Targeted Retreatment of COPD Exacerbations

• Sponsor: Imperial College London (Other)
• Overall Status: Completed
• CT.gov ID: NCT02300220
• Collaborator: (none)
• Enrollment: 144
• Locations: 4
• Arms: 2
• Actual Duration (Months): 56.6
• Patients Per Site: 36
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This study investigates the effects of targeted re-treatment of patients who do not recover from an exacerbation of COPD. Half of the patients will receive ciprofloxacin while the other half will receive a placebo.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease (COPD)	Drug: Ciprofloxacin; Drug: Placebo	Phase 3

Detailed Description

COPD is a long term lung condition where patients suffer recurrent symptom flare-ups, called 'exacerbations'. Patients who have lots of exacerbations have a worse quality of life, poorer ability to breath, and may die earlier than those who don't. Previous research by our group has shown that patients who have an exacerbation and have not completely recovered two weeks after the start of treatment are more likely to suffer another one early than those who completely recover.

This study aims to test whether we can prevent this early re-exacerbation by giving an extra course of antibiotics, compared to a placebo. Patients who experience an exacerbation of COPD and are treated with antibiotics will, two weeks after the start of their treatment, be invited to attend a screening visit. Patients will be eligible for the study if they have not fully recovered at this visit (i.e. if they either still have symptoms or if blood tests show there is still inflammation present) and fulfil other diagnostic measures for COPD. Patients will be allocated to the treatment groups at random, and if eligible will be treated with a further 1 week of ciprofloxacin 500mg twice daily or a placebo.

Patients will then be followed up in the study for a further 3 months, and the primary study outcome will be the time to the next exacerbation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 144 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Targeted Retreatment of Incompletely Recovered COPD Exacerbations With Ciprofloxacin: a Double-blind, Randomised, Placebo-controlled, Multicentre Phase III Trial
• Actual Study Start Date: May 5, 2014
• Actual Primary Completion Date: Jan 22, 2019
• Actual Study Completion Date: Jan 22, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ciprofloxacin 500 mg, twice daily for 1 week (oral).	Drug: Ciprofloxacin; 500 mg, twice daily for 1 week (oral)
Placebo Comparator: Placebo one capsule, twice daily for 1 week.	Drug: Placebo; One capsule, twice daily for 1 week

Outcome Measures

Primary Outcome Measures

1. Time to the Next COPD Exacerbation [Up to 90 days]

   The primary outcome will be the time to the next COPD exacerbation following targeted retreatment with the IMP or placebo, censored at 90 days.

Secondary Outcome Measures

1. Duration of the Initial Exacerbation [Up to 90 days]

   Secondary endpoints will include duration of the initial exacerbation following targeted retreatment with the IMP or placebo.

2. Number of Participants With Serious Non Fatal Adverse Events [7 days of treatment]

   Secondary endpoints will include adverse events following targeted retreatment with the IMP or placebo.

3. Changes in Lung Function [Baseline and 90 days]

   Secondary endpoints will include changes from randomization to 90 days in FEV1.

4. Number of Participants Who Have Resistance Bacteria in the Sputum [Up to 90 days]

   Bacterial load and resistance Secondary endpoints will include resistance following targeted retreatment with the IMP or placebo.

5. Hospital Readmission [90 days of treatment]

   Secondary endpoints will include hospital readmission following targeted retreatment with the IMP or placebo.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Diagnosis of COPD confirmed spirometrically at screening

2. COPD exacerbation with treatment commenced 14 days prior to study enrolment and treated with 5-14 days of a non-quinolone antibiotic.

3. Exacerbation here will be defined as an episode of symptomatic worsening of COPD that was treated by the patient's attending clinician. Confirmation of the initial exacerbation diagnosis will be provided from the case notes, referral letter, or directly from the treating clinician, and will be documented in the CRF.

4. Age: ≥ 45 years of age at screening.

5. Persistent symptoms and/or a CRP≥8mg/L when assessed 2 weeks after exacerbation onset

6. Able to complete questionnaires for health status and symptoms and keep written diary cards

7. Severity of disease: Patients with a measured FEV1<80% of predicted normal values at 2 weeks post exacerbation

8. Able and willing to give signed and dated written informed consent to participate.

Exclusion Criteria:

1. Other clinically predominant chronic respiratory disease.

2. Intubated and receiving mechanical ventilation

3. Patients with known hypersensitivity to the antibiotic under evaluation, to other quinolones or any excipients of the IMP/placebo.

