- Email: [email protected]
A randomized, double-blind, multicenter Phase II study comparing the efficacy and safety of oral nemonoxacin with oral levofloxacin in the treatment of community-acquired pneumonia
Accepted Manuscript A randomized, double-blind, multicenter phase II study comparing the efficacy and safety of oral nemonoxacin with oral levofloxacin in the treatment of communityacquired pneumonia Yang Liu, Yingyuan Zhang, Jufang Wu, Demei Zhu, Shenghua Sun, Li Zhao, Xuefeng Wang, Hua Liu, Zhenyi Ren, Changzheng Wang, Qingyu Xiu, Zuke Xiao, Zhaolong Cao, Shehuai Cui, Heping Yang, Yongjie Liang, Ping Chen, Yuan Lv, Chengping Hu, Xiaoju Lv, Shuang Liu, Jiulong Kuang, Jianguo Li, Dexi Wang, Liwen Chang PII:
S1684-1182(15)00915-9
DOI:
10.1016/j.jmii.2015.09.005
Reference:
JMII 723
To appear in:
Journal of Microbiology, Immunology and Infection
Received Date: 15 September 2015 Accepted Date: 25 September 2015
Please cite this article as: Liu Y, Zhang Y, Wu J, Zhu D, Sun S, Zhao L, Wang X, Liu H, Ren Z, Wang C, Xiu Q, Xiao Z, Cao Z, Cui S, Yang H, Liang Y, Chen P, Lv Y, Hu C, Lv X, Liu S, Kuang J, Li J, Wang D, Chang L, A randomized, double-blind, multicenter phase II study comparing the efficacy and safety of oral nemonoxacin with oral levofloxacin in the treatment of community-acquired pneumonia, Journal of Microbiology, Immunology and Infection (2015), doi: 10.1016/j.jmii.2015.09.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT ORIGINAL ARTICLE
2
A randomized, double-blind, multicenter phase II study comparing the efficacy and
3
safety of oral nemonoxacin with oral levofloxacin in the treatment of
4
community-acquired pneumonia
5
Yang Liua,b, Yingyuan Zhanga,b,*, Jufang Wua,b, Demei Zhua,b, Shenghua Sunc, Li Zhaod, Xuefeng Wange,
6
Hua Liuf, Zhenyi Reng, Changzheng Wangh, Qingyu Xiui, Zuke Xiaoj, Zhaolong Caok, Shehuai Cuil, Heping
7
Yangm, Yongjie Liangn, Ping Cheno, Yuan Lvp, Chengping Huq, Xiaoju Lvr, Shuang Lius, Jiulong Kuangt,
8
Jianguo Liu, Dexi Wangv, and Liwen Changw
9
a
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China
10
b
China Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China
11
c
Department of Respiratory Medicine, The Third Xiangya Hospital, Central South University, Hunan, China
12
d
Department of Respiratory Medicine, Shengjing Hospital, China Medical University, Liaoning, China
13
e
Department of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University, Zhejiang, China
14
f
Department of Respiratory Medicine, Gansu Provincial People’s Hospital, Lanzhou, China
15
g
Department of Respiratory Medicine, Hangzhou First People’s Hospital, Zhejiang, China
16
h
Department of Respiratory Medicine, Xinqiao Hospital, The Third Military Medical University,
17
Chongqing, China
18
i
19
Shanghai, China
20
j
Department of Respiratory Medicine, Jiangxi Provincial People’s Hospital, Jiangxi, China
21
k
Department of Respiratory Medicine, Peking University People’s Hospital, Beijing, China
22
l
AC C
EP
TE D
M AN U
SC
RI PT
1
Department of Respiratory Medicine, Changzheng Hospital, The Second Military Medical University,
Department of Respiratory Medicine, Daping Hospital, The Third Military Medical University, Chongqing,
1
ACCEPTED MANUSCRIPT 23
China
24
m
25
Chongqing, China
26
n
Department of Respiratory Medicine, East Hospital, Tongji University, Shanghai, China
27
o
Department of Respiratory Medicine, The General Hospital of Shenyang Military Command, Liaoning,
28
China
29
p
Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China
30
q
Department of Respiratory Medicine, Xiangya Hospital, Central South University, Hunan, China
31
r
Center for Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
32
s
Department of Respiratory Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
33
t
Department of Respiratory Medicine, The Second Affiliated Hospital, Nanchang University, Jiangxi, China
34
u
35
Guangdong, China
36
v
Department of Respiratory Medicine, Guangzhou Red Cross Hospital, Guangdong, China
37
w
TaiGen Biotechnology Co., Ltd., Taipei, Taiwan
38
Running title: Nemonoxacin versus Levofloxacin in Treatment of CAP
39
* Corresponding author. Institute of Antibiotics, Huashan Hospital, Fudan University, 12 Middle Wulumuqi
40
Road, Shanghai 200040, China. Tel.: +86 21 52888190; fax: +86 21 62484347
41
E-mail address: [email protected] (Y-Y. Zhang)
42
ClinicalTrials.gov identifier: NCT01537250
43
KEYWORDS: clinical trial; community-acquired pneumonia; efficacy; nenomoxacin; safety
M AN U
SC
RI PT
Department of Respiratory Medicine, Southwest Hospital, The Third Military Medical University,
AC C
EP
TE D
Department of Respiratory Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University,
2
ACCEPTED MANUSCRIPT Abstract
45
Background/Purpose: To compare the clinical efficacy and safety of nemonoxacin with levofloxacin in the
46
treatment of community-acquired pneumonia (CAP) in a phase II clinical trial.
47
Methods: A total of 192 CAP patients were randomized to receive oral nemonoxacin (500 mg or 750 mg) or
48
levofloxacin (500 mg) once daily for 7-10 days. Clinical and bacteriological responses were determined at
49
test of cure (TOC) visit in full analysis set (FAS).
50
Results: The clinical cure rate of nemonoxacin 500 mg, nemonoxacin 750 mg and levofloxacin 500 mg was
51
93.3%, 87.3%, 88.5%, respectively in FAS (n=168); and 93.0%, 93.9%, 88.9%, respectively in per-protocol
52
set (n=152). Either 500 mg or 750 mg nemonoxacin was proved noninferior to levofloxacin 500 mg at TOC
53
visit in FAS in terms of clinical efficacy. Overall bacteriological success rate was 83.3% in both
54
nemonoxacin groups and 80.0% in levofloxacin 500 mg group in bacteriological FAS. The comprehensive
55
efficacy rate was comparable among the three groups (87.5% for nemonoxacin 500 mg, 93.8% for
56
nemonoxacin 750 mg and 81.3% for levofloxacin 500 mg group). Most of the drug-related adverse events
57
were mild and moderate gastrointestinal symptoms including nausea and vomiting, transient neutropenia and
58
elevated liver enzymes. No drug-related serious adverse events were observed. Conclusion: Oral
59
nemonoxacin, either 500 mg or 750 mg, once daily for 7-10 days demonstrated high clinical and
60
bacteriological success rates in Chinese adult CAP patients. Nemonoxacin 500 mg once daily for 7-10 days
61
will be recommended in future phase III clinical trials.
SC
M AN U
TE D
EP
AC C
62
RI PT
44
63
3
ACCEPTED MANUSCRIPT Introduction
65
Community-acquired pneumonia (CAP) is a common lower respiratory tract infection with high morbidity
66
and mortality.1,2 CAP can be caused by a variety of pathogens, e.g. Streptococcus pneumoniae, Haemophilus
67
influenzae and Mycoplasma pneumoniae.3,4 In recent years the emergence and spread of antibiotic-resistant
68
pathogens has become big challenge in clinical management of CAP. The CHINET bacterial resistance
69
surveillance data in 2013 showed that the prevalence of penicillin-intermediate (PISP) or penicillin-resistant
70
S. pneumoniae (PRSP) increased up to 32.9% (PISP 11.6%, PRSP 21.3%) and 9.4% (PISP 5.4%, PRSP 4.0%)
71
in children and adult isolates, respectively.5 Surveillance studies also showed the high prevalence of S.
72
pneumoniae strains resistant to erythromycin or clindamycin, especially in PISP and PRSP strains.6
73
Quinolone drugs are active against CAP pathogens including penicillin non-susceptible S. pneumoniae and
74
were recommended for adult CAP.2
SC
M AN U
Nemonoxacin, a non-fluorinated quinolone targeting DNA gyrase and topoisomerase IV, has
TE D
75
RI PT
64
broad-spectrum activity against gram-positive and some atypical pathogens, including penicillin-resistant S.
77
pneumoniae and methicillin-resistant S. aureus (MRSA).7-9,10,11 Nemonoxacin is also active against
78
gram-negative bacteria such as H. influenzae and K. pneumoniae.7,11 A study in mice showed that the
79
efficacy of nemonoxacin was better than that of levofloxacin in the treatment of gram-positive bacterial
80
infections, including those caused by PRSP and MRSA.12
AC C
81
EP
76
Phase I studies have been previously conducted in healthy volunteers in the United States and China to
82
examine the safety and clinical pharmacokinetics (PK) of nemonoxacin following single and multiple oral
83
doses.6,13-14 Results showed that after oral administration, nemonoxacin was absorbed rapidly and well
84
tolerated. Nemonoxacin attained peak plasma concentration (Cmax) within 1-2 hours after oral administration
85
and exhibited a linear PK profile within the dose range of 250-750 mg and moderate food effects. Cmax
4
ACCEPTED MANUSCRIPT 86
(AUC0-∞) was dose-dependent after multiple doses. Nemonoxacin was excreted primarily in urine. About
87
60-70% of the drug was eliminated within 72 hours in unchanged form. The elimination half-life was 9-16
88
hours. There was no accumulation following administration for 10 consecutive days.6,13 Van Rensburg et al reported a clinical trial investigating the efficacy and safety of nemonoxacin
RI PT
89
compared with that of levofloxacin in CAP outpatients in 2010.15 The results showed that nemonoxacin was
91
noninferior to levofloxacin in either the evaluable intent-to-treat (ITT) or clinical per protocol (PPc)
92
populations. Both treatments were well tolerated without any serious drug-related adverse reaction.
