Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
Solithromycin, Chronic Obstructive Pulmonary Disease, Inflammation, Macrolide
Brief summary
This study examines the potential benefit of a new antibiotic, Solithromycin, for the long-term treatment of Chronic Obstructive Pulmonary Disease (COPD). Solithromycin is hypothesised to work by reducing inflammation in the lungs of patients with COPD. Stable COPD patients will receive treatment with solithromycin for 28 days and comparisons will be made between any effects observed with Solithromycin and a placebo. This will include any changes in inflammatory proteins, lung function and reported symptoms.
Detailed description
Chronic obstructive pulmonary disease (COPD) is a common and debilitating respiratory illness, that kills around 30,000 people annually in the UK. The primary risk factor is cigarette smoking, which causes inflammation in the air passages of the lungs. This inflammation is irreversible and results in progressive lung destruction. Currently, there are no effective anti-inflammatory medications available for COPD. Inhalers remain the mainstay of regular treatment for COPD. Macrolide antibiotics however, are occasionally used as a supplementary treatment for some patients. They have been shown to be anti-inflammatory. However, concerns exist over the development of bacterial resistance to such antibiotics. Consequently they are not widely prescribed for COPD. Solithromycin is a new macrolide antibiotic, which has been shown to possess superior anti-inflammatory properties. Importantly, bacteria are far less likely to develop resistance to this new medication. The current study will assess the effect of solithromycin as an anti-inflammatory treatment for COPD. 30 patients will be recruited to receive 28 days of treatment with solithromycin or placebo, followed by a 28 day wash out period (no study medication), before taking a further 28 days of treatment (the medication not taken first time around, i.e. either solithromycin or placebo). This study is a single-centre (Harefield Hospital), double-blind (study team and patient are not told what treatment they are taking), randomised (order in which solithromycin and placebo are taken), placebo-controlled and has a crossover design (subjects take both solithromycin and placebo separately). Sputum, blood and fluid from the nasal lining will be periodically sampled to examine any effect on the levels of inflammatory cells and proteins during the study. Any changes in lung function parameters or symptoms (COPD Assessment Test) will also be assessed.
Interventions
DRUGSolithromycin
DRUGPlacebo
Sponsors
Melinta Therapeutics, Inc.
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. History of cigarette smoking \>10 pack-years. 2. Post-bronchodilator FEV1/FVC of \<0.70 and FEV1 of 30-79% of predicted normal value. 3. Patients on prescribed inhaled corticosteroids can be enrolled. 4. Females of non-childbearing potential: surgically sterile (e.g. tubal ligation) or at least 2 years post-menopausal. 5. Females of childbearing potential (including females less than 2 years post-menopausal) must have a negative pregnancy test at enrollment and must agree to use highly effective methods of birth control (i.e. diaphragm plus spermicide or male condom plus spermicide, oral contraceptive in combination with a second method, contraceptive implant, injectable contraceptive, indwelling intrauterine device, sexual abstinence, or a vasectomized partner) while participating in the study and for 30 days after the last dose of study drug. 6. The patient must be willing and able to comply with all study visits and procedures. 7. The patient must be a suitable candidate for oral therapy and be able to swallow capsules intact. 8. The patient must provide written informed consent. 9. No evidence of active bacterial infection in sputum by qPCR evaluation.
Exclusion criteria
1. Acute exacerbation of COPD within the previous 60 days or during the washout period of the study. 2. Any condition that could possibly affect oral drug absorption, e.g. gastroenteritis, status post gastrectomy, status post bariatric surgery. 3. Currently taking medication for HIV, chronic hepatitis B, or hepatitis C virus (HCV) infection. 4. Currently taking theophylline or other xanthine medication. 5. Currently taking warfarin. 6. Known concomitant infection (pulmonary or otherwise) which would require additional systemic antibiotics. 7. QTc greater than 450 msec for males or females as corrected by the Fridericia formula. 8. Current use of drugs known to prolong the QT interval, including Class Ia (quinidine, procainamide) or Class III (amiodarone, sotalol) antiarrhythmics. 9. Concomitant use of drugs, foods, or herbal products known to be moderate to potent inhibitors of CYP3A4 isozymes: oral antifungal agents (e.g. ketoconazole, itraconazole, posaconazole, fluconazole and voriconazole); HIV protease inhibitors (e.g. ritonavir and saquinavir), HCV protease inhibitors (e.g. boceprevir and telaprevir), nefazodone, fluvoxamine, conivaptan, diltiazem, verapamil, aprepitant, ticlopidine, crizotinib, imatinib; grapefruit or grapefruit juice. 