An International, Multicenter, Randomized, Double-blind, Double-dummy, Two-way, Parallel Group, Controlled Study to Compare the Efficacy and Safety of Intravenous and Oral Nemonoxacin Versus Tavanic® in Adult Patients With Community-acquired Pneumonia

Sponsor

R-Pharm (Industry)

Overall Status

Completed

CT.gov ID

NCT03551210

Collaborator

OCT Clinical Trials (Other)

342

Enrollment

Locations

Arms

19.7

Actual Duration (Months)

13.7

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate the clinical efficacy of treatment with Nemonoxacin compared with Tavanic® in patients with community-acquired pneumonia (CAP).

Condition or Disease	Intervention/Treatment	Phase
Pneumonia, Bacterial	Drug: Nemonoxacin Drug: Nemonoxacin Drug: Tavanic Drug: Tavanic Drug: Placebo (250 ml) Drug: Placebo (100 ml)	Phase 3

Detailed Description

Treatment-naive patients with CAP and patients with treatment failure will be screened and if eligible will be randomized to receive either treatment with investigational product or comparator. Patients will start to receive intravenous therapy with Nemonoxacin or Tavanic® and then upon a decision of investigator patients will be switched to oral therapy with the same product.

Intravenous therapy will include two consequence infusions (antibiotic solution and placebo solution) to maintain blinding. Intravenous therapy should be given for at least 3 days and may be prolonged by a decision of investigator up to 7 days. Then investigator will switch a patient from intravenous to oral therapy on Day 4(8) of the study if the specific criteria of clinical stability are achieved. To maintain blinding during oral antibiotic therapy each Tavanic® tablet was placed into a capsule shell (over-encapsulated), that is identical in appearance to a Nemonoxacin-containing capsules.

The average duration of treatment (including intravenous and oral therapy) for each patient will be 7(14) days and during this period patients should stay at hospital. After completion of the treatment patients can be discharged from the hospital and should return for examinations within 1-2 days after the last dose (end of treatment visit). Then the patients should attend the investigational site within 7-9 days after the last dose (test of cure visit). Then the investigator will contact the patients by phone within 21-23 days after the last dose (long-term follow-up visit).

Study Design

Study Type:

Interventional

Actual Enrollment :

342 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

All eligible patients will be randomized to receive either treatment with Nemonoxacin or Tavanic® in a ratio of 1:1.All eligible patients will be randomized to receive either treatment with Nemonoxacin or Tavanic® in a ratio of 1:1.

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

An International, Multicenter, Randomized, Double-blind, Double-dummy, Two-way, Parallel Group, Controlled Study to Compare the Efficacy and Safety of Intravenous and Oral Nemonoxacin Versus Tavanic® in Adult Patients With Community-acquired Pneumonia

Actual Study Start Date :

May 4, 2016

Actual Primary Completion Date :

Dec 13, 2017

Actual Study Completion Date :

Dec 26, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nemonoxacin Nemonoxacin solution for infusion, 500 mg (250 ml), daily, as single intravenous infusion over 90-110 minutes followed by infusion of Placebo (100 ml), solution for infusion, over a minimum duration of 60 minutes. Then will be switched to oral therapy with Nemonoxacin capsules, 500 mg once daily (two 250 mg capsules).	Drug: Nemonoxacin Solution for infusion, 500 mg (250 ml) Drug: Nemonoxacin Capsules, 250 mg Drug: Placebo (100 ml) 0.9% NaCl (100 ml), solution for infusion
Active Comparator: Tavanic® Tavanic® solution for infusion, 500 mg (100 ml), daily, as single intravenous infusion over a minimum duration of 60 minutes with previous infusion of Placebo (250 ml), solution for infusion, over 90-110 minutes. Then will be switched to oral therapy with Tavanic®, over-encapsulated film coated tablets, 500 mg once daily (two capsules each containing 250 mg film coated tablet).	Drug: Tavanic Solution for infusion, 500 mg (100 ml) Other Names: Levofloxacin Drug: Tavanic Film coated tablets (each tablet is placed into a capsule shell (overencapsulated) for blinding purposes), 250 mg Other Names: Levofloxacin Drug: Placebo (250 ml) 0.9% NaCl (250 ml), solution for infusion

Arm

Intervention/Treatment

Experimental: Nemonoxacin

Nemonoxacin solution for infusion, 500 mg (250 ml), daily, as single intravenous infusion over 90-110 minutes followed by infusion of Placebo (100 ml), solution for infusion, over a minimum duration of 60 minutes. Then will be switched to oral therapy with Nemonoxacin capsules, 500 mg once daily (two 250 mg capsules).

Drug: Nemonoxacin

Solution for infusion, 500 mg (250 ml)

Drug: Nemonoxacin

Capsules, 250 mg

Drug: Placebo (100 ml)

0.9% NaCl (100 ml), solution for infusion

Active Comparator: Tavanic®

Tavanic® solution for infusion, 500 mg (100 ml), daily, as single intravenous infusion over a minimum duration of 60 minutes with previous infusion of Placebo (250 ml), solution for infusion, over 90-110 minutes. Then will be switched to oral therapy with Tavanic®, over-encapsulated film coated tablets, 500 mg once daily (two capsules each containing 250 mg film coated tablet).

Drug: Tavanic

Solution for infusion, 500 mg (100 ml)

Other Names:

Levofloxacin

Drug: Tavanic

Film coated tablets (each tablet is placed into a capsule shell (overencapsulated) for blinding purposes), 250 mg

Other Names:

Levofloxacin

Drug: Placebo (250 ml)

0.9% NaCl (250 ml), solution for infusion

Outcome Measures

Primary Outcome Measures

Number of patients with clinical success as judged by the investigator [Visit 4 (within 7-9 days after last dose)]
Clinical response is evaluated as clinical success if: all signs and symptoms of pneumonia are resolved or improved with no worsening or appearance of new signs and symptoms of pneumonia; there is no requirement for additional antibiotic therapy; chest roentgenograms (CT scans) are cured or improved

Secondary Outcome Measures

Number of patients with clinical success as judged by the investigator [Visit 2(day 4/8 ot treatment), Visit 3 (within 1-2 days after last dose)]
Clinical response is evaluated as clinical success if: all signs and symptoms of pneumonia are resolved or improved with no worsening or appearance of new signs and symptoms of pneumonia; there is no requirement for additional antibiotic therapy
Number of patients with infection relapse [Visit 5 (within 21-23 days after last dose)]
Time to switch therapy from intravenous to oral therapy [Up to Visit 2 (day 4/8 ot treatment)]
Number of patients required for other antibiotic treatment [Up to 21-23 days after last dose]
Number of patients with microbiological success [Visit 2 (day 4/8 ot treatment), 3 (within 1-2 days after last dose), 4 (within 7-9 days after last dose)]
Microbiological response is evaluated as microbiological success if culture study demonstrates eradication of pathogen or no material available for culture because of clinical success

Other Outcome Measures

Number of patients with Adverse Events [Up to 21-23 days after the last dose]
Number of patients with changes in vital signs [Up to 7-9 days after the last dose]
Number of patients with abnormal laboratory values [Up to 7-9 days after the last dose]
Number of patients with abnormal ECG changes [Up to 7-9 days after the last dose]
Cmax of Nemonoxacin [Day 1 pre-dose and 0, 0.5, 2.5, 4, 6, 12, 16 and 22.5 (= Day 2 pre-dose) hrs after the end of first infusion on Day 1 of treatment]
The peak Nemonoxacin concentration at Day 1-2 of treatment
C-22.5h of Nemonoxacin [22.5 hrs after the end of first infusion on Day 1 of treatment]
22.5-h drug concentration of Nemonoxacin
AUC (0-22.5) of Nemonoxacin [Day 1 pre-dose and 0, 0.5, 2.5, 4, 6, 12, 16 and 22.5 (= Day 2 pre-dose) hrs after the end of first infusion on Day 1 of treatment]
Area under the concentration-time curve from 0 to 22.5 h of Nemonoxacin
AUC(0-∞) of Nemonoxacin [Day 1 pre-dose and 0, 0.5, 2.5, 4, 6, 12, 16 and 22.5 (= Day 2 pre-dose) hrs after the end of first infusion on Day 1 of treatment]
Areas under the concentration-time curve from 0 h to infinity of Nemonoxacin
CL of Nemonoxacin [Day 1 pre-dose and 0, 0.5, 2.5, 4, 6, 12, 16 and 22.5 (= Day 2 pre-dose) hrs after the end of first infusion on Day 1 of treatment]
Total systemic clearance of Nemonoxacin
Vss of Nemonoxacin [Day 1 pre-dose and 0, 0.5, 2.5, 4, 6, 12, 16 and 22.5 (= Day 2 pre-dose) hrs after the end of first infusion on Day 1 of treatment]
Volume of distribution at steady state of Nemonoxacin
T1/2 of Nemonoxacin [Day 1 pre-dose and 0, 0.5, 2.5, 4, 6, 12, 16 and 22.5 (= Day 2 pre-dose) hrs after the end of first infusion on Day 1 of treatment]
Terminal elimination half-life of Nemonoxacin

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent obtained from the patient.
Patients with moderate to severe community-acquired pneumonia who need inpatient treatment but do not need intensive care unit treatment.
The presence of at least 3 of the following symptoms / signs:

cough;
purulent sputum production;
tachypnea (respiratory rate > 24 breathes/minute);
chills;
fever (rectal / tympanic temperature ≥ 38.5°C or axillary / oral / cutaneous temperature ≥ 38.5°C);
white blood cells (WBC) count of ≥ 10.0 x 10^9/L or ≥ 15% immature neutrophils (bands; regardless of peripheral WBC count).

Radiological evidence of (a) new infiltrate(s) consistent with bacterial pneumonia at baseline.
Treatment-naive patients or patients who have received single dose of a short-acting antibacterial drug within 24 hours of enrollment or patients with treatment failure who have received antibiotics (with the exception of quinolones or fluoroquinolones) for less than 72 hours.
Consent to use contraception during participation in the study (for women of childbearing potential and men).

Exclusion Criteria:

Known hypersensitivity to quinolones, fluoroquinolones or any of the excipients.
History of tendon disease / disorder related to quinolone treatment.
Known congenital or documented-acquired QT / QTc(F) prolongation on ECG (QTc(F) interval more than 450 ms); concomitant use of drugs, reported to increase the QT interval; uncorrected hypokalaemia and uncorrected hypomagnesemia; clinically relevant bradycardia; clinically relevant heart failure with reduced left-ventricular ejection fraction; previous history of symptomatic arrhythmias.
History of bronchiectasis, cystic fibrosis, bronchial obstructions excluding chronic obstructive pulmonary disease.
History of epilepsy and/or history of psychotic disorder.
Patients with history of myasthenia gravis.
Patients with diabetes mellitus.
Known glucose-6-phosphate dehydrogenase deficiency.
Active hepatitis or decompensated cirrhosis.
Alanine transaminase or aspartate transaminase increase > 3 fold upper limit of normal (ULN).
Patients with creatinine ≥ 1.1 fold ULN.
Patients requiring concomitant systemic or inhaled antibiotics (e.g., tobramycin).
Known or suspected active tuberculosis or endemic fungal infection.
Concomitant immunosuppressive therapy including a long-term (more than 2 weeks) treatment with oral or intravenous glucocorticoids at doses of 20 mg and higher of prednisone daily or an equivalent dose of other glucocorticoids.
Patients known to have HIV-positive status or AIDS or known to have other disease that seriously affects the immune system such as active haematological or solid organ malignancy, or splenectomy.
History of drug or alcohol abuse.
Patients have received quinolones or fluoroquinolones within 14 days before enrollment.
Previous enrolment in this study or participation in another study within the previous 4 weeks.
Patients with any severe medical condition as determined by medical history that, in the opinion of the investigator, does not allow the patient to carry out all planned procedure of the protocol.

Contacts and Locations

Locations

	Site	City	Country
1	Central city hospital #7	Ekaterinburg	Russian Federation
2	City clinical hospital #40	Ekaterinburg	Russian Federation
3	Regional budget healthcare institution "Ivanovo regional clinical hospital"	Ivanovo	Russian Federation
4	City clinical hospital #1 n.a. N.I. Pirogov of Moscow Healthcare Department	Moscow	Russian Federation
5	City Clinical hospital n.a. V. V. Vinogradov	Moscow	Russian Federation
6	FSOE Main Military Clinical Hospital n.a. academician N.N. Burdenko of the Ministry of Defence of the Russian Federation	Moscow	Russian Federation
7	SBHI Moscow City clinical hospital # 15 n.a. O.M. Filatov of Moscow Healthcare Department	Moscow	Russian Federation
8	City Clinical Hospital #25	Novosibirsk	Russian Federation
9	City clinical hospital #2	Novosibirsk	Russian Federation
10	SBHI of Novosibirsk region City Clinical Hospital of Emergency Medical Care №2	Novosibirsk	Russian Federation
11	Republic Hospital named after V.A. Baranov	Petrozavodsk	Russian Federation
12	Pskov regional clinical hospital	Pskov	Russian Federation
13	Baltic Medicine LLC	Saint Petersburg	Russian Federation
14	City Hospital #15	Saint Petersburg	Russian Federation
15	City Hospital #26	Saint Petersburg	Russian Federation
16	City hospital #38 n.a. N.A. Semashko	Saint Petersburg	Russian Federation
17	Mariinsky City Hospital	Saint Petersburg	Russian Federation
18	Multidisciplinary City Hospital # 2	Saint Petersburg	Russian Federation
19	Scientific Research Institute of Influenza of the Ministry of Healthcare of Russian Federation	Saint Petersburg	Russian Federation
20	Regional clinical hospital	Saratov	Russian Federation
21	Clinical hospital of emergency medical care	Smolensk	Russian Federation
22	Scientific Research Institute of Antimicrobial Therapy of Smolensk State Medical University	Smolensk	Russian Federation
23	Siberian State Medical University of the Ministry of Healthcare of Russian Federation	Tomsk	Russian Federation
24	Ulyanovsk Regional Clinical Hospital	Ulyanovsk	Russian Federation
25	Voronezh Regional Clinical Hospital #1	Voronezh	Russian Federation