4. Patients with a prior history of tendonopathy or tendon rupture

5. Elderly patients taking long term systemic corticosteroids

6. Patients on long term antibiotics for other conditions

7. Patient too unwell for randomisation, i.e. requiring retreatment in the judgment of the study doctor

8. Female patients who are pregnant or planning on becoming pregnant during the study, or are breastfeeding.

9. Patient taking clinically significant contraindicated medication as per the SmPC s, such as use of concomitant tizanidine or methotrexate.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Aintree University Hospital NHS Foundation Trust	Liverpool		United Kingdom	L9 7AL
2	St Georges University Hospitals NHS Foundation Trust	London		United Kingdom	SW17 0RE
3	Royal Brompton and Harefield Hospital NHS Foundation Trust	London		United Kingdom	SW36NP
4	St Mary's Hospital	London		United Kingdom	W2 1NY

Sponsors and Collaborators

• Imperial College London

Investigators

• Principal Investigator: Wisia Wedzicha, Professor, Imperial College London

Study Documents (Full-Text)

• Study Protocol - Jul 20, 2015
• Statistical Analysis Plan - Jan 15, 2019

More Information

Publications

None provided.

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT02300220
• Other Study ID Numbers: 14IC2031; 2012-002198-72
• First Posted: Nov 24, 2014
• Last Update Posted: Mar 8, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Imperial College London: Chronic Obstructive Pulmonary Disease (COPD)
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Ciprofloxacin

Study Results

Participant Flow

Arm/Group Title	Ciproflaxacin	Placebo
Arm/Group Description	Retreatment with Ciproflaxacin	Retreatment with Placebo
Period Title: Overall Study
STARTED	72	72
COMPLETED	68	65
NOT COMPLETED	4	7

Baseline Characteristics

Arm/Group Title	Ciprofloxacin	Placebo	Total
Arm/Group Description	500 mg, twice daily for 1 week (oral). Ciprofloxacin: 500 mg, twice daily for 1 week (oral)	one capsule, twice daily for 1 week. Placebo: One capsule, twice daily for 1 week	Total of all reporting groups
Overall Participants	72	72	144
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	17 23.6%	20 27.8%	37 25.7%
>=65 years	55 76.4%	52 72.2%	107 74.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.1 (8.8)	69.1 (7.4)	69.1 (8.1)
Sex: Female, Male (Count of Participants)
Female	28 38.9%	25 34.7%	53 36.8%
Male	44 61.1%	47 65.3%	91 63.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 1.4%	0 0%	1 0.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 2.8%	1 1.4%	3 2.1%
White	69 95.8%	69 95.8%	138 95.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	2 2.8%	2 1.4%
Region of Enrollment (participants) [Number]
United Kingdom	72 100%	72 100%	144 100%

Outcome Measures

1. Primary Outcome

Title	Time to the Next COPD Exacerbation
Description	The primary outcome will be the time to the next COPD exacerbation following targeted retreatment with the IMP or placebo, censored at 90 days.
Time Frame	Up to 90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ciprofloxacin	Placebo
Arm/Group Description	500 mg, twice daily for 1 week (oral). Ciprofloxacin: 500 mg, twice daily for 1 week (oral)	one capsule, twice daily for 1 week. Placebo: One capsule, twice daily for 1 week
Measure Participants	72	72
Median (Inter-Quartile Range) [days]	72	58

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ciprofloxacin, Placebo
	Comments	The primary endpoint was assessed using a Cox's proportional hazard model with pre-specified adjustment for patient's self-reported history of exacerbations over the previous year and with stratification for study centre. The onset of exacerbation will be monitored up to 90 days or at patient withdrawal.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.764
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.071
	Confidence Interval	(2-Sided) 95%; 0.684 to 1.676
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Duration of the Initial Exacerbation
Description	Secondary endpoints will include duration of the initial exacerbation following targeted retreatment with the IMP or placebo.
Time Frame	Up to 90 days

Outcome Measure Data

Analysis Population Description

Missing participants data 16 for ciprofloxacin and 15 for placebo

Arm/Group Title	Ciprofloxacin	Placebo
Arm/Group Description	500 mg, twice daily for 1 week (oral). Ciprofloxacin: 500 mg, twice daily for 1 week (oral)	one capsule, twice daily for 1 week. Placebo: One capsule, twice daily for 1 week
Measure Participants	56	57
Median (Inter-Quartile Range) [days]	3	4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ciprofloxacin, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.703
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Number of Participants With Serious Non Fatal Adverse Events
Description	Secondary endpoints will include adverse events following targeted retreatment with the IMP or placebo.
Time Frame	7 days of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ciprofloxacin	Placebo
Arm/Group Description	500 mg, twice daily for 1 week (oral). Ciprofloxacin: 500 mg, twice daily for 1 week (oral)	one capsule, twice daily for 1 week. Placebo: One capsule, twice daily for 1 week
Measure Participants	72	72
Count of Participants [Participants]	1 1.4%	9 12.5%