SC
90
We conducted a randomized, double-blind, multicenter clinical trial to evaluate the safety and efficacy
94
of 500 mg and 750 mg oral doses of nemonoxacin compared with 500 mg levofloxacin, once daily for 7-10
95
days in the treatment of CAP patients in Chinese population.
96
Methods
97
Study design
98
A phase II, randomized, double blind, double dummy, multicenter study was designed to compare the
99
efficacy and safety of oral nemonoxacin with those of levofloxacin in Chinese adult CAP patients. The
TE D
M AN U
93
primary objective of this study was to demonstrate the noninferiority of nemonoxacin versus levofloxacin
101
with regard to safety and clinical efficacy. The study was conducted in compliance with good clinical
102
practice guidelines and the Declaration of Helsinki. The study protocol was approved by the Ethics
103
Committees of all participating institutions. All subjects provided their written informed consent before
104
enrollment in the study.
105
Study treatments
106
Eligible subjects were randomized during the period from August 2009 to August 2010 to one of the three
107
treatment groups in a 1:1:1 ratio to receive oral dose of 500 mg or 750 mg nemonoxacin (TaiGen
AC C
EP
100
5
ACCEPTED MANUSCRIPT Biotechnology Co., Ltd., Taiwan) or 500 mg levofloxacin and the matched placebo, once daily for 7-10 days.
109
The first dose was administered on site in the clinic immediately after enrollment. As for all the subsequent
110
doses, patients took their study drug in the morning after an overnight fast and before breakfast.
111
Patients: inclusion criteria
112
Male or female subjects were eligible if they were 18-70 years of age, body weight within the range of
113
40-100 kg, body mass index (BMI) ≥ 18 kg/m2, and had diagnosis of mild to moderate CAP. Diagnosis was
114
based on two or more of the following clinical manifestations and a chest radiograph showing the presence
115
of a new lobar or multilobar infiltrates consistent with CAP within 48 h. Clinical manifestations included: (1)
116
productive cough with purulent sputum or deterioration of existing respiratory symptoms; (2) fever (oral
117
temperature ≥ 37.3°C); (3) evidence of pulmonary consolidation and/or rales; (4) peripheral white blood cell
118
count > 10×109 /L or < 4×109 /L or neutrophils > 70%. The above-mentioned (2) or (4) must be present when
119
subjects were enrolled.
120
Patients: exclusion criteria
121
Pregnant or lactating women were excluded from the study. Subjects were also excluded if they had any of
122
the following conditions: active tuberculosis, bronchiectasis, lung abscess, aspiration pneumonia, lung
123
malignancies, non-infectious interstitial lung disease, pulmonary edema, atelectasis, pulmonary embolism,
124
pulmonary eosinophilia or pulmonary vasculitis; nosocomial pneumonia; history of hypersensitivity or
125
allergic reaction to any quinolone; history of epilepsy, mental disorders or other diseases of central nervous
126
system; renal failure; liver dysfunction; malabsorption syndrome or other gastrointestinal disease;
127
immunodeficiency such as HIV infection, CD4+ < 200/mm3 or neutropenia, or blood or solid organ
128
malignancies; long-term use of steroids; severe pneumonia; 12-lead ECG showing abnormal cardiac
129
conduction or QT interval prolongation (male QTc > 430 ms, female QTc > 450 ms); treatment with
AC C
EP
TE D
M AN U
SC
RI PT
108
6
ACCEPTED MANUSCRIPT chemotherapeutic drugs or oncolytics within 6 months before randomization, or requiring such agents during
131
the trial; alcohol or drug abuse; administration of any quinolone within 2 weeks before randomization;
132
received any investigational drug within 3 months before enrollment; donation of 500 ml blood within 3
133
months; requiring combined antimicrobial therapy due to dual infection.
134
Primary and secondary endpoints
135
Clinical response at test of cure (TOC) visit (7 to 10 days post-treatment) was the primary efficacy endpoint
136
of this study. The clinical efficacy were defined as: clinical cure (complete resolution of all signs and
137
symptoms of pneumonia, or recovered to pretreatment state), clinical failure (persistence or worsening of
138
signs and symptoms after therapy, or emergence of new pneumonia-related symptoms or signs and/or use of
139
other antimicrobial therapy targeting pneumonia; or discontinuation within 3 days after initiation of study
140
treatment due to adverse drug reaction), and unevaluable (missing posttreatment information, or use of
141
systemic antimicrobial agents for other indications not permitted by protocol, or early discontinuation of
142
treatment due to other causes unrelated to the study drug).
SC
M AN U
TE D
143
RI PT
130
Secondary endpoints included clinical and bacteriological response at the end of treatment in full analysis set and per-protocol set and at the TOC in per-protocol set.
145
Microbiological assessment
146
Sputum samples were collected by every reasonable effort for Gram stain and culture before the first dose of
147
study drug. Atypical pathogens were identified by serological assay. Microbiological response was
148
categorized as: eradication (original pathogen[s] was absent at TOC visit), presumed eradication (subject
149
was considered clinically cured, and a repeat sputum/blood culture was absent), and persistence (original
150
pathogen[s] persisted at the TOC visit), and presumed persistence (subject still had clinical signs and
151
symptoms and a repeat sputum culture was absent). Antimicrobial susceptibility test of nemonoxacin and
AC C
EP
144
7
ACCEPTED MANUSCRIPT levofloxacin was carried out by microdilution assay based on Clinical and Laboratory Standard Institute
153
(CLSI) document M100-S21. Only patients with positive admission cultures were included in the analysis of
154
bacteriological response.
155
Comprehensive efficacy assessment
156
The clinically evaluable subjects with positive bacterial culture at baseline were included for comprehensive
157
assessment. The clinical signs and symptoms, radiologic and laboratory tests and microbiological
158
examination were combined to evaluate the comprehensive efficacy. Comprehensive response was
159
categorized as: cure (at TOC visit, clinical response was cure and microbiological response was eradication
160
or presumed eradication) and failure (at TOC visit, clinical response was failure or microbiological response
161
was persistence or presumed persistence). Comprehensive efficacy was evaluated as failure if one of the
162
clinical or microbiological responses was failure and another missing, and unknown if one of the clinical or
163
microbiological responses was cure / (presumed) eradication and the other was missing.
164
Safety assessment
165
All clinical and laboratory adverse events that occurred during clinical trial were carefully observed and
166
recorded for all subjects who received at least one dose of the study drug. The adverse events were
167
categorized as definitely related, probably related, possibly related, possibly unrelated or definitely unrelated
168
according to their relation to the study drug.
169
Patient populations
170
The following five patient populations were defined in this study for analysis of clinical and microbiological
171
efficacy.
172 173
AC C
EP
TE D
M AN U
SC
RI PT
152
Full analysis set (FAS): All subjects were included in the full analysis set except for those not receiving any study drug; without the target disease; non-compliant with good clinical practice; or missing the
8
ACCEPTED MANUSCRIPT 174
follow-up information after first visit. Per protocol set (PPS): All subjects in FAS were included in the per protocol set except for those
176
inadequately enrolled with an exclusion criterion; requiring treatment with other effective antibiotics, but not
177
including those who were evaluated as failure at the end of treatment and then received other antibiotic
178
therapy; or non-compliant patients evidenced by taking less than 80% or more than 120% of his/her
179
prescribed dose.
182 183 184 185 186
SC
primary efficacy endpoint of this study.
M AN U
181
FAS and PPS were applicable for efficacy analysis. Clinical response at the TOC visit in FAS was the
Safety set (SS): All subjects who received at least one dose of the study drug will be included in safety set. SS was applicable for safety analysis.
Bacteriological full analysis set (BFAS): All subjects in FAS whose first sputum culture or blood culture was positive were included.
TE D
180
RI PT
175
Bacteriological per protocol set (BPPS): All subjects in PPS whose first sputum culture or blood culture was positive were included.
188
Statistical analysis
189
SAS 9.1.3 software was used for all statistical analysis. Noninferiority was defined as the lower limit of the
190
95% CI for the difference between groups being greater than -15%. In addition to noninferiority analysis,
191
two-sided exact 95% confidence interval (CI) was used to compare the difference of clinical success rates
192
between treatment groups.
193
Results
194
Patient disposition
195
A total of 192 Patients were randomized in this study from 21 centers in China: 168 subjects who received at
AC C
EP
187
9
ACCEPTED MANUSCRIPT least one dose of the study drug in FAS (60 in nemonoxacin 500 mg group, 56 in nemonoxacin 750 mg group,
197
and 52 in levofloxacin group), 152 in PPS (57 in nemonoxacin 500 mg group, 50 in nemonoxacin 750 mg
198
group, and 45 in levofloxacin group), 177 in SS (62 in nemonoxacin 500 mg group, 59 in nemonoxacin 750
199
mg group, and 56 in levofloxacin group). There were 57 patients in BFAS and 50 in BPPS (Figure 1).
