidine oral rinse (n=25) compared to controls (n=25) using qPCR and next-generation sequencing of the bacterial 16S rRNA gene comparing total bacterial biomass

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: Chlorhexidine; Other: Placebo	Phase 2

Detailed Description

Our hypothesis is that 8 weeks of chlorhexidine oral rinse will decrease microbiota biomass compared to baseline and those on placebo. Furthermore, we hypothesize that chlorhexidine treatment will: i) decrease lung and oral microbiota diversity; ii) alter microbiota taxonomic composition in the lung and oral cavity; iii) decrease systemic inflammation as measured by blood high sensitivity C-reactive protein (hsCRP), fibrinogen and leukocyte count; and iv) demonstrate a trend towards improvement in respiratory health status as measured by the Breathlessness, Cough, and Sputum Scale (BCSS)[1, 2] and St. George's Respiratory Questionnaire (SGRQ).

Subaim 1: Determine if chlorhexidine alters the lung and oral rinse microbiota diversity and taxonomic composition. Our hypothesis is that chlorhexidine oral rinse will decrease the diversity (Shannon and inverse Simpson diversity indices) and taxonomic composition of both oral and lung microbiota compared to those on placebo as determined by next-generation sequencing of the bacterial 16S rRNA gene.

Subaim 2: Determine the impact of chlorhexidine on systemic inflammation. Our hypothesis is that the decrease in lung microbiota biomass is associated with a decrease in systemic inflammation as measured by blood hsCRP, fibrinogen, and leukocyte count.

Subaim 3: Determine if respiratory symptoms associate with the lung microbiota biomass. Our hypothesis is that chlorhexidine will demonstrate improved respiratory health status as measured by the BCSS and SGRQ.

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: The Effect of Chlorhexidine on the Oral and Lung Microbiota in Chronic Obstructive
• Actual Study Start Date: Sep 1, 2014
• Actual Primary Completion Date: Dec 15, 2019
• Actual Study Completion Date: Jan 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Chlorhexidine Oral Rinse	Drug: Chlorhexidine; Oral Rinse; Other: Placebo; Oral Rinse
Placebo Comparator: Placebo Oral Rinse	Drug: Chlorhexidine; Oral Rinse; Other: Placebo; Oral Rinse

Outcome Measures

Primary Outcome Measures

1. Change in Sputum Bacteria Biomass [Baseline, 8 weeks]

   Samples underwent DNA extraction and 16S rRNA quantification and 16S rRNA V4 MiSeq sequencing was performed at the University of Minnesota Genomics Center. The biomass was the number of bacteria as measured by 16S rRNA copy number. To adjust biomass for the size of the sputum sample, raw counts were normalized by dividing by the sample volume or mass.

Secondary Outcome Measures

1. Breathlessness, Cough, and Sputum Scale (BCSS) [Baseline, 8 weeks]

   The Breathlessness, Cough, and Sputum Scale (BCSS) is a brief, three-item, patient-reported outcome measure in which each of the three symptoms assessed by the measure is represented by a single item. Patients are asked to evaluate each symptom/item on a 5-point Likert-type scale, ranging from 0 to 4. Total scores range from 0 to 12 with higher scores indicating a more severe manifestation of the symptom.

2. Change in St George Respiratory Quotient (SGRQ) [baseline, 8 weeks]

   The St George Respiratory Quotient (SGRQ) contains 50 items measuring symptoms of and activities affected by obstructive airway disease. Total score is a sum of item scores and ranges from 0 to 100, with higher scores indicating more limitations. The minimally significant difference is 4.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Willingness to undergo sputum induction

• Capability to provide written informed consent

• Age ≥ 40 years and ≤ 85 years

• FEV1/FVC ratio (post bronchodilator) ≤70%

• FEV1 (post bronchodilator) ≤ 65%

• Presence or high likelihood of chronic cough and sputum production defined as one of the following:

Presence of chronic cough and sputum will be defined by responses to the first two questions on the SGRQ. Subjects who respond positively to both question 1 (cough) and question 2 (sputum) on the SGRQ as either "several days per week" or "almost every day" will be eligible.

COPD exacerbation within the previous 12 months defined as taking antibiotics and/or prednisone for respiratory symptoms, hospitalization or emergency department visit for respiratory illness.

• Current or former smoker with lifetime cigarette consumption of > 10 pack-years

• Negative serum pregnancy test at the baseline visit if patient is a pre-menopausal female (menopause defined as absence of a menstrual cycle in the last 12 months)

• Must be fluent in speaking the English language

• Have a minimum of four teeth

Exclusion Criteria:

• Not fully recovered for at least 30 days from a COPD exacerbation.

• Treated with antibiotics in the last 2 months.

• The presence of dentures (full plate).

• Active oral infection being treated by health care professional.

• Current use of chlorhexidine or over-the-counter mouth washes in the last 2 months.