10. Any use within the prior 7 days of drugs or herbal products known to be moderate to potent inducers of CYP3A4 isozymes: St. John's Wort, rifampin, rifabutin, anti-convulsants (e.g. phenobarbital, carbamazepine, phenytoin, rufinamide), modafinil, armodafinil, etraverine, efavirenz, bosentan. 11. Required current use of drugs with narrow therapeutic indices that are principally metabolized by CYP3A4 or transported by P-glycoprotein (P-gp), for which a drug interaction with solithromycin could result in higher and possibly unsafe exposures to these drugs: e.g. the P-gp substrates digoxin or colchicine and the CYP3A4 substrates alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, midazolam, pimozide, quinidine, sirolimus, tacrolimus, everolimus, and terfenadine). 12. History of organ transplant. 13. Cytotoxic chemotherapy or radiation therapy within the previous 3 months. 14. Known neuromuscular disorder from clinical history (e.g. myasthenia gravis, Parkinson's disease). 15. Known significant renal, hepatic, or hematologic impairment. 16. Women who are pregnant or breast feeding 17. Prior participation in this protocol. 18. Any investigational drugs taken or investigational devices used within 4 weeks before administration of the first dose of the study drug. 19. History of intolerance or hypersensitivity to macrolide antibiotics. 20. Any concomitant condition that, in the opinion of the Investigator, would preclude an evaluation of a response or make it unlikely that the contemplated course of therapy and follow-up could be completed (e.g. life expectancy \<30 days).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Sputum Neutrophils Per mL at 28 Days | 28 days | A number of sputum neutrophils per mL after treatment with solithromycin and placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Concentrations of Sputum MMP-9 Before and After Treatment With Solithromycin and Placebo at 28 Days | 28 days | — |
| Concentrations of CXCL8 in Nasal Lining Fluid With Solithromycin and Placebo at 28 Days | 28 days | — |
| FEV1 After Treatment With Solithromycin and Placebo at 28 Days | 28 days | — |
| R5-R20 After Treatment at 28 Days | 28 days | R5-R20 assessed by impulse oscillometry after treatment with solithromycin and placebo. |
| COPD Assessment Test (CAT) Scores | 28 days | COPD Assessment Test (CAT) scores after treatment with solithromycin and placebo. score of 0-40 to indicate the impact of the disease, the higher score better outcome |
| The Number of Adult COPD Patients With Treatment-related Adverse Events, as Assessed by CTCAE v4.0. | 28 days | — |
| Concentrations of Sputum CXCL8 at 28 Days | 28 days | Concentrations of sputum CXCL8 after treatment with solithromycin and placebo. |
| Concentrations of Sputum IL-6 Before and After Treatment With Solithromycin and Placebo at 28 Days | 28 days | — |
| Concentrations of Sputum MPO Before and After Treatment With Solithromycin and Placebo at 28 Days | 28 days | — |
| Concentrations of Sputum MCP-1 Before and After Treatment With Solithromycin and Placebo. | 28 days | — |
| Concentrations of Sputum TNF-α Before and After Treatment With Solithromycin and Placebo. | 28 days | — |
Other
| Measure | Time frame |
|---|---|
| Exploratory Outcome: Activity of NF-κB in Sputum Macrophages From Patients, Before and After Treatment With Solithromycin and Placebo. | 28 days |
| Exploratory Outcome: Levels of the Serum Biomarker C-reactive Protein Before and After Treatment With Solithromycin and Placebo. | 28 days |
| Exploratory Outcome: Levels of Serum Biomarkers Fibrinogen Before and After Treatment With Solithromycin and Placebo. | 28 days |
| Exploratory Outcome: Activity of PI3K in Sputum Macrophages From Patients, Before and After Treatment With Solithromycin and Placebo. | 84 days |
| Exploratory Outcome: Activity of HDAC2 in Sputum Macrophages From Patients, Before and After Treatment With Solithromycin and Placebo. | 28 days |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participant All participants cross-over study | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Adverse Event | 1 | 0 |
| First Intervention | Withdrawal by Subject | 0 | 1 |
| Second Intervention | Adverse Event | 2 | 0 |
| Second Intervention | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | All Participant | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 6 Participants | — |
| Age, Categorical Between 18 and 65 years | 0 Participants | — |
| Age, Continuous | 69.3 years STANDARD_DEVIATION 3.6 | — |
| BMI | 26.7 kg/m^2 STANDARD_DEVIATION 3 | — |
| COPD Assessment Test (CAT) | 17 scores on a scale STANDARD_DEVIATION 7.3 | — |
| FEV1 | 1.29 litre STANDARD_DEVIATION 0.03 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United Kingdom | 6 participants | — |
| Sex: Female, Male Female | 3 Participants | — |
| Sex: Female, Male Male | 3 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 5 / 6 | 1 / 6 |
| serious Total, serious adverse events | 1 / 6 | 0 / 6 |
Outcome results
Primary
Number of Sputum Neutrophils Per mL at 28 Days
A number of sputum neutrophils per mL after treatment with solithromycin and placebo.