RI PT
196
The demographic characteristics such as age, gender, race, height, weight, BMI, history of smoking and
201
drinking were comparable between the three treatment groups. The mean age of the subjects was 38.5 ± 14.4
202
years in nemonoxacin 500 mg group, 38.3 ± 15.4 years in nemonoxacin 750 mg group, and 39.7 ± 15.1 years
203
in levofloxacin 500 mg group, respectively. Mean BMI was 22.5 ± 3.6 kg/m2 (nemonoxacin 500 mg), 22.6 ±
204
3.0 kg/m2 (nemonoxacin 750 mg), and 22.2 ± 3.4 kg/m2 (levofloxacin 500 mg), respectively. Most subjects
205
had no history of smoking (85.7%-93.3%) or drinking (76.9%-83.9%).
206
Underlying diseases
207
The most common underlying disease was hypertension (5.0%-7.1%), followed by diabetes mellitus
208
(0%-5.4%), tuberculosis (1.8%-3.3%) and chronic bronchitis (1.7%-3.6%). There was no significant
209
difference between the three groups with regard to underlying diseases in FAS.
210
Dose and duration
211
In FAS, the mean duration of therapy was 9.4 ± 1.3 days in nemonoxacin 500 mg group, 9.2 ± 1.9 days in
212
nemonoxacin 750 mg group, and 9.4 ± 1.7 days in levofloxacin 500 mg group. The mean total dose
213
administered during the study was 4708.3 ± 619.5 mg (nemonoxacin 500 mg), 6910.7 ± 1428.2 mg
214
(nemonoxacin 750 mg), and 4682.7 ± 851.9 mg (levofloxacin 500 mg), respectively.
215
Clinical efficacy
216
The clinical primary efficacy variable was evaluated at the TOC visit in the FAS of this study. The clinical
217
cure rate at the TOC in the FAS population was 93.3% in nemonoxacin 500 mg group, 87.3% in
AC C
EP
TE D
M AN U
SC
200
10
ACCEPTED MANUSCRIPT nemonoxacin 750 mg group and 88.5% in levofloxacin 500 mg group, respectively (Table 1). No significant
219
difference was observed between these three treatment groups. The 95% CI for the treatment difference
220
(4.9%) between nemonoxacin 500 mg and levofloxacin 500 mg was -5.86% to 15.61%, while the 95% CI for
221
the treatment difference (-1.2%) between nemonoxacin 750 mg and levofloxacin 500 mg group was -13.56%
222
to 11.18%. The treatment efficacy of either nemonoxacin 500 mg or 750 mg was noninferior to that of
223
levofloxacin 500 mg in FAS population because the lower limit of 95% CI of the treatment difference was
224
greater than -15%. Noninferiority of nemonoxacin 500 mg or 750 mg to levofloxacin at 500 mg was
225
demonstrated in treatment of adult CAP patients.
227 228
SC
M AN U
226
RI PT
218
The results at the TOC visit in PPS population also showed that there was no significant difference between these three treatment groups (Table 1 and Table 2).
Logistic regression analysis showed that there was no significant difference in clinical efficacy (P > 0.05) between nemonoxacin 500 mg, nemonoxacin 750 mg and levofloxacin 500 mg treatment groups in the
230
FAS and PPS populations (Table 3).
231
TE D
229
Clinical response was also assessed at TOC visit in terms of primary baseline pathogens which were identified in 90 (53.6%) of the 168 subjects in FAS (Table 4). Sixty-one strains of bacteria were isolated from
233
57 patients and 33 atypical pathogens identified serologically. All the patients with S. pneumoniae (n =11) or
234
S. aureus (n = 4) isolate were cured in the three groups except treatment failure in one case with S.
235
pneumoniae isolate in levofloxacin 500 mg group. Of the 18 patients infected with H. influenzae, 15 were
236
cured, but treatment failure each in the three groups. One patient in nemonoxacin 750 mg and two patients in
237
levofloxacin 500 mg group who were infected with K. pneumoniae were evaluated as treatment failure. The
238
other 13 patients with baseline K. pneumoniae isolate were cured. Thirty-three patients were infected with
239
only atypical pathogens in FAS, including M. pneumoniae (n = 29), C. pneumoniae (n = 1) and L.
AC C
EP
232
11
ACCEPTED MANUSCRIPT pneumophila (n = 3). Treatment failure was determined for one patient with single M. pneumoniae infection
241
in nemonoxacin 750 mg group. The other 32 patients with atypical pathogen infection were cured.
242
Bacteriological efficacy
243
The bacteriological primary efficacy was evaluated at the TOC visit in the BFAS of this study. A total of 61
244
pathogens were isolated at baseline from 57 subjects in BFAS population, including 20 strains in
245
nemonoxacin 500 mg group, 19 strains in nemonoxacin 750 mg group and 22 strains in levofloxacin 500 mg
246
group. The bacteriological response at the TOC visit in BFAS and BPPS populations was presented in Table
247
5 by treatment group.
SC
M AN U
248
RI PT
240
The bacteriological success rate for bacteriological evaluable set was 83.3% (15/18) (both in
249
nemonoxacin 500 mg and 750 mg groups) and 80.0% (16/20) (levofloxacin 500 mg group). No significant
250
difference was observed between the three treatment groups by logistic regression analysis. Of the 61 pathogens isolated at baseline, the most common was S. pneumoniae, H. influenzae and K.
TE D
251
pneumoniae, followed by some strains of S. aureus (including MRSA) and P. aeruginosa. At the TOC visit,
253
all the baseline S. pneumoniae (6), S. aureus (including MRSA, 4) and H. influenzae (5) strains were
254
eradicated in nemonoxacin 500 mg and 750 mg groups. The K. pneumoniae and P. aeruginosa strains were
255
eradicated except one each in nemonoxacin 750 mg group. All the baseline isolates in levofloxacin 500 mg
256
group were eradicated except one S. pneumoniae, one H. influenzae and two K. pneumoniae strains.
257
Comprehensive efficacy
258
The comprehensive efficacy was evaluated in terms of clinical and bacteriological efficacy at the TOC visit
259
in the BPPS population of this study. Fifty subjects were included for assessment of comprehensive efficacy,
260
including 17 each in nemonoxacin 500 mg and 750 mg groups and 16 in levofloxacin 500 mg group. The
261
comprehensive success rate at TOC in the BPPS population was 87.5% in nemonoxacin 500 mg group,
AC C
EP
252
12
ACCEPTED MANUSCRIPT 262
93.8% in nemonoxacin 750 mg group and 81.3% in levofloxacin 500 mg group. Logistic regression analysis
263
did not find significant difference between these three treatment groups.
264
All the common respiratory pathogens isolated from this study including S. pneumoniae and H. influenzae were susceptible to nemonoxacin and levofloxacin (Table 6). S. aureus including one MRSA
266
strain were also sensitive to nemonoxacin.
267
Safety and tolerability
268
A total of 177 subjects who received at least one dose of study drug were included in SS population.
269
Sixty-two patients received nemonoxacin 500 mg, 59 received nemonoxacin 750 mg and 56 received
270
levofloxacin 500 mg. The incidence of treatment emergent adverse events (TEAEs) was 41.9% in
271
nemonoxacin 500 mg group, 55.9% in nemonoxacin 750 mg group and 42.9% in levofloxacin 500 mg,
272
respectively (Table 7). The incidence of drug-related TEAEs was similar in the three treatment groups:
273
30.6%, 35.6% and 25.0%, respectively (P > 0.05).
TE D
M AN U
SC
RI PT
265
A total of 28 drug-related TEAEs were observed in 19 subjects in nemonoxacin 500 mg group,
275
including 3 clinical AEs (mainly anorexia, nausea, and epigastric discomfort) in 3 (4.8%) patients and 25
276
episodes of laboratory abnormality (mainly leukopenia and elevated alanine aminotransferase) in 16 (25.8%)
277
patients. No patient had both drug-related AE and laboratory abnormality.
AC C
EP
274
278
A total of 43 drug-related TEAEs were observed in 21 subjects in nemonoxacin 750 mg group,
279
including 22 clinical AEs in 12 (20.3%) patients and 21 episodes of laboratory abnormality in 13 (22.0%)
280
patients. The most common drug-related TEAEs (≥ 2%) were nausea, vomiting, leukopenia and abnormal
281
liver function. Four patients experienced both clinical AEs and laboratory abnormality during the study.
282 283
A total of 24 drug-related TEAEs were observed in 14 subjects in levofloxacin 500 mg group, including 8 clinical AEs in 5 (8.9%) patients and 16 episodes of laboratory abnormality in 11 (19.6%) patients. The
13
ACCEPTED MANUSCRIPT 284
most common drug-related TEAEs (≥ 2%) were nausea, vomiting, leukopenia, neutropenia and elevated
285
urinary protein. Two patients experienced both clinical AEs and laboratory abnormality during the study Drug related QT interval prolongation was observed in all three treatment groups: 3.2% (n = 2) in
287
nemonoxacin 500 mg group, 5.1% (n = 3) in nemonoxacin 750 mg group and 1.8% (n = 1) in levofloxacin
288
500 mg group. Prolongation of QT interval was all shorter than 30 ms except in one female patient in
289
nemonoxacin 750 mg group (557 ms). Two cases of drug related cardiac bundle branch block were observed
290
in nemonoxacin 500 mg group (3.2%). One case of drug related ventricular premature beats was observed in
291
levofloxacin 500 mg group.
SC
M AN U
292
RI PT
286
All the drug-related TEAEs were mild to moderate in severity, more than 90% of which were defined as mild. The proportion of AEs classified as mild was 96.4% in nemonoxacin 500 mg group, 93.0% in
294
nemonoxacin 750 mg and 92.0% in levofloxacin 500 mg, respectively. Only one patient in nemonoxacin 750
295
mg group experienced facial twitch which resulted in discontinuation of the study drug. This symptom
296
disappeared quickly after discontinuation of the study drug. No drug related serious adverse event was
297
observed in this study.