4. Secondary Outcome

Title	Changes in Lung Function
Description	Secondary endpoints will include changes from randomization to 90 days in FEV1.
Time Frame	Baseline and 90 days

Outcome Measure Data

Analysis Population Description

Only the participants who completed the study

Arm/Group Title	Ciprofloxacin	Placebo
Arm/Group Description	500 mg, twice daily for 1 week (oral). Ciprofloxacin: 500 mg, twice daily for 1 week (oral)	one capsule, twice daily for 1 week. Placebo: One capsule, twice daily for 1 week
Measure Participants	63	63
Mean (Standard Deviation) [litres]	0.0229 (0.199)	0.0041 (0.198)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ciprofloxacin, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.239
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Number of Participants Who Have Resistance Bacteria in the Sputum
Description	Bacterial load and resistance Secondary endpoints will include resistance following targeted retreatment with the IMP or placebo.
Time Frame	Up to 90 days

Outcome Measure Data

Analysis Population Description

Lower participants number due to the number of patients with a pathogenic organism with newly acquired ciprofloxacin resistance, present in a sputum sample collected at 90 days

Arm/Group Title	Ciprofloxacin	Placebo
Arm/Group Description	500 mg, twice daily for 1 week (oral). Ciprofloxacin: 500 mg, twice daily for 1 week (oral)	one capsule, twice daily for 1 week. Placebo: One capsule, twice daily for 1 week
Measure Participants	16	17
Count of Participants [Participants]	0 0%	1 1.4%

6. Secondary Outcome

Title	Hospital Readmission
Description	Secondary endpoints will include hospital readmission following targeted retreatment with the IMP or placebo.
Time Frame	90 days of treatment

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Ciprofloxacin	Placebo
Arm/Group Description	500 mg, twice daily for 1 week (oral). Ciprofloxacin: 500 mg, twice daily for 1 week (oral)	one capsule, twice daily for 1 week. Placebo: One capsule, twice daily for 1 week
Measure Participants	0	0

Adverse Events

Time Frame	90 days + 1 month
Arm/Group Title	Ciprofloxacin		Placebo
Arm/Group Description	500 mg, twice daily for 1 week (oral). Ciprofloxacin: 500 mg, twice daily for 1 week (oral)		one capsule, twice daily for 1 week. Placebo: One capsule, twice daily for 1 week
All Cause Mortality
	Ciprofloxacin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/72 (1.4%)		1/72 (1.4%)
Serious Adverse Events
	Ciprofloxacin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/72 (1.4%)		9/72 (12.5%)
Cardiac disorders
Cardiovascular	0/72 (0%)	0	1/72 (1.4%)	1
Gastrointestinal disorders
Gastrointestinal	0/72 (0%)	0	2/72 (2.8%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Oncology	1/72 (1.4%)	1	1/72 (1.4%)	1
Psychiatric disorders
Psychological	0/72 (0%)	0	1/72 (1.4%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory	0/72 (0%)	0	4/72 (5.6%)	4
Other (Not Including Serious) Adverse Events
	Ciprofloxacin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/72 (16.7%)		8/72 (11.1%)
Gastrointestinal disorders
Nausea	1/72 (1.4%)	1	1/72 (1.4%)	1
Vomiting	0/72 (0%)	0	1/72 (1.4%)	1
Diarrhoea	5/72 (6.9%)	5	1/72 (1.4%)	1
Dyspepsia	1/72 (1.4%)	1	0/72 (0%)	0
Abdominal Colic/Pain	2/72 (2.8%)	2	2/72 (2.8%)	2
Musculoskeletal and connective tissue disorders
Ankle Pain/Tendonitis	2/72 (2.8%)	2	0/72 (0%)	0
Nervous system disorders
Dry Mouth	1/72 (1.4%)	1	0/72 (0%)	0
Tremor	0/72 (0%)	0	1/72 (1.4%)	1
Skin and subcutaneous tissue disorders
Pruritis/Rash	0/72 (0%)	0	2/72 (2.8%)	2

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.