| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001032 |
| E.1.2 | Term | Acute pyelonephritis |
| E.1.2 | System Organ Class | 100000004862 |
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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 |
| To evaluate the efficacy of intravenous (iv) and iv to oral (iv/po) dosing regimens of omadacycline and levofloxacin in the treatment of adults with Acute Pyelonephritis (AP) |
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| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety of omadacycline in the treatment of adults with AP.
- To evaluate the pharmacokinetics (PK) of omadacycline in adults with AP. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Written and signed informed consent must be obtained before any assessment is performed.
2.a. Females age 18-65 years.
b. Females age 18 years or older.
Inclusion 2a will be followed for first 100 subjects enrolled. Following an interim analysis, see adaptive design section for additional information, inclusion 2b may be allowed. An administrative memo will be issued to sites to formally notify them if/when Inclusion 2b will be followed. No subjects >65 years may be enrolled until an administrative memo is received and acknowledged by the investigator.
3. Clinical signs and symptoms of acute uncomplicated pyelonephritis with onset or worsening within 96 hours prior to randomization. Clinical signs and symptoms are defined as:
• Flank pain or costovertebral angle tenderness on physical examination plus at least one of the following:
- Chills or rigors or warmth associated with fever (oral, tympanic, rectal or core temperature > 38°C [> 100.4°F], which must be observed and documented by a health care provider), or
- Nausea or Vomiting
4. A clean-catch midstream urine sample with dipstick analysis positive (at least ++) for leukocyte esterase or pyuria (white blood cell [WBC] count > 10/μL in unspun urine or ≥ 10 per high power field in spun urine sediment).
5. Female subjects must have a negative pregnancy test at Screening, and agree to comply with using an acceptable form of birth control (eg, abstinence, oral contraceptive, intrauterine device [IUD], barrier contraception [condom], tubal ligation, hysterectomy, bilateral oophorectomy, postmenopausal or vasectomized partner) from Screening through PTE.
6. Ability to communicate well with the investigator, to understand and comply with the requirements of the study.
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| E.4 | Principal exclusion criteria |
1. Pregnant or nursing (breastfeeding) women.
2. Receipt of any dose of a potentially therapeutic antibacterial agent from 72 hours prior to randomization until the first dose of test article.
3. Anticipated need for systemic antibacterial therapy other than test article during the study period.
4. Infection at baseline that in the Investigator’s judgment would require more than 10 days of antibacterial therapy.
5. Symptoms of AP present longer than 7 days prior to randomization.
6. Confirmed or suspected AP caused by a pathogen that is resistant to tetracyclines or fluoroquinolones, including infection caused by fungi or mycobacteria.
7. Known or suspected rapidly-progressing or life-threatening illness including septic shock. Septic shock can be identified using the clinical criteria of hypotension requiring vasopressor therapy to maintain mean arterial blood pressure of 65mmHg or greater and having a serum lactate level greater than 2 mmol/L after adequate fluid resuscitation.
8. Use of an indwelling urinary catheter, nephrostomy tubes or other indwelling urinary tract device within the 30 days prior to randomization.
9. Confirmed or suspected urinary retention from any cause, including neurogenic bladder or obstruction.
10. History of surgically modified or abnormal urinary tract anatomy (eg, bladder diverticula or redundant urine collection system).
11. Confirmed or suspected complete or partial obstruction of the urinary tract, or obstructive uropathy that is scheduled to be medically or surgically relieved during the study therapy period.
12. Confirmed or suspected renal disease or condition that, in the opinion of the investigator, may confound the assessment of efficacy, including but not limited to the following:
•Perinephric or intrarenal abscess
•Emphysematous pyelonephritis
•Chronic pyelonephritis, including xanthogranulomatous pyelonephritis
•Polycystic kidney disease
•Renal carcinoma
13. History of renal transplant or a surgically created intestinal conduit for urinary diversion.
14. Suspected or confirmed non-renal source of infection.
15. Confirmed or suspected vaginitis or sexually transmitted infection or lower UTI without symptoms/signs of AP.
16. Has any of the following at Screening:
• ALT or aspartate aminotransferase (AST) ≥ 3 × Upper Limit of Normal (ULN)
• total bilirubin > 1.5 × ULN
• suspected or confirmed clinical evidence of end-stage liver disease (eg, ascites, hepatic encephalopathy)
17. History of unstable cardiac disease within the 3 months prior to randomization.
18. Significant immunological disease determined by any of the following:
•Current or anticipated neutropenia defined as less than 500 neutrophils/mm3
•Known infection with Human Immunodeficiency Virus (HIV) and a cluster of differentiation 4 (CD4) count that is unknown or documented to be less than 200 cells/mm3 within the last year, or other Acquired Immune Deficiency Syndrome (AIDS) defining illness as determined by the investigator.
19. Receipt of cancer chemotherapy, radiotherapy, or potent, non corticosteroid immunosuppressant drugs within the 3 months prior to randomization, or the receipt of systemic corticosteroids equivalent to or greater than 40 mg of prednisone per day (see equivalent corticosteroid doses in Appendix 2) or 40 mg of prednisone per day for more than 14 days in the 30 days prior to randomization.
20. History of hypersensitivity or allergic reaction to any tetracycline or fluoroquinolone antibiotic.
21. Inability to swallow 6 tablets in succession.
22. History of pseudotumor cerebri, or prior (within 2 weeks prior to randomization) or planned concomitant use of isotretinoin.
23. History of systemic lupus erythematosus or lupus-like syndrome.
24. Has current evidence of pancreatitis.
25. History of myasthenia gravis.
26. Screening calculated creatinine clearance (CrCl) < 50 mL/minute, using the Cockcroft Gault equation, requires any form of dialysis, or other evidence of severe renal disease.
27. History of tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, or central nervous system effects .
28. Has a QT interval > 500 msec, or known long QT syndrome.
29. Current use of antiarrhythmic agents of Class IA (eg, quinidine, procainamide) or Class III (eg, amiodarone, sotalol).
30. Use of other investigational drugs within 5 half-lives or 30 days prior to randomization, whichever is longer.
31. Has previously been treated with omadacycline or previously enrolled in this study.
32. Unable or unwilling, in the opinion of the investigator, to comply with the protocol requirements, or has any concomitant condition or planned medical intervention that, in the opinion of the investigator, is likely to interfere with evaluation of the response of the infection under study, determination of AEs, or completion of the expected course of treatment.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy outcome is overall response at the Post Therapy Evaluation (PTE) Visit in the microbiological intent-to-treat (micro-ITT) population, which is a composite of per-subject microbiologic response and investigator’s assessment of clinical response. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Safety endpoints: all treatment-emergent adverse events (TEAEs).
Efficacy endpoints: the number and percentage of subjects with an overall response of success, failure and indeterminate at the EOT (micro-ITT and microbiologically evaluable (ME) populations) and PTE Visits will be determined by treatment group. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety endpoints: at each Visit;
Efficacy endpoints: at the EOT and PTE Visits. |
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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 | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Georgia |
| Latvia |
| Russian Federation |
| Ukraine |
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| 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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| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| 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 | 0 |
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