• Known allergy or sensitivity to chlorhexidine

• Unstable cardiac disease

• Clinical diagnosis of asthma, bronchiectasis, cystic fibrosis, or severe alpha-1 antitrypsin deficiency

• Active lung cancer or history of lung cancer if it has been less than 2 years since lung resection or other treatment. If history of lung cancer, must have no evidence of recurrence in the 2 years preceding the baseline visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Medical Center	Minneapolis	Minnesota	United States	55417

Sponsors and Collaborators

• University of Minnesota
• Veterans Medical Research Foundation
• Flight Attendant Medical Research Institute

Investigators

• Principal Investigator: Chris Wendt, MD, VA Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 31, 2014
• Informed Consent Form - Feb 15, 2017

More Information

Publications

None provided.

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT02252588
• Other Study ID Numbers: 4526
• First Posted: Sep 30, 2014
• Last Update Posted: Dec 29, 2020
• Last Verified: Dec 1, 2020

• Keywords provided by University of Minnesota: COPD; Bacteria
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Chlorhexidine

Study Results

Participant Flow

Arm/Group Title	Chlorhexidine	Placebo
Arm/Group Description	Oral Rinse Chlorhexidine: Oral Rinse Placebo: Oral Rinse	Oral Rinse Chlorhexidine: Oral Rinse Placebo: Oral Rinse
Period Title: Overall Study
STARTED	24	20
COMPLETED	20	20
NOT COMPLETED	4	0

Baseline Characteristics

Arm/Group Title	Chlorhexidine	Placebo	Total
Arm/Group Description	Oral Rinse Chlorhexidine: Oral Rinse Placebo: Oral Rinse	Oral Rinse Chlorhexidine: Oral Rinse Placebo: Oral Rinse	Total of all reporting groups
Overall Participants	24	20	44
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	5 20.8%	5 25%	10 22.7%
>=65 years	19 79.2%	15 75%	34 77.3%
Sex: Female, Male (Count of Participants)
Female	22 91.7%	1 5%	23 52.3%
Male	2 8.3%	19 95%	21 47.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 4.2%	0 0%	1 2.3%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 5%	1 2.3%
White	23 95.8%	19 95%	42 95.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	24 100%	20 100%	44 100%

Outcome Measures

1. Primary Outcome

Title	Change in Sputum Bacteria Biomass
Description	Samples underwent DNA extraction and 16S rRNA quantification and 16S rRNA V4 MiSeq sequencing was performed at the University of Minnesota Genomics Center. The biomass was the number of bacteria as measured by 16S rRNA copy number. To adjust biomass for the size of the sputum sample, raw counts were normalized by dividing by the sample volume or mass.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Chlorhexidine	Placebo
Arm/Group Description	Oral Rinse Chlorhexidine: Oral Rinse Placebo: Oral Rinse	Oral Rinse Chlorhexidine: Oral Rinse Placebo: Oral Rinse
Measure Participants	20	20
Mean (Standard Deviation) [log10 molecules/uL/mL]	-0.24 (11.7)	-0.14 (0.32)

2. Secondary Outcome

Title	Breathlessness, Cough, and Sputum Scale (BCSS)
Description	The Breathlessness, Cough, and Sputum Scale (BCSS) is a brief, three-item, patient-reported outcome measure in which each of the three symptoms assessed by the measure is represented by a single item. Patients are asked to evaluate each symptom/item on a 5-point Likert-type scale, ranging from 0 to 4. Total scores range from 0 to 12 with higher scores indicating a more severe manifestation of the symptom.
Time Frame	Baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Chlorhexidine	Placebo
Arm/Group Description	Oral Rinse Chlorhexidine: Oral Rinse Placebo: Oral Rinse	Oral Rinse Chlorhexidine: Oral Rinse Placebo: Oral Rinse
Measure Participants	20	20
Mean (Standard Deviation) [units on a scale]	0.42 (1.24)	-0.38 (1.13)

3. Secondary Outcome

Title	Change in St George Respiratory Quotient (SGRQ)
Description	The St George Respiratory Quotient (SGRQ) contains 50 items measuring symptoms of and activities affected by obstructive airway disease. Total score is a sum of item scores and ranges from 0 to 100, with higher scores indicating more limitations. The minimally significant difference is 4.
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Chlorhexidine	Placebo
Arm/Group Description	Oral Rinse Chlorhexidine: Oral Rinse Placebo: Oral Rinse	Oral Rinse Chlorhexidine: Oral Rinse Placebo: Oral Rinse
Measure Participants	20	20
Mean (Standard Deviation) [score on a scale]	-4.7 (8)	1.7 (8.9)

Adverse Events

Time Frame	8 weeks
Arm/Group Title	Chlorhexidine		Placebo
Arm/Group Description	Oral Rinse Chlorhexidine: Oral Rinse Placebo: Oral Rinse		Oral Rinse Chlorhexidine: Oral Rinse Placebo: Oral Rinse
All Cause Mortality
	Chlorhexidine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/20 (0%)
Serious Adverse Events
	Chlorhexidine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Chlorhexidine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/24 (8.3%)		4/20 (20%)
General disorders
Other oral side effects	2/24 (8.3%)	2	0/20 (0%)	0
Respiratory, thoracic and mediastinal disorders
Congestion, Sinus Infection, and Cough	0/24 (0%)	0	3/20 (15%)	3
Skin and subcutaneous tissue disorders
Irritation and/or sores of the lining of the mouth	0/24 (0%)	0	1/20 (5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.