298
Discussion
299
The results of this study demonstrated that oral nemonoxacin 500 mg or 750 mg once daily for 7-10 days
300
achieved excellent clinical and microbiological efficacy in treatment of CAP in Chinese adults. Both
301
nemonoxacin 750 mg and 500 mg were noninferior to levofloxacin 500 mg for treatment of adult CAP in
302
terms of primary efficacy at the TOC visit in FAS population. The microbiological efficacy or
303
bacteriological eradication rate was comparable between nemonoxacin and levofloxacin regimens.
304 305
AC C
EP
TE D
293
Our results prove that nemonoxacin is highly active with broad-spectrum activity against major CAP pathogens. CAP patients infected with S. pneumoniae, H. influenzae, M. pneumoniae, C. pneumoniae, or L.
14
ACCEPTED MANUSCRIPT pneumophila were all cured clinically at TOC visit. It should be noted that three of the four S. aureus isolates
307
at baseline were MRSA, all in nemonoxacin treatment group. All the patients with S. aureus infection were
308
successfully cured. The excellent clinical and bacteriological efficacy suggest good activity of nemonoxacin
309
against these resistant strains although the number of patients with MRSA was fewer. In vitro studies showed
310
that nemonoxacin had good activity against gram-positive bacteria including MRSA.16,17
311
RI PT
306
Nemonoxacin was well tolerated in both treatment groups in this trial. More than 93% of the
drug-related TEAEs were mild. Only one patient discontinued the study drug due to TEAE. Drug related
313
TEAEs were mainly mild gastrointestinal disorders, transient leukopenia and elevated liver enzymes. The
314
incidence of drug related TEAEs in the present study was similar to that reported in a phase II clinical trial
315
carried out in South Africa, in which the incidence of adverse events was 30.3% in nemonoxacin 500 mg
316
group, 31.4% in nemonoxacin 750 mg group and 30.0% in levofloxacin 500 mg group. The most common
317
AEs in the South Africa study were mild gastrointestinal disorders and transient neutropenia. 15
TE D
M AN U
SC
312
The overall incidence of drug related TEAEs in nemonoxacin 750 mg group (35.6%) was slightly
319
higher than that in nemonoxacin 500 mg group (30.6%). These suggest that nemonoxacin 500 mg treatment
320
regimen may be safer than 750 mg regimen in treatment of adult CAP. In future phase III clinical trials,
321
nemonoxacin 500 mg regimen will be recommended based on its similar efficacy and better safety profile
322
compared with 750 mg regimen.
AC C
323
EP
318
In summary, oral nemonoxacin (500 mg or 750 mg) once daily for 7-10 days showed good clinical and
324
microbiological efficacy in treatment of adult CAP. Either 750 mg or 500 mg nemonoxacin once daily has
325
proved noninferior to levofloxacin 500 mg at test of cure visit and both regimens were well tolerated. The
326
incidence of drug related TEAEs in nemonoxacin 750 mg group was slightly higher than that in
327
nemonoxacin 500 mg group but the difference was not significant. Based on the above results, nemonoxacin
15
ACCEPTED MANUSCRIPT 328
500 mg once daily for 7-10 days will be recommended for future phase III clinical trials.
AC C
EP
TE D
M AN U
SC
RI PT
329
16
ACCEPTED MANUSCRIPT Conflicts of interest
331
TaiGen Biotechnology Co., Ltd. provided the study drug nemonoxacin used in this study. One of the
332
Liwen Chang, is an employee of TaiGen Biotechnology Co., Ltd.
333
Acknowledgements
334
This study was supported by the major research and development project of innovative drugs under the
335
auspices of Ministry of Science and Technology of China (2008ZX09312-010 and 2012ZX09303004-001).
336
We thank all the study subjects for their cooperation and the laboratory technicians for assistance in
337
performing the antimicrobial susceptibility tests.
M AN U
SC
RI PT
330
AC C
EP
TE D
338
17
ACCEPTED MANUSCRIPT 339
References
340
1.
Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the
342
Global Burden of Disease Study 2010. Lancet 2012;380:2095-128.
343
2.
RI PT
341
Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of
345
America/American Thoracic Society consensus guidelines on the management of
346
community-acquired pneumonia in adults. Clin Infect Dis 2007;44:S27-72. 3.
M AN U
347
SC
344
Peto L, Nadjm B, Horby P, Ngan TT, van Doorn R, Van Kinh N, et al. The bacterial aetiology of adult
348
community-acquired pneumonia in Asia: a systematic review. Trans R Soc Trop Med Hyg
349
2014;108:326-37.
patterns. Eur Respir J Suppl 2002;36:20s-7s.
351 5.
resistance in China. Chin J Infect Chemother 2014;14:369-78.
353 354
Hu FP, Zhu DM, Wang F, Guo Y, Yang Y, Jiang XF, et al. CHINET 2013 surveillance of bacterial
6.
EP
352
Woodhead M. Community-acquired pneumonia in Europe: causative pathogens and resistance
TE D
4.
Guo B, Wu X, Zhang Y, Shi Y, Yu J, Cao G, et al. Safety and clinical pharmacokinetics of
AC C
350
355
nemonoxacin, a novel non-fluorinated quinolone, in healthy Chinese volunteers following single and
356
multiple oral doses. Clin Drug Investig 2012;32:475-86.
357
7.
Adam HJ, Laing NM, King CR, Lulashnyk B, Hoban DJ, Zhanel GG. In vitro activity of nemonoxacin,
358
a novel nonfluorinated quinolone, against 2,440 clinical isolates. Antimicrob Agents Chemother
359
2009;53:4915-20.
360
8.
Chen YH, Liu CY, Lu JJ, King CH, Hsueh PR. In vitro activity of nemonoxacin (TG-873870), a novel
18
ACCEPTED MANUSCRIPT 361
non-fluorinated quinolone, against clinical isolates of Staphylococcus aureus, enterococci and
362
Streptococcus pneumoniae with various resistance phenotypes in Taiwan. J Antimicrob Chemother
363
2009;64:1226-29. 9.
Chen YH, Liu CY, Ko WC, Liao CH, Lu PL, Huang CH, et al. Trends in the susceptibility of
RI PT
364
methicillin-resistant Staphylococcus aureus to nine antimicrobial agents, including ceftobiprole,
366
nemonoxacin, and tyrothricin: results from the Tigecycline In Vitro Surveillance in Taiwan (TIST)
367
study, 2006-2010. Eur J Clin Microbiol Infect Dis 2014;33:233-39.
10. Lai CC, Tan CK, Lin SH, Liao CH, Chou CH, Hsu HL, et al. Comparative in vitro activities of
M AN U
368
SC
365
369
nemonoxacin, doripenem, tigecycline and 16 other antimicrobials against Nocardia brasiliensis,
370
Nocardia asteroides and unusual Nocardia species. J Antimicrob Chemother 2009;64:73-8.
371
11. Lauderdale TL, Shiau YR, Lai JF, Chen HC, King CH. Comparative in vitro activities of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, and other quinolones against clinical isolates.
373
Antimicrob Agents Chemother 2010;54:1338-42.
376
nemonoxacin, a novel non-fluorinated quinolone. J Antimicrob Chemother 2010;65:2411-15.
EP
375
12. Li CR, Li Y, Li GQ, Yang XY, Zhang WX, Lou RH, et al. In vivo antibacterial activity of
13. Chung DT, Tsai CY, Chen SJ, Chang LW, King CH, Hsu CH, et al. Multiple-dose safety, tolerability,
AC C
374
TE D
372
377
and pharmacokinetics of oral nemonoxacin (TG-873870) in healthy volunteers. Antimicrob Agents
378
Chemother 2010;54:411-17.
379
14. Lin L, Chang LW, Tsai CY, Hsu CH, Chung DT, Aronstein WS, et al. Dose escalation study of the
380
safety, tolerability, and pharmacokinetics of nemonoxacin (TG-873870), a novel potent
381
broad-spectrum nonfluorinated quinolone, in healthy volunteers. Antimicrob Agents Chemother
382
2010;54:405-10.
19
ACCEPTED MANUSCRIPT 383
15. Van Rensburg DJ, Perng RP, Mitha IH, Bester AJ, Kasumba J, Wu RG, et al. Efficacy and safety of
384
nemonoxacin versus levofloxacin for community-acquired pneumonia. Antimicrob Agents Chemother
385
2010;54:4098-106.
387 388
16. Lai CC, Lee KY, Lin SW, Chen YH, Kuo HY, Hung CC, et al. Nemonoxacin (TG-873870) for
RI PT
386
treatment of community-acquired pneumonia. Expert Rev Anti Infect Ther 2014;12:401-17. 17. Poole RM. Nemonoxacin: first global approval. Drugs 2014;74:1445-53.
AC C
EP
TE D
M AN U
SC
389
20
ACCEPTED MANUSCRIPT 390
Table 1 Clinical response at the test of cure visit. Nemonoxacin 500 mg
Nemonoxacin 750 mg
Levofloxacin 500 mg
N (%)
N (%)
N (%)
56 (93.3)
48 (87.3)
4 (6.7)
7 (12.7)
0
1
Clinical failure Unevaluable
Clinical cure
51 (89.5)
Clinical failure
6 (10.5)
Unevaluable
TE D EP 21
46 (88.5) 6 (11.5) 0
44 (89.8)
39 (88.6)
5 (10.2)
5 (11.4)
1
1
* Unevaluable cases were not included in the denominator.
