Clinical Trial Results:
A single-centre, double-blind, randomised, placebo-controlled crossover study to evaluate the effect of solithromycin on airway inflammation in male and female patients with chronic obstructive pulmonary disease.
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Summary
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EudraCT number |
2014-003077-42 |
Trial protocol |
GB |
Global end of trial date |
05 Jan 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Feb 2018
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First version publication date |
09 Feb 2018
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Other versions |
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Summary report(s) |
Final report |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CE01-204
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02628769 | ||
WHO universal trial number (UTN) |
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Other trial identifiers |
REC number: 14/LO/2066 | ||
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Sponsors
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Sponsor organisation name |
Imperial College London
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Sponsor organisation address |
AHSC Joint Research Compliance Office 510B, Charing Cross Hospital, Fulham Palace Road, London, United Kingdom, W6 8RF
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Public contact |
Louise Donnelly, Imperial College London, 44 02075947895,
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Scientific contact |
Louise Donnelly, Imperial College London, 44 02075947895, l.donnelly@imperial.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
06 Nov 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
05 Jan 2017
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The main objective was to assess the effect, at day 28, of oral Solithromycin (CEM-101) on the number of sputum neutrophils per mL in subjects with chronic obstructive pulmonary disease (COPD) compared to placebo.
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Protection of trial subjects |
This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP).
Each subject was given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study and it was ensured that the Informed Consent Form was signed and dated before any study specific procedure was performed. Opportunity was given to ask questions and subjects were allowed time to consider the information provided. Subjects were also notified that they were free to discontinue from the study at any time. Written informed consent was obtained from all subjects prior to initiation of the study. Trial subjects were monitored at baseline and weekly throughout the study by the study doctor.
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Background therapy |
Relevant treatment [prior/current medications, including all prescription/non-prescription medications, herbal medications, and vitamin supplements, and prior/current non-pharmacological (surgery, procedures) treatments] received by the subject within 7 days before administration of study drug were recorded. All enrolled subjects were receiving long acting combination corticosteroid and β2-agonist inhaled preparations and 5 subjects received tiotropium bromide, a long-acting inhaled anticholinergic bronchodilator, for treatment of COPD. In addition to these treatments, 5 subjects received salbutamol, a short-acting β2-agonist inhaler, for rescue therapy. Other concomitant medications used by at least 2 subjects included omeprazole (n=3) and statins (n=2). | ||
Evidence for comparator |
Solithromycin (CEM-101) is a novel macrolide and the first fluoroketolide. It is active against Gram-positive, Gram-negative and atypical bacteria and is in clinical development for the treatment of community-acquired bacterial pneumonia and gonorrhoea. Development of solithromycin resistance has not been observed to date in clinical trials and solithromycin is active against bacterial strains that are resistant to other macrolides. It is 8-16 times more active than azithromycin and has a one day duration of action. In a small clinical Phase 1 study, oral solithromycin (400 mg) once daily was substantially concentrated in lung epithelial lining fluid (~10-fold) and alveolar macrophages (~200-fold) compared to plasma concentrations, indicating its suitability for local effects in the lung. Solithromycin was found to have greater anti-inflammatory effects than other macrolides, such as erythromycin, azithromycin, clarythromycin and telithromycin (10-fold greater effect) in suppressing TNF-α, CXCL8 and MMP-9 release and activity from a human macrophage cell line and from monocytes from COPD patients. In addition solithromycin completely inhibited oxidative stress-activated NF-κB in these cells. Furthermore, solithromycin was effective in suppressing corticosteroid resistance indicating that, as well as a direct anti-inflammatory effect through NF-κB inhibition, it may also reverse corticosteroid resistance in COPD. | ||
Actual start date of recruitment |
01 Dec 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 6
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Worldwide total number of subjects |
6
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EEA total number of subjects |
6
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
6
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment started 1st December 2014 in the UK with the first screening visit 29th September 2015 Trial was terminated early 18th January 2017 | |||||||||||||||||||||
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Pre-assignment
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Screening details |
Screening procedures to determine subject eligibility were performed with 21 days to the first dose administration | |||||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
6 | |||||||||||||||||||||
Number of subjects completed |
6 | |||||||||||||||||||||
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Period 1
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||||||||||||||
Blinding implementation details |
Participants were randomly assigned in a 1:1 ratio to receive either Solithromycin (400mcg) orally once a day for 28 days or matching placebo. Participants who were randomized to Solithromycin initially then received placebo for 28 days after a 28 day wash out period and vice versa.
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Solithromycin | |||||||||||||||||||||
Arm description |
Subjects received 400 mcg Solithromycin for 28 days and then matching placebo for an additional period of 28 days following a washout period of 28 days between the two treatments. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Solithromycin
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Investigational medicinal product code |
CEM-101
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
400 mcg taken orally as 2X200 mcg capsules of Solithromycin once a day for 28 days
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Arm title
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Placebo | |||||||||||||||||||||
Arm description |
Matching placebo was administered orally as capsules once a day for 28 days | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Capsule was taken once a day orally for 28 days
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Baseline characteristics reporting groups
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Reporting group title |
Overall study (overall period)
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Reporting group description |
All subjects | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Solithromycin
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Reporting group description |
Subjects received 400 mcg Solithromycin for 28 days and then matching placebo for an additional period of 28 days following a washout period of 28 days between the two treatments. | ||
Reporting group title |
Placebo
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Reporting group description |
Matching placebo was administered orally as capsules once a day for 28 days | ||
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End point title |
Sputum neutrophil counts [1] | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Measurement of sputum neutrophils after drug or placebo
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to early termination of the study, there were too few subjects and data collected to perform statistical analysis |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in sputum neutrophil counts from baseline [2] | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Measurements taken at baseline and 28 days after solithromycin or placebo
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to early termination of the study, there were too few subjects and data collected to perform statistical analysis |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Sputum CXCL8 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Sputum levels of CXCL8 after 28 days with either solithromycin or placebo
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| No statistical analyses for this end point | |||||||||||||
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End point title |
CXCL8 Nasal Epithelial Lining Fluid | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Nasal fluid CXCL8 measurements after 28 days with either Solithromycin or placebo
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Small airway resistance (R5-R20) | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Measurement 28 days after solithromycin or placebo
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Effect of solithromycin and placebo on CAT score | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Measurement taken after 28 days with either solithromycin or placebo
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Effect on lung function (FEV1 % predicted) | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Measurement 28 days after solithromycin or placebo
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Effect on lung funtion (FEV1) | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Measurements taken after 28 days with either solithromycin or placebo
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From the time of informed consent up till discharge from the study
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18
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Reporting groups
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Reporting group title |
Solithromycin
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Reporting group description |
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Reporting group title |
Placebo
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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29 Jan 2015 |
Amendment 1 was introduced after MHRA review, to update the reference safety information, to include additional criteria for drug discontinuation and to ensure appropriate reporting of SAEs. Appendix B was added to include safety information from the Phase 2 CAPB study with a listing of serious adverse drug reactions. The study procedures included new drug discontinuation criteria based on laboratory findings of increased hepatic transaminases, QT prolongation > 500 ms or change from baseline > 60 ms, increases in heart rate > 120 bpm or change from baseline > 30 bpm, and adverse events associated with inhibition of nicotinic acetylcholine receptors. Additional detail was incorporated to describe procedures for reporting of SAEs to regulatory authorities. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| The trial was terminated early due to cholestatic hepatitis in one subject and ALT elevation in two others during or following solithromycin dosing. Data suggested a trend towards reduced sputum and neutrophil numbers but data set is too small. | |||
