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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03551210

Enrollment

342

Registered

2018-06-11

Start date

2016-05-04

Completion date

2017-12-26

Last updated

2023-02-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pneumonia, Bacterial

Keywords

nemonoxacin, community-acquired pneumonia, quinolones

Brief summary

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).

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).

Interventions

DRUGNemonoxacin

Solution for infusion, 500 mg (250 ml)

DRUGTavanic

Solution for infusion, 500 mg (100 ml)

DRUGPlacebo (250 ml)

0.9% NaCl (250 ml), solution for infusion

DRUGPlacebo (100 ml)

0.9% NaCl (100 ml), solution for infusion

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Intervention model description

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

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

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: 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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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

Measure	Time frame	Description
Area Under the Concentration-time Curve (AUC) 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	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
Сlearance (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
Volume of Distribution at Steady State (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
Terminal Elimination Half-life (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
Nemnoxacin Concentration Changes	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	Cmax - The peak Nemonoxacin concentration at Day 1-2 of treatment C-22.5hours - 22.5-h drug concentration of Nemonoxacin

Countries

Russia

Participant flow

Recruitment details

The recruitment of subjects was conducted by 25 clinical sites in Russia between May 2016 and 2017. Totally 356 patients were screened and 342 eligible patients were randomized to receive Nemonoxacin or Tavanic in 1:1 ratio (171 subjects in each group).

Participants by arm

Arm	Count
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). Nemonoxacin: Solution for infusion, 500 mg (250 ml) Nemonoxacin: Capsules, 250 mg Placebo (100 ml): 0.9% NaCl (100 ml), solution for infusion	169
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). Tavanic: Solution for infusion, 500 mg (100 ml) Tavanic: Film coated tablets (each tablet is placed into a capsule shell (overencapsulated) for blinding purposes), 250 mg Placebo (250 ml): 0.9% NaCl (250 ml), solution for infusion	166
Total	335

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Absence of visit 4 and 5	1	0
Overall Study	Adverse Event	5	6
Overall Study	Lost to Follow-up	1	1
Overall Study	Needed in other antibiotic treatment	2	5
Overall Study	No drug for dispensing	0	1
Overall Study	Withdrawal by Subject	1	7

Baseline characteristics

Characteristic	Nemonoxacin	Tavanic®	Total
Age, Continuous	42.0 years	43.3 years	42.6 years
Body Mass Index (BMI)	25.4 kg/m^2 STANDARD_DEVIATION 5.4	26.1 kg/m^2 STANDARD_DEVIATION 5.6	25.8 kg/m^2 STANDARD_DEVIATION 5.5
Race/Ethnicity, Customized Asian	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized European	168 Participants	166 Participants	334 Participants
Sex: Female, Male Female	66 Participants	66 Participants	132 Participants
Sex: Female, Male Male	103 Participants	100 Participants	203 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 171	0 / 169
other Total, other adverse events	86 / 171	67 / 169
serious Total, serious adverse events	0 / 171	2 / 169

Outcome results

Primary

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

Time frame: Visit 4 (within 7-9 days after last dose)

Population: Modified Intent-To-Treat population (mITT) - all randomized patients received at least one dose of investigational drugs, in compliance with at lest minimal disease criteria (inclusion criteria 3 and 4) and had at least one assessment of clinical efficacy in this study

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Nemonoxacin	Number of Patients With Clinical Success as Judged by the Investigator	Clinical success	158 Participants
Nemonoxacin	Number of Patients With Clinical Success as Judged by the Investigator	Clinical non-efficacy	6 Participants
Nemonoxacin	Number of Patients With Clinical Success as Judged by the Investigator	Indefinite response	5 Participants
Tavanic®	Number of Patients With Clinical Success as Judged by the Investigator	Clinical success	145 Participants
Tavanic®	Number of Patients With Clinical Success as Judged by the Investigator	Clinical non-efficacy	8 Participants
Tavanic®	Number of Patients With Clinical Success as Judged by the Investigator	Indefinite response	13 Participants