Time frame: 28 days
Population: Due to the early termination of the study, there were too few subjects and data collected to perform statistical analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Solithromycin | Number of Sputum Neutrophils Per mL at 28 Days | 2.47 10^6 cells/ml sputum | Standard Error 0.76 |
| Placebo | Number of Sputum Neutrophils Per mL at 28 Days | 5.30 10^6 cells/ml sputum | Standard Error 1.21 |
Secondary
Concentrations of CXCL8 in Nasal Lining Fluid With Solithromycin and Placebo at 28 Days
Time frame: 28 days
Population: Due to the early termination of the study, there were too few subjects and data collected to perform statistical analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Solithromycin | Concentrations of CXCL8 in Nasal Lining Fluid With Solithromycin and Placebo at 28 Days | 1.39 ng/ml | Standard Error 0.58 |
| Placebo | Concentrations of CXCL8 in Nasal Lining Fluid With Solithromycin and Placebo at 28 Days | 5.14 ng/ml | Standard Error 1.6 |
Secondary
Concentrations of Sputum CXCL8 at 28 Days
Concentrations of sputum CXCL8 after treatment with solithromycin and placebo.
Time frame: 28 days
Population: Due to the early termination of the study, there were too few subjects and data collected to perform statistical analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Solithromycin | Concentrations of Sputum CXCL8 at 28 Days | 2.99 ng/ml | Standard Error 0.76 |
| Placebo | Concentrations of Sputum CXCL8 at 28 Days | 4.29 ng/ml | Standard Error 0.43 |
Secondary
Concentrations of Sputum IL-6 Before and After Treatment With Solithromycin and Placebo at 28 Days
Time frame: 28 days
Population: No data collected for this Outcome due to early termination of the trial
Secondary
Concentrations of Sputum MCP-1 Before and After Treatment With Solithromycin and Placebo.
Time frame: 28 days
Population: No data collected for this Outcome due to early termination of the trial
Secondary
Concentrations of Sputum MMP-9 Before and After Treatment With Solithromycin and Placebo at 28 Days
Time frame: 28 days
Population: No data collected for this Outcome due to early termination of the trial
Secondary
Concentrations of Sputum MPO Before and After Treatment With Solithromycin and Placebo at 28 Days
Time frame: 28 days
Population: No data collected for this Outcome due to early termination of the trial
Secondary
Concentrations of Sputum TNF-α Before and After Treatment With Solithromycin and Placebo.
Time frame: 28 days
Population: No data collected for this Outcome due to early termination of the trial
Secondary
COPD Assessment Test (CAT) Scores
COPD Assessment Test (CAT) scores after treatment with solithromycin and placebo. score of 0-40 to indicate the impact of the disease, the higher score better outcome
Time frame: 28 days
Population: Due to the early termination of the study, there were too few subjects and data collected to perform statistical analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Solithromycin | COPD Assessment Test (CAT) Scores | 16 score on a scale | Standard Error 4 |
| Placebo | COPD Assessment Test (CAT) Scores | 15 score on a scale | Standard Error 5 |
Secondary
FEV1 After Treatment With Solithromycin and Placebo at 28 Days
Time frame: 28 days
Population: Due to the early termination of the study, there were too few subjects and data collected to perform statistical analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Solithromycin | FEV1 After Treatment With Solithromycin and Placebo at 28 Days | 1.13 litre | Standard Error 0.16 |
| Placebo | FEV1 After Treatment With Solithromycin and Placebo at 28 Days | 1.05 litre | Standard Error 0.08 |
Secondary
R5-R20 After Treatment at 28 Days
R5-R20 assessed by impulse oscillometry after treatment with solithromycin and placebo.
Time frame: 28 days
Population: Due to the early termination of the study, there were too few subjects and data collected to perform statistical analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Solithromycin | R5-R20 After Treatment at 28 Days | 0.31 kiloPascals per liter per second | Standard Error 0.06 |
| Placebo | R5-R20 After Treatment at 28 Days | 0.21 kiloPascals per liter per second | Standard Error 0.05 |
Secondary
The Number of Adult COPD Patients With Treatment-related Adverse Events, as Assessed by CTCAE v4.0.
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Solithromycin | The Number of Adult COPD Patients With Treatment-related Adverse Events, as Assessed by CTCAE v4.0. | 5 Participants |
| Placebo | The Number of Adult COPD Patients With Treatment-related Adverse Events, as Assessed by CTCAE v4.0. | 0 Participants |
Other Pre-specified
Exploratory Outcome: Activity of HDAC2 in Sputum Macrophages From Patients, Before and After Treatment With Solithromycin and Placebo.
Time frame: 28 days
Population: No data collected for this Outcome due to early termination of the trial
Other Pre-specified
Exploratory Outcome: Activity of NF-κB in Sputum Macrophages From Patients, Before and After Treatment With Solithromycin and Placebo.
Time frame: 28 days
Population: No data collected for this Outcome due to early termination of the trial
Other Pre-specified
Exploratory Outcome: Activity of PI3K in Sputum Macrophages From Patients, Before and After Treatment With Solithromycin and Placebo.
Time frame: 84 days
Population: No data collected for this Outcome due to early termination of the trial
Other Pre-specified
Exploratory Outcome: Levels of Serum Biomarkers Fibrinogen Before and After Treatment With Solithromycin and Placebo.
Time frame: 28 days
Population: No data collected for this Outcome due to early termination of the trial
Other Pre-specified
Exploratory Outcome: Levels of the Serum Biomarker C-reactive Protein Before and After Treatment With Solithromycin and Placebo.
Time frame: 28 days
Population: No data collected for this Outcome due to early termination of the trial