AC C
391
0
M AN U
Per protocol set
SC
Clinical cure
RI PT
Full analysis set
ACCEPTED MANUSCRIPT
Table 2 Clinical efficacy and treatment difference of the three groups at the test of cure visit. Levofloxacin 500 mg N (%)
Nemonoxacin 500 mg N (%)
Treatment
P value (95% CI)
4.9%
Per protocol set
40 (88.9)
53 (93.0)
4.1%
0.851 (-7.23%, 15.42%)
EP
TE D
Treatment difference = nemonoxacin group - levofloxacin group.
0.569 (-5.86%, 15.61%)
M AN U
56 (93.3)
AC C
393
46 (88.5)
SC
difference Full analysis set
RI PT
392
22
N (%)
Nemonoxacin 750 mg Treatment
P value (95% CI)
difference
48 (87.3)
-1.2%
0.71 (-13.56%, 11.18%)
46 (93.9)
5.0%
0.62 (-6.39%, 16.36%)
ACCEPTED MANUSCRIPT 394
Table 3 Logistic regression analysis of the efficacy of nemonoxacin treatments compared with
395
levofloxacin at the test of cure visit. Nemonoxacin 500 mg 95% CI
Wald χ2
P
OR
95% CI
Wald χ2
Full analysis set
1.83
(0.49, 6.86)
0.7947
0.3727
0.89
(0.28, 2.86)
0.0354
0.8508
Per protocol set
1.66
(0.42, 6.57)
0.5155
0.4728
1.92
(0.43, 8.53)
0.7297
0.3930
EP
TE D
M AN U
SC
OR, the ratio between nemonoxacin treatment and levofloxacin in terms of clinical efficacy rate.
23
P
RI PT
OR
AC C
396
Nemonoxacin 750 mg
ACCEPTED MANUSCRIPT
397
Table 4 Clinical efficacy at test of cure visit by primary baseline pathogens in full analysis set. Number of isolates
Nemonoxacin 500 mg
Nemonoxacin 750 mg
RI PT
Pathogens n1/n2 (%)
a
n1/n2 (%)
n1/n2 (%)
4/4 (100)
3/4 (75.0)
2/2 (100)
0/0
2/2 (100)
3/4 (75.0)
a
Typical pathogen
Levofloxacin 500 mg a
S. pneumoniae
11
2/2 (100)
S. aureus
4
2/2 (100)
H. influenzae
9
3/3 (100)
H. parainfluenzae
9
2/3 (66.7)
3/4 (75.0)
2/2 (100)
K. pneumoniae
16
4/4 (100)
2/3 (66.7)
7/9 (77.8)
M. pneumoniae
29
7/7 (100)
13/14 (92.9)
8/8 (100)
L. pneumophila
3
2/2 (100)
0/0
1/1 (100)
C. pneumoniae
1
0/0
1/1 (100)
0/0
SC
M AN U
c
b
EP
TE D
Atypical pathogen only
a
n1: the number of strains actually or presumably eradicated; n2, total number of evaluable strains.
399
b
There were five S. pneumoniae isolates at the end of treatment. One strain was unevaluable because the subject received acetylspiramycin before the test of cure
400
visit.
401
c
AC C
398
Of the 4 S. aureus isolates, 3 were methicillin-resistant, including 2 in nemonoxacin 500 mg group and 1 in nemonoxacin 750 mg group.
24
ACCEPTED MANUSCRIPT
402
Table 5 Bacteriological efficacy at the test of cure visit by treatment group. Nemonoxacin 750 mg
N (%) Bacteriological full analysis seta
SC
RI PT
Nemonoxacin 500 mg
Levofloxacin 500 mg
N (%)
N (%)
15 (83.3)
16 (80.0)
15 (83.3)
Bacteriological failurec
3 (16.7)
3 (16.7)
4 (20.0)
0
1
0
14 (82.4)
15 (93.8)
13 (81.3)
3 (17.7)
1 (6.2)
3 (18.7)
1
0
M AN U
Bacteriological successb
Unevaluable
Bacteriological failure
0
AC C
Unevaluable
EP
Bacteriological success
TE D
Bacteriological per protocol set
403
a
Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila were not included.
404
b
Bacteriological success included eradication and presumed eradication.
405
c
Bacteriological failure included persistence, presumed persistence and partial eradication.
25
ACCEPTED MANUSCRIPT
Table 6 In vitro susceptibilities of primary baseline isolates to the study drugs. Nemonoxacin
Levofloxacin
Bacteria (n)
MIC50 (mg/L)
MIC90 (mg/L)
0.125
0.25
0.03-1
0.25
0.5
S. aureusb (4)
0.06-1
K. pneumoniae (19)
0.06-＞32
0.5
0.008-1
0.06
M AN U
TE D
taken. b
32
0.06-＞32
0.125
＞32
1
0.008-1
0.06
1
Thirteen S. pneumoniae strains were isolated in all randomized groups and two of those were excluded from BFAS because of wrong drugs
MIC50 and MIC90 were not calculated because of few strains.
EP
a
0.125-32
AC C
410
MIC range (mg/L)
0.015-1
408 409
MIC90 (mg/L)
S. pneumoniae (13)a
H. influenzae and H. parainfluenzae (16) 407
MIC50 (mg/L)
SC
MIC range (mg/L)
RI PT
406
26
ACCEPTED MANUSCRIPT
Table 7 Summary of the most common treatment-related adverse events (≥ 2% in any one group) by system organ and preferred term.
System organ class and preferred term
(N = 62) n (%)
Subjects with any treatment-related adverse event
19 (30.6) 1 (1.6)
M AN U
Nausea
Levofloxacin 500 mg
(N = 59)
(N = 56)
n (%)
n (%)
21 (35.6)
14 (25.0)
SC
Digestive system
Nemonoxacin 750 mg
RI PT
Nemonoxacin 500 mg
6 (10.2)
1 (1.8)
Vomiting
0
4 (6.8)
2 (3.6)
Stomach upset
0
2 (3.4)
1 (1.8)
Leukopenia
4 (6.5)
6 (10.2)
4 (7.1)
Neutropenia
2 (3.2)
2 (3.4)
2 (3.6)
2 (3.2)
1 (1.7)
0
1 (1.6)
2 (3.4)
1 (1.8)
0
3 (5.1)
0
3 (4.8)
0
1 (1.8)
0
1 (1.7)
2 (3.6)
2 (3.2)
3 (5.1)
1 (1.8)
2 (3.2)
0
0
Percentage of neutrophils increased Metabolic and nutritional Abnormal liver function Elevated alanine aminotransferase Elevated urinary protein Cardiovascular system QT interval prolongation Bundle branch block
EP
Percentage of eosinophils increased
TE D
Blood and lymphatic system
AC C
411
27
ACCEPTED MANUSCRIPT FIGURE LEGEND
412
Figure 1. Patient disposition flow chart. NEMO, nemonoxacin; LEVO, levofloxacin; SS,
414
safety set; FAS, full analysis set; PPS, per protocol set; BFAS, bacteriological full analysis set;
415
BPPS, bacteriological per protocol set.
AC C
EP
TE D
M AN U
SC
RI PT
413
28
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1684-1182(15)00915-9
DOI:
10.1016/j.jmii.2015.09.005
Reference:
JMII 723
To appear in:
Journal of Microbiology, Immunology and Infection
Received Date: 15 September 2015 Accepted Date: 25 September 2015
Please cite this article as: Liu Y, Zhang Y, Wu J, Zhu D, Sun S, Zhao L, Wang X, Liu H, Ren Z, Wang C, Xiu Q, Xiao Z, Cao Z, Cui S, Yang H, Liang Y, Chen P, Lv Y, Hu C, Lv X, Liu S, Kuang J, Li J, Wang D, Chang L, A randomized, double-blind, multicenter phase II study comparing the efficacy and safety of oral nemonoxacin with oral levofloxacin in the treatment of community-acquired pneumonia, Journal of Microbiology, Immunology and Infection (2015), doi: 10.1016/j.jmii.2015.09.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT ORIGINAL ARTICLE
2
A randomized, double-blind, multicenter phase II study comparing the efficacy and
3
safety of oral nemonoxacin with oral levofloxacin in the treatment of
4
community-acquired pneumonia
5
Yang Liua,b, Yingyuan Zhanga,b,*, Jufang Wua,b, Demei Zhua,b, Shenghua Sunc, Li Zhaod, Xuefeng Wange,
6
Hua Liuf, Zhenyi Reng, Changzheng Wangh, Qingyu Xiui, Zuke Xiaoj, Zhaolong Caok, Shehuai Cuil, Heping
7
Yangm, Yongjie Liangn, Ping Cheno, Yuan Lvp, Chengping Huq, Xiaoju Lvr, Shuang Lius, Jiulong Kuangt,
8
Jianguo Liu, Dexi Wangv, and Liwen Changw
9
a
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China
10
b
China Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China
11
c
Department of Respiratory Medicine, The Third Xiangya Hospital, Central South University, Hunan, China
12
d
Department of Respiratory Medicine, Shengjing Hospital, China Medical University, Liaoning, China
13
e
Department of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University, Zhejiang, China
14
f
Department of Respiratory Medicine, Gansu Provincial People’s Hospital, Lanzhou, China
15
g
Department of Respiratory Medicine, Hangzhou First People’s Hospital, Zhejiang, China
16
h
Department of Respiratory Medicine, Xinqiao Hospital, The Third Military Medical University,
17
Chongqing, China
18
i
19
Shanghai, China
20
j
Department of Respiratory Medicine, Jiangxi Provincial People’s Hospital, Jiangxi, China
21
k
Department of Respiratory Medicine, Peking University People’s Hospital, Beijing, China
22
l
AC C
EP
TE D
M AN U
SC
RI PT
1
Department of Respiratory Medicine, Changzheng Hospital, The Second Military Medical University,
Department of Respiratory Medicine, Daping Hospital, The Third Military Medical University, Chongqing,
1
ACCEPTED MANUSCRIPT 23
China
24
m
25
Chongqing, China
26
n
Department of Respiratory Medicine, East Hospital, Tongji University, Shanghai, China
27
o
Department of Respiratory Medicine, The General Hospital of Shenyang Military Command, Liaoning,
28
China
29
p
Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China
30
q
Department of Respiratory Medicine, Xiangya Hospital, Central South University, Hunan, China
31
r
Center for Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
32
s
Department of Respiratory Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
33
t
Department of Respiratory Medicine, The Second Affiliated Hospital, Nanchang University, Jiangxi, China
34
u
35
Guangdong, China
36
v
Department of Respiratory Medicine, Guangzhou Red Cross Hospital, Guangdong, China
37
w
TaiGen Biotechnology Co., Ltd., Taipei, Taiwan
38
Running title: Nemonoxacin versus Levofloxacin in Treatment of CAP
39
* Corresponding author. Institute of Antibiotics, Huashan Hospital, Fudan University, 12 Middle Wulumuqi
40
Road, Shanghai 200040, China. Tel.: +86 21 52888190; fax: +86 21 62484347
41
E-mail address: [email protected] (Y-Y. Zhang)
42
ClinicalTrials.gov identifier: NCT01537250
43
KEYWORDS: clinical trial; community-acquired pneumonia; efficacy; nenomoxacin; safety
M AN U
SC
RI PT
Department of Respiratory Medicine, Southwest Hospital, The Third Military Medical University,
AC C
EP
TE D
Department of Respiratory Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University,
2
ACCEPTED MANUSCRIPT Abstract
45
Background/Purpose: To compare the clinical efficacy and safety of nemonoxacin with levofloxacin in the
46
treatment of community-acquired pneumonia (CAP) in a phase II clinical trial.
47
Methods: A total of 192 CAP patients were randomized to receive oral nemonoxacin (500 mg or 750 mg) or
48
levofloxacin (500 mg) once daily for 7-10 days. Clinical and bacteriological responses were determined at
49
test of cure (TOC) visit in full analysis set (FAS).
50
Results: The clinical cure rate of nemonoxacin 500 mg, nemonoxacin 750 mg and levofloxacin 500 mg was
51
93.3%, 87.3%, 88.5%, respectively in FAS (n=168); and 93.0%, 93.9%, 88.9%, respectively in per-protocol
52
set (n=152). Either 500 mg or 750 mg nemonoxacin was proved noninferior to levofloxacin 500 mg at TOC
53
visit in FAS in terms of clinical efficacy. Overall bacteriological success rate was 83.3% in both
54
nemonoxacin groups and 80.0% in levofloxacin 500 mg group in bacteriological FAS. The comprehensive
55
efficacy rate was comparable among the three groups (87.5% for nemonoxacin 500 mg, 93.8% for
56
nemonoxacin 750 mg and 81.3% for levofloxacin 500 mg group). Most of the drug-related adverse events
57
were mild and moderate gastrointestinal symptoms including nausea and vomiting, transient neutropenia and
58
elevated liver enzymes. No drug-related serious adverse events were observed. Conclusion: Oral
59
nemonoxacin, either 500 mg or 750 mg, once daily for 7-10 days demonstrated high clinical and
60
bacteriological success rates in Chinese adult CAP patients. Nemonoxacin 500 mg once daily for 7-10 days
61
will be recommended in future phase III clinical trials.
SC
M AN U
TE D
EP
AC C
62
RI PT
44
63
3
ACCEPTED MANUSCRIPT Introduction
65
Community-acquired pneumonia (CAP) is a common lower respiratory tract infection with high morbidity
66
and mortality.1,2 CAP can be caused by a variety of pathogens, e.g. Streptococcus pneumoniae, Haemophilus
67
influenzae and Mycoplasma pneumoniae.3,4 In recent years the emergence and spread of antibiotic-resistant
68
pathogens has become big challenge in clinical management of CAP. The CHINET bacterial resistance
69
surveillance data in 2013 showed that the prevalence of penicillin-intermediate (PISP) or penicillin-resistant
70
S. pneumoniae (PRSP) increased up to 32.9% (PISP 11.6%, PRSP 21.3%) and 9.4% (PISP 5.4%, PRSP 4.0%)
71
in children and adult isolates, respectively.5 Surveillance studies also showed the high prevalence of S.
72
pneumoniae strains resistant to erythromycin or clindamycin, especially in PISP and PRSP strains.6
73
Quinolone drugs are active against CAP pathogens including penicillin non-susceptible S. pneumoniae and
74
were recommended for adult CAP.2
SC
M AN U
Nemonoxacin, a non-fluorinated quinolone targeting DNA gyrase and topoisomerase IV, has
TE D
75
RI PT
64
broad-spectrum activity against gram-positive and some atypical pathogens, including penicillin-resistant S.
77
pneumoniae and methicillin-resistant S. aureus (MRSA).7-9,10,11 Nemonoxacin is also active against
78
gram-negative bacteria such as H. influenzae and K. pneumoniae.7,11 A study in mice showed that the
79
efficacy of nemonoxacin was better than that of levofloxacin in the treatment of gram-positive bacterial
80
infections, including those caused by PRSP and MRSA.12
AC C
81
EP
76
Phase I studies have been previously conducted in healthy volunteers in the United States and China to
82
examine the safety and clinical pharmacokinetics (PK) of nemonoxacin following single and multiple oral
83
doses.6,13-14 Results showed that after oral administration, nemonoxacin was absorbed rapidly and well
84
tolerated. Nemonoxacin attained peak plasma concentration (Cmax) within 1-2 hours after oral administration
85
and exhibited a linear PK profile within the dose range of 250-750 mg and moderate food effects. Cmax
4
ACCEPTED MANUSCRIPT 86
(AUC0-∞) was dose-dependent after multiple doses. Nemonoxacin was excreted primarily in urine. About
87
60-70% of the drug was eliminated within 72 hours in unchanged form. The elimination half-life was 9-16
88
hours. There was no accumulation following administration for 10 consecutive days.6,13 Van Rensburg et al reported a clinical trial investigating the efficacy and safety of nemonoxacin
RI PT
89
compared with that of levofloxacin in CAP outpatients in 2010.15 The results showed that nemonoxacin was
91
noninferior to levofloxacin in either the evaluable intent-to-treat (ITT) or clinical per protocol (PPc)
92
populations. Both treatments were well tolerated without any serious drug-related adverse reaction.
SC
90
We conducted a randomized, double-blind, multicenter clinical trial to evaluate the safety and efficacy
94
of 500 mg and 750 mg oral doses of nemonoxacin compared with 500 mg levofloxacin, once daily for 7-10
95
days in the treatment of CAP patients in Chinese population.
96
Methods
97
Study design
98
A phase II, randomized, double blind, double dummy, multicenter study was designed to compare the
99
efficacy and safety of oral nemonoxacin with those of levofloxacin in Chinese adult CAP patients. The
TE D
M AN U
93
primary objective of this study was to demonstrate the noninferiority of nemonoxacin versus levofloxacin
101
with regard to safety and clinical efficacy. The study was conducted in compliance with good clinical
102
practice guidelines and the Declaration of Helsinki. The study protocol was approved by the Ethics
103
Committees of all participating institutions. All subjects provided their written informed consent before
104
enrollment in the study.
105
Study treatments
106
Eligible subjects were randomized during the period from August 2009 to August 2010 to one of the three
107
treatment groups in a 1:1:1 ratio to receive oral dose of 500 mg or 750 mg nemonoxacin (TaiGen
AC C
EP
100
5
ACCEPTED MANUSCRIPT Biotechnology Co., Ltd., Taiwan) or 500 mg levofloxacin and the matched placebo, once daily for 7-10 days.
109
The first dose was administered on site in the clinic immediately after enrollment. As for all the subsequent
110
doses, patients took their study drug in the morning after an overnight fast and before breakfast.
111
Patients: inclusion criteria
112
Male or female subjects were eligible if they were 18-70 years of age, body weight within the range of
113
40-100 kg, body mass index (BMI) ≥ 18 kg/m2, and had diagnosis of mild to moderate CAP. Diagnosis was
114
based on two or more of the following clinical manifestations and a chest radiograph showing the presence
115
of a new lobar or multilobar infiltrates consistent with CAP within 48 h. Clinical manifestations included: (1)
116
productive cough with purulent sputum or deterioration of existing respiratory symptoms; (2) fever (oral
117
temperature ≥ 37.3°C); (3) evidence of pulmonary consolidation and/or rales; (4) peripheral white blood cell
118
count > 10×109 /L or < 4×109 /L or neutrophils > 70%. The above-mentioned (2) or (4) must be present when
119
subjects were enrolled.
120
Patients: exclusion criteria
121
Pregnant or lactating women were excluded from the study. Subjects were also excluded if they had any of
122
the following conditions: active tuberculosis, bronchiectasis, lung abscess, aspiration pneumonia, lung
123
malignancies, non-infectious interstitial lung disease, pulmonary edema, atelectasis, pulmonary embolism,
124
pulmonary eosinophilia or pulmonary vasculitis; nosocomial pneumonia; history of hypersensitivity or
125
allergic reaction to any quinolone; history of epilepsy, mental disorders or other diseases of central nervous
126
system; renal failure; liver dysfunction; malabsorption syndrome or other gastrointestinal disease;
127
immunodeficiency such as HIV infection, CD4+ < 200/mm3 or neutropenia, or blood or solid organ
128
malignancies; long-term use of steroids; severe pneumonia; 12-lead ECG showing abnormal cardiac
129
conduction or QT interval prolongation (male QTc > 430 ms, female QTc > 450 ms); treatment with
AC C
EP
TE D
M AN U
SC
RI PT
108
6
ACCEPTED MANUSCRIPT chemotherapeutic drugs or oncolytics within 6 months before randomization, or requiring such agents during
131
the trial; alcohol or drug abuse; administration of any quinolone within 2 weeks before randomization;
132
received any investigational drug within 3 months before enrollment; donation of 500 ml blood within 3
133
months; requiring combined antimicrobial therapy due to dual infection.
134
Primary and secondary endpoints
135
Clinical response at test of cure (TOC) visit (7 to 10 days post-treatment) was the primary efficacy endpoint
136
of this study. The clinical efficacy were defined as: clinical cure (complete resolution of all signs and
137
symptoms of pneumonia, or recovered to pretreatment state), clinical failure (persistence or worsening of
138
signs and symptoms after therapy, or emergence of new pneumonia-related symptoms or signs and/or use of
139
other antimicrobial therapy targeting pneumonia; or discontinuation within 3 days after initiation of study
140
treatment due to adverse drug reaction), and unevaluable (missing posttreatment information, or use of
141
systemic antimicrobial agents for other indications not permitted by protocol, or early discontinuation of
142
treatment due to other causes unrelated to the study drug).
SC
M AN U
TE D
143
RI PT
130
Secondary endpoints included clinical and bacteriological response at the end of treatment in full analysis set and per-protocol set and at the TOC in per-protocol set.
145
Microbiological assessment
146
Sputum samples were collected by every reasonable effort for Gram stain and culture before the first dose of
147
study drug. Atypical pathogens were identified by serological assay. Microbiological response was
148
categorized as: eradication (original pathogen[s] was absent at TOC visit), presumed eradication (subject
149
was considered clinically cured, and a repeat sputum/blood culture was absent), and persistence (original
150
pathogen[s] persisted at the TOC visit), and presumed persistence (subject still had clinical signs and
151
symptoms and a repeat sputum culture was absent). Antimicrobial susceptibility test of nemonoxacin and
AC C
EP
144
7
ACCEPTED MANUSCRIPT levofloxacin was carried out by microdilution assay based on Clinical and Laboratory Standard Institute
153
(CLSI) document M100-S21. Only patients with positive admission cultures were included in the analysis of
154
bacteriological response.
155
Comprehensive efficacy assessment
156
The clinically evaluable subjects with positive bacterial culture at baseline were included for comprehensive
157
assessment. The clinical signs and symptoms, radiologic and laboratory tests and microbiological
158
examination were combined to evaluate the comprehensive efficacy. Comprehensive response was
159
categorized as: cure (at TOC visit, clinical response was cure and microbiological response was eradication
160
or presumed eradication) and failure (at TOC visit, clinical response was failure or microbiological response
161
was persistence or presumed persistence). Comprehensive efficacy was evaluated as failure if one of the
162
clinical or microbiological responses was failure and another missing, and unknown if one of the clinical or
163
microbiological responses was cure / (presumed) eradication and the other was missing.
164
Safety assessment
165
All clinical and laboratory adverse events that occurred during clinical trial were carefully observed and
166
recorded for all subjects who received at least one dose of the study drug. The adverse events were
167
categorized as definitely related, probably related, possibly related, possibly unrelated or definitely unrelated
168
according to their relation to the study drug.
169
Patient populations
170
The following five patient populations were defined in this study for analysis of clinical and microbiological
171
efficacy.
172 173
AC C
EP
TE D
M AN U
SC
RI PT
152
Full analysis set (FAS): All subjects were included in the full analysis set except for those not receiving any study drug; without the target disease; non-compliant with good clinical practice; or missing the
8
ACCEPTED MANUSCRIPT 174
follow-up information after first visit. Per protocol set (PPS): All subjects in FAS were included in the per protocol set except for those
176
inadequately enrolled with an exclusion criterion; requiring treatment with other effective antibiotics, but not
177
including those who were evaluated as failure at the end of treatment and then received other antibiotic
178
therapy; or non-compliant patients evidenced by taking less than 80% or more than 120% of his/her
179
prescribed dose.
182 183 184 185 186
SC
primary efficacy endpoint of this study.
M AN U
181
FAS and PPS were applicable for efficacy analysis. Clinical response at the TOC visit in FAS was the
Safety set (SS): All subjects who received at least one dose of the study drug will be included in safety set. SS was applicable for safety analysis.
Bacteriological full analysis set (BFAS): All subjects in FAS whose first sputum culture or blood culture was positive were included.
TE D
180
RI PT
175
Bacteriological per protocol set (BPPS): All subjects in PPS whose first sputum culture or blood culture was positive were included.
188
Statistical analysis
189
SAS 9.1.3 software was used for all statistical analysis. Noninferiority was defined as the lower limit of the
190
95% CI for the difference between groups being greater than -15%. In addition to noninferiority analysis,
191
two-sided exact 95% confidence interval (CI) was used to compare the difference of clinical success rates
192
between treatment groups.
193
Results
194
Patient disposition
195
A total of 192 Patients were randomized in this study from 21 centers in China: 168 subjects who received at
AC C
EP
187
9
ACCEPTED MANUSCRIPT least one dose of the study drug in FAS (60 in nemonoxacin 500 mg group, 56 in nemonoxacin 750 mg group,
197
and 52 in levofloxacin group), 152 in PPS (57 in nemonoxacin 500 mg group, 50 in nemonoxacin 750 mg
198
group, and 45 in levofloxacin group), 177 in SS (62 in nemonoxacin 500 mg group, 59 in nemonoxacin 750
199
mg group, and 56 in levofloxacin group). There were 57 patients in BFAS and 50 in BPPS (Figure 1).
RI PT
196
The demographic characteristics such as age, gender, race, height, weight, BMI, history of smoking and
201
drinking were comparable between the three treatment groups. The mean age of the subjects was 38.5 ± 14.4
202
years in nemonoxacin 500 mg group, 38.3 ± 15.4 years in nemonoxacin 750 mg group, and 39.7 ± 15.1 years
203
in levofloxacin 500 mg group, respectively. Mean BMI was 22.5 ± 3.6 kg/m2 (nemonoxacin 500 mg), 22.6 ±
204
3.0 kg/m2 (nemonoxacin 750 mg), and 22.2 ± 3.4 kg/m2 (levofloxacin 500 mg), respectively. Most subjects
205
had no history of smoking (85.7%-93.3%) or drinking (76.9%-83.9%).
206
Underlying diseases
207
The most common underlying disease was hypertension (5.0%-7.1%), followed by diabetes mellitus
208
(0%-5.4%), tuberculosis (1.8%-3.3%) and chronic bronchitis (1.7%-3.6%). There was no significant
209
difference between the three groups with regard to underlying diseases in FAS.
210
Dose and duration
211
In FAS, the mean duration of therapy was 9.4 ± 1.3 days in nemonoxacin 500 mg group, 9.2 ± 1.9 days in
212
nemonoxacin 750 mg group, and 9.4 ± 1.7 days in levofloxacin 500 mg group. The mean total dose
213
administered during the study was 4708.3 ± 619.5 mg (nemonoxacin 500 mg), 6910.7 ± 1428.2 mg
214
(nemonoxacin 750 mg), and 4682.7 ± 851.9 mg (levofloxacin 500 mg), respectively.
215
Clinical efficacy
216
The clinical primary efficacy variable was evaluated at the TOC visit in the FAS of this study. The clinical
217
cure rate at the TOC in the FAS population was 93.3% in nemonoxacin 500 mg group, 87.3% in
AC C
EP
TE D
M AN U
SC
200
10
ACCEPTED MANUSCRIPT nemonoxacin 750 mg group and 88.5% in levofloxacin 500 mg group, respectively (Table 1). No significant
219
difference was observed between these three treatment groups. The 95% CI for the treatment difference
220
(4.9%) between nemonoxacin 500 mg and levofloxacin 500 mg was -5.86% to 15.61%, while the 95% CI for
221
the treatment difference (-1.2%) between nemonoxacin 750 mg and levofloxacin 500 mg group was -13.56%
222
to 11.18%. The treatment efficacy of either nemonoxacin 500 mg or 750 mg was noninferior to that of
223
levofloxacin 500 mg in FAS population because the lower limit of 95% CI of the treatment difference was
224
greater than -15%. Noninferiority of nemonoxacin 500 mg or 750 mg to levofloxacin at 500 mg was
225
demonstrated in treatment of adult CAP patients.
227 228
SC
M AN U
226
RI PT
218
The results at the TOC visit in PPS population also showed that there was no significant difference between these three treatment groups (Table 1 and Table 2).
Logistic regression analysis showed that there was no significant difference in clinical efficacy (P > 0.05) between nemonoxacin 500 mg, nemonoxacin 750 mg and levofloxacin 500 mg treatment groups in the
230
FAS and PPS populations (Table 3).
231
TE D
229
Clinical response was also assessed at TOC visit in terms of primary baseline pathogens which were identified in 90 (53.6%) of the 168 subjects in FAS (Table 4). Sixty-one strains of bacteria were isolated from
233
57 patients and 33 atypical pathogens identified serologically. All the patients with S. pneumoniae (n =11) or
234
S. aureus (n = 4) isolate were cured in the three groups except treatment failure in one case with S.
235
pneumoniae isolate in levofloxacin 500 mg group. Of the 18 patients infected with H. influenzae, 15 were
236
cured, but treatment failure each in the three groups. One patient in nemonoxacin 750 mg and two patients in
237
levofloxacin 500 mg group who were infected with K. pneumoniae were evaluated as treatment failure. The
238
other 13 patients with baseline K. pneumoniae isolate were cured. Thirty-three patients were infected with
239
only atypical pathogens in FAS, including M. pneumoniae (n = 29), C. pneumoniae (n = 1) and L.
AC C
EP
232
11
ACCEPTED MANUSCRIPT pneumophila (n = 3). Treatment failure was determined for one patient with single M. pneumoniae infection
241
in nemonoxacin 750 mg group. The other 32 patients with atypical pathogen infection were cured.
242
Bacteriological efficacy
243
The bacteriological primary efficacy was evaluated at the TOC visit in the BFAS of this study. A total of 61
244
pathogens were isolated at baseline from 57 subjects in BFAS population, including 20 strains in
245
nemonoxacin 500 mg group, 19 strains in nemonoxacin 750 mg group and 22 strains in levofloxacin 500 mg
246
group. The bacteriological response at the TOC visit in BFAS and BPPS populations was presented in Table
247
5 by treatment group.
SC
M AN U
248
RI PT
240
The bacteriological success rate for bacteriological evaluable set was 83.3% (15/18) (both in
249
nemonoxacin 500 mg and 750 mg groups) and 80.0% (16/20) (levofloxacin 500 mg group). No significant
250
difference was observed between the three treatment groups by logistic regression analysis. Of the 61 pathogens isolated at baseline, the most common was S. pneumoniae, H. influenzae and K.
TE D
251
pneumoniae, followed by some strains of S. aureus (including MRSA) and P. aeruginosa. At the TOC visit,
253
all the baseline S. pneumoniae (6), S. aureus (including MRSA, 4) and H. influenzae (5) strains were
254
eradicated in nemonoxacin 500 mg and 750 mg groups. The K. pneumoniae and P. aeruginosa strains were
255
eradicated except one each in nemonoxacin 750 mg group. All the baseline isolates in levofloxacin 500 mg
256
group were eradicated except one S. pneumoniae, one H. influenzae and two K. pneumoniae strains.
257
Comprehensive efficacy
258
The comprehensive efficacy was evaluated in terms of clinical and bacteriological efficacy at the TOC visit
259
in the BPPS population of this study. Fifty subjects were included for assessment of comprehensive efficacy,
260
including 17 each in nemonoxacin 500 mg and 750 mg groups and 16 in levofloxacin 500 mg group. The
261
comprehensive success rate at TOC in the BPPS population was 87.5% in nemonoxacin 500 mg group,
AC C
EP
252
12
ACCEPTED MANUSCRIPT 262
93.8% in nemonoxacin 750 mg group and 81.3% in levofloxacin 500 mg group. Logistic regression analysis
263
did not find significant difference between these three treatment groups.
264
All the common respiratory pathogens isolated from this study including S. pneumoniae and H. influenzae were susceptible to nemonoxacin and levofloxacin (Table 6). S. aureus including one MRSA
266
strain were also sensitive to nemonoxacin.
267
Safety and tolerability
268
A total of 177 subjects who received at least one dose of study drug were included in SS population.
269
Sixty-two patients received nemonoxacin 500 mg, 59 received nemonoxacin 750 mg and 56 received
270
levofloxacin 500 mg. The incidence of treatment emergent adverse events (TEAEs) was 41.9% in
271
nemonoxacin 500 mg group, 55.9% in nemonoxacin 750 mg group and 42.9% in levofloxacin 500 mg,
272
respectively (Table 7). The incidence of drug-related TEAEs was similar in the three treatment groups:
273
30.6%, 35.6% and 25.0%, respectively (P > 0.05).
TE D
M AN U
SC
RI PT
265
A total of 28 drug-related TEAEs were observed in 19 subjects in nemonoxacin 500 mg group,
275
including 3 clinical AEs (mainly anorexia, nausea, and epigastric discomfort) in 3 (4.8%) patients and 25
276
episodes of laboratory abnormality (mainly leukopenia and elevated alanine aminotransferase) in 16 (25.8%)
277
patients. No patient had both drug-related AE and laboratory abnormality.
AC C
EP
274
278
A total of 43 drug-related TEAEs were observed in 21 subjects in nemonoxacin 750 mg group,
279
including 22 clinical AEs in 12 (20.3%) patients and 21 episodes of laboratory abnormality in 13 (22.0%)
280
patients. The most common drug-related TEAEs (≥ 2%) were nausea, vomiting, leukopenia and abnormal
281
liver function. Four patients experienced both clinical AEs and laboratory abnormality during the study.
282 283
A total of 24 drug-related TEAEs were observed in 14 subjects in levofloxacin 500 mg group, including 8 clinical AEs in 5 (8.9%) patients and 16 episodes of laboratory abnormality in 11 (19.6%) patients. The
13
ACCEPTED MANUSCRIPT 284
most common drug-related TEAEs (≥ 2%) were nausea, vomiting, leukopenia, neutropenia and elevated
285
urinary protein. Two patients experienced both clinical AEs and laboratory abnormality during the study Drug related QT interval prolongation was observed in all three treatment groups: 3.2% (n = 2) in
287
nemonoxacin 500 mg group, 5.1% (n = 3) in nemonoxacin 750 mg group and 1.8% (n = 1) in levofloxacin
288
500 mg group. Prolongation of QT interval was all shorter than 30 ms except in one female patient in
289
nemonoxacin 750 mg group (557 ms). Two cases of drug related cardiac bundle branch block were observed
290
in nemonoxacin 500 mg group (3.2%). One case of drug related ventricular premature beats was observed in
291
levofloxacin 500 mg group.
SC
M AN U
292
RI PT
286
All the drug-related TEAEs were mild to moderate in severity, more than 90% of which were defined as mild. The proportion of AEs classified as mild was 96.4% in nemonoxacin 500 mg group, 93.0% in
294
nemonoxacin 750 mg and 92.0% in levofloxacin 500 mg, respectively. Only one patient in nemonoxacin 750
295
mg group experienced facial twitch which resulted in discontinuation of the study drug. This symptom
296
disappeared quickly after discontinuation of the study drug. No drug related serious adverse event was
297
observed in this study.
298
Discussion
299
The results of this study demonstrated that oral nemonoxacin 500 mg or 750 mg once daily for 7-10 days
300
achieved excellent clinical and microbiological efficacy in treatment of CAP in Chinese adults. Both
301
nemonoxacin 750 mg and 500 mg were noninferior to levofloxacin 500 mg for treatment of adult CAP in
302
terms of primary efficacy at the TOC visit in FAS population. The microbiological efficacy or
303
bacteriological eradication rate was comparable between nemonoxacin and levofloxacin regimens.
304 305
AC C
EP
TE D
293
Our results prove that nemonoxacin is highly active with broad-spectrum activity against major CAP pathogens. CAP patients infected with S. pneumoniae, H. influenzae, M. pneumoniae, C. pneumoniae, or L.
14
ACCEPTED MANUSCRIPT pneumophila were all cured clinically at TOC visit. It should be noted that three of the four S. aureus isolates
307
at baseline were MRSA, all in nemonoxacin treatment group. All the patients with S. aureus infection were
308
successfully cured. The excellent clinical and bacteriological efficacy suggest good activity of nemonoxacin
309
against these resistant strains although the number of patients with MRSA was fewer. In vitro studies showed
310
that nemonoxacin had good activity against gram-positive bacteria including MRSA.16,17
311
RI PT
306
Nemonoxacin was well tolerated in both treatment groups in this trial. More than 93% of the
drug-related TEAEs were mild. Only one patient discontinued the study drug due to TEAE. Drug related
313
TEAEs were mainly mild gastrointestinal disorders, transient leukopenia and elevated liver enzymes. The
314
incidence of drug related TEAEs in the present study was similar to that reported in a phase II clinical trial
315
carried out in South Africa, in which the incidence of adverse events was 30.3% in nemonoxacin 500 mg
316
group, 31.4% in nemonoxacin 750 mg group and 30.0% in levofloxacin 500 mg group. The most common
317
AEs in the South Africa study were mild gastrointestinal disorders and transient neutropenia. 15
TE D
M AN U
SC
312
The overall incidence of drug related TEAEs in nemonoxacin 750 mg group (35.6%) was slightly
319
higher than that in nemonoxacin 500 mg group (30.6%). These suggest that nemonoxacin 500 mg treatment
320
regimen may be safer than 750 mg regimen in treatment of adult CAP. In future phase III clinical trials,
321
nemonoxacin 500 mg regimen will be recommended based on its similar efficacy and better safety profile
322
compared with 750 mg regimen.
AC C
323
EP
318
In summary, oral nemonoxacin (500 mg or 750 mg) once daily for 7-10 days showed good clinical and
324
microbiological efficacy in treatment of adult CAP. Either 750 mg or 500 mg nemonoxacin once daily has
325
proved noninferior to levofloxacin 500 mg at test of cure visit and both regimens were well tolerated. The
326
incidence of drug related TEAEs in nemonoxacin 750 mg group was slightly higher than that in
327
nemonoxacin 500 mg group but the difference was not significant. Based on the above results, nemonoxacin
15
ACCEPTED MANUSCRIPT 328
500 mg once daily for 7-10 days will be recommended for future phase III clinical trials.
AC C
EP
TE D
M AN U
SC
RI PT
329
16
ACCEPTED MANUSCRIPT Conflicts of interest
331
TaiGen Biotechnology Co., Ltd. provided the study drug nemonoxacin used in this study. One of the
332
Liwen Chang, is an employee of TaiGen Biotechnology Co., Ltd.
333