95% CI: [-0.7, 13]

p-value: =0.49995% CI: [0.49, 4.29]Regression, Logistic

Secondary

Number of Patients Required for Other Antibiotic Treatment

Time frame: Up to 21-23 days after last dose

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Nemonoxacin	Number of Patients Required for Other Antibiotic Treatment	2 Participants
Tavanic®	Number of Patients Required for Other Antibiotic Treatment	5 Participants

p-value: =0.26Barnard test

Secondary

Number of Patients With Clinical Success as Judged by the Investigator

Time frame: Visit 2(day 4/8 ot treatment), Visit 3 (within 1-2 days after last dose)

Arm	Measure	Group	Category	Value (COUNT_OF_PARTICIPANTS)
Nemonoxacin	Number of Patients With Clinical Success as Judged by the Investigator	Visit 2	Clinical success	164 Participants
Nemonoxacin	Number of Patients With Clinical Success as Judged by the Investigator	Visit 2	Clinical non-efficacy	4 Participants
Nemonoxacin	Number of Patients With Clinical Success as Judged by the Investigator	Visit 2	Indefinite response	1 Participants
Nemonoxacin	Number of Patients With Clinical Success as Judged by the Investigator	Visit 3	Clinical success	160 Participants
Nemonoxacin	Number of Patients With Clinical Success as Judged by the Investigator	Visit 3	Clinical non-efficacy	6 Participants
Nemonoxacin	Number of Patients With Clinical Success as Judged by the Investigator	Visit 3	Indefinite response	3 Participants
Tavanic®	Number of Patients With Clinical Success as Judged by the Investigator	Visit 3	Clinical non-efficacy	7 Participants
Tavanic®	Number of Patients With Clinical Success as Judged by the Investigator	Visit 2	Clinical success	154 Participants
Tavanic®	Number of Patients With Clinical Success as Judged by the Investigator	Visit 3	Clinical success	151 Participants
Tavanic®	Number of Patients With Clinical Success as Judged by the Investigator	Visit 2	Clinical non-efficacy	5 Participants
Tavanic®	Number of Patients With Clinical Success as Judged by the Investigator	Visit 3	Indefinite response	8 Participants
Tavanic®	Number of Patients With Clinical Success as Judged by the Investigator	Visit 2	Indefinite response	7 Participants

Comparison: Visit 2p-value: =0.0895% CI: [-0.6, 9.7]Barnard's test

Comparison: Visit 3p-value: =0.24695% CI: [-2, 9.8]Barnard's test

Secondary

Number of Patients With Infection Relapse

Time frame: Visit 5 (within 21-23 days after last dose)

Population: All patients of mITT population achieved clinical success on Visit 4

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Nemonoxacin	Number of Patients With Infection Relapse	0 Participants
Tavanic®	Number of Patients With Infection Relapse	2 Participants

p-value: =0.154Barnard test

Secondary

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

Time frame: Visit 2 (day 4/8 ot treatment), 3 (within 1-2 days after last dose), 4 (within 7-9 days after last dose)

Population: b-mITT - Patients in the mITT population whose bacterial culture had at least one baseline bacterial isolate

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Nemonoxacin	Number of Patients With Microbiological Success	Visit 2	17 Participants
Nemonoxacin	Number of Patients With Microbiological Success	Visit 3	19 Participants
Nemonoxacin	Number of Patients With Microbiological Success	Visit 4	19 Participants
Tavanic®	Number of Patients With Microbiological Success	Visit 2	16 Participants
Tavanic®	Number of Patients With Microbiological Success	Visit 3	16 Participants
Tavanic®	Number of Patients With Microbiological Success	Visit 4	16 Participants

p-value: =0.14Barnard's test

p-value: 0.515Barnard's test

Secondary

Time to Switch Therapy From Intravenous to Oral Therapy

Time frame: Up to Visit 2 (day 4/8 ot treatment)

Arm	Measure	Value (MEDIAN)
Nemonoxacin	Time to Switch Therapy From Intravenous to Oral Therapy	4 days
Tavanic®	Time to Switch Therapy From Intravenous to Oral Therapy	4 days

p-value: =0.14Log Rank

Other Pre-specified

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

Time frame: 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