E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Obstructive Pulmonary Disease. |
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E.1.1.1 | Medical condition in easily understood language |
Chronic bronchitis and emphysema (lung damage relating to cigarette smoking). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10009033 |
E.1.2 | Term | Chronic obstructive pulmonary disease |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
COPD results from chronic inflammation in the small passages of the lung. At present, there are no effective therapies capable of dampening this inflammation to prevent disease progression. Even steroids, which are normally potent anti-inflammatories, have little or no effect in COPD. Macrolide antibiotics have previously been shown to possess anti-inflammatory actions on cells of the immune system. In addition, they kill many different kinds of bacteria, which reside in the lungs of COPD patients and are responsible for perpetuating this inflammatory process. Although macrolides are occasionally used as an additional long-term therapy in some COPD patients, many clinicians are concerned that widespread use may lead to the generation of antibiotic resistance amongst many different kinds of bacteria. This could be catastrophic for COPD patients given the high frequency of chest infections and pneumonia. As such, the risks of long-term macrolide use are considered to outweigh any possbil |
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E.2.2 | Secondary objectives of the trial |
In healthy lungs, special white blood cells tightly regulate and coordinate inflammation through the release of important chemical signals. In COPD however, these same white blood cells are faulty and continually promote chemical release leading to inflammation and lung damage. This is the result of defective messages within the cell. Steroids are anti-inflammatory drugs normally capable of switching off these messages to halt the release of these pro-inflammatory chemicals. In other inflammatory lung conditions (e.g. asthma) they are highly effective medications. In COPD however, the cell messages are resistant to steroids and are not switched off. As such, steroids are ineffective anti-inflammatories for COPD.
Solithromycin has previously been shown to suppress the faulty messages and subsequent release of inflammatory signals from cells grown in the laboratory. During these experiments it was also shown that solithromycin could restore the sensitivity of these cells to steroids. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female patients greater than 45 years of age. 2. History of cigarette smoking more than 10 pack-years. 3. FEV1/FVC of <0.70 and FEV1 of 30-79% of the predicted normal value. 4. Patients on prescribed inhaled corticosteroids can be enrolled. 5. Females of non-childbearing potential who are either surgically sterile (e.g. tubal ligation) or at least 2 years post-menopausal. 6. Females of childbearing potential (including females less than 2 years post-menopausal) who have a negative pregnancy test at enrollment and 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. 7. The patient must be a suitable candidate for oral therapy and be able to swallow capsules intact. 8. No evidence of active bacterial infection in sputum by qPCR evaluation.
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E.4 | Principal exclusion criteria |
1. Acute exacerbation of COPD within the previous 60 days. 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 which would require additional systemic antibiotics. 7. QTc greater than 470 msec 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).
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E.5 End points |
E.5.1 | Primary end point(s) |
The change in the number of sputum neutrophils per ml in patients treated with solithromycin (compared to any chnage with placebo). A differential cell count will be performed on fixed cytospin preparations stained with Diff-Quick. Comparisons will be made between the pre- and post- treatment values. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Data will be collected to evaluate this endpoint throughout the two treatment periods, each of 28 days. |
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E.5.2 | Secondary end point(s) |
To assess concentrations of sputum CXCL8, IL-6, MPO, MMP-9, and TNF-α, nasal CXCL8 and systemic biomarkers of inflammation (C-reative protein and fibrinogen) in patients treated with solithromycin compared to patients treated with placebo
To assess forced expiratory volume at 1 second (FEV1), forced vital capacity (FVC), resistance at 5Hz (R5) and the COPD Assessment Test (CAT) score in patients treated with solithromycin compared to patients treated with placebo
To assess the safety and tolerability of oral solithromycin in adult patients with COPD
An exploratory end point will be to assess the activity of HDAC2, PI3K, NF-κB (and potentially other cytokines/chemokines) in sputum macrophages from patients treated with solithromycin compared to those patients treated with placebo. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Data will be collected to evaluate this endpoint throughout the two treatment periods, each of 28 days. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial will be the follow up phone call after the last patient visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 1 |