Efficacy and Safety of Nemonoxacin vs Levofloxacin in Adult Patients With Community-Acquired Pneumonia

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

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

Study Overview

• Status: Completed
• Conditions: Pneumonia, Bacterial
• Intervention / Treatment: Drug: Nemonoxacin; Drug: Nemonoxacin; Drug: Placebo (100 ml); Drug: Tavanic; Drug: Tavanic; Drug: Placebo (250 ml)

Detailed Description

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

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

The average duration of treatment (including intravenous and oral therapy) for each patient was 7(14) days and during this period patients should have stayed at hospital. After completion of the treatment patients could have been discharged from the hospital and returned for examinations within 1-2 days after the last dose (end of treatment visit). Then the patients attended the investigational site within 7-9 days after the last dose (test of cure visit). Then the investigator contacted the patients by phone within 21-23 days after the last dose (long-term follow-up visit).

• Study Type: Interventional
• Enrollment (Actual): 342
• Phase: Phase 3

Contacts and Locations

Study Locations

• Russian Federation
  • Ekaterinburg, Russian Federation
    • Central City Hospital #7
  • Ekaterinburg, Russian Federation
    • City Clinical Hospital #40
  • Ivanovo, Russian Federation
    • Regional budget healthcare institution "Ivanovo regional clinical hospital"
  • Moscow, Russian Federation
    • City clinical hospital #1 n.a. N.I. Pirogov of Moscow Healthcare Department
  • Moscow, Russian Federation
    • City Clinical hospital n.a. V. V. Vinogradov
  • Moscow, Russian Federation
    • FSOE Main Military Clinical Hospital n.a. academician N.N. Burdenko of the Ministry of Defence of the Russian Federation
  • Moscow, Russian Federation
    • SBHI Moscow City clinical hospital # 15 n.a. O.M. Filatov of Moscow Healthcare Department
  • Novosibirsk, Russian Federation
    • City Clinical Hospital #25
  • Novosibirsk, Russian Federation
    • City Clinical Hospital #2
  • Novosibirsk, Russian Federation
    • SBHI of Novosibirsk region City Clinical Hospital of Emergency Medical Care №2
  • Petrozavodsk, Russian Federation
    • Republic Hospital named after V.A. Baranov
  • Pskov, Russian Federation
    • Pskov Regional Clinical Hospital
  • Saint Petersburg, Russian Federation
    • Baltic Medicine LLC
  • Saint Petersburg, Russian Federation
    • City Hospital #15
  • Saint Petersburg, Russian Federation
    • City Hospital #26
  • Saint Petersburg, Russian Federation
    • City hospital #38 n.a. N.A. Semashko
  • Saint Petersburg, Russian Federation
    • Mariinsky City Hospital
  • Saint Petersburg, Russian Federation
    • Multidisciplinary City Hospital # 2
  • Saint Petersburg, Russian Federation
    • Scientific Research Institute of Influenza of the Ministry of Healthcare of Russian Federation
  • Saratov, Russian Federation
    • Regional Clinical Hospital
  • Smolensk, Russian Federation
    • Clinical hospital of emergency medical care
  • Smolensk, Russian Federation
    • Scientific Research Institute of Antimicrobial Therapy of Smolensk State Medical University
  • Tomsk, Russian Federation
    • Siberian State Medical University of the Ministry of Healthcare of Russian Federation
  • Ulyanovsk, Russian Federation
    • Ulyanovsk Regional Clinical Hospital
  • Voronezh, Russian Federation
    • Voronezh Regional Clinical Hospital #1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. cough;
  2. purulent sputum production;
  3. tachypnea (respiratory rate > 24 breathes/minute);
  4. chills;
  5. fever (rectal / tympanic temperature ≥ 38.5°C or axillary / oral / skin temperature ≥ 38.5°C);
  6. 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.
• Female patients who are pregnant or nursing.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Clinical Success as Judged by the Investigator	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	Visit 4 (within 7-9 days after last dose)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Clinical Success as Judged by the Investigator	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	Visit 2(day 4/8 ot treatment), Visit 3 (within 1-2 days after last dose)
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	Microbiological response is evaluated as microbiological success if culture study demonstrates eradication of pathogen or no material available for culture because of clinical success	Visit 2 (day 4/8 ot treatment), 3 (within 1-2 days after last dose), 4 (within 7-9 days after last dose)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nemnoxacin Concentration Changes	Cmax - The peak Nemonoxacin concentration at Day 1-2 of treatment C-22.5hours - 22.5-h drug concentration 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 (AUC) of Nemonoxacin	AUC (0-22.5) - Area under the concentration-time curve from 0 to 22.5 hours of Nemonoxacin AUC(0-∞) - Areas under the concentration-time curve from 0 h to infinity 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
Сlearance (CL) of Nemonoxacin	Total systemic clearance 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 (Vss) of Nemonoxacin	Volume of distribution at steady state 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 (T1/2) of Nemonoxacin	Terminal elimination half-life 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

Collaborators and Investigators

• Sponsor: R-Pharm
• Collaborators: OCT Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2016
• Primary Completion (Actual): December 13, 2017
• Study Completion (Actual): December 26, 2017

Study Registration Dates

• First Submitted: May 28, 2018
• First Submitted That Met QC Criteria: May 28, 2018
• First Posted (Actual): June 11, 2018

Study Record Updates

• Last Update Posted (Estimate): February 16, 2023
• Last Update Submitted That Met QC Criteria: January 18, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: community-acquired pneumonia; quinolones; nemonoxacin
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Pneumonia; Pneumonia, Bacterial; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Anti-Infective Agents, Urinary; Renal Agents; Levofloxacin; Ofloxacin
• Other Study ID Numbers: CJ01060044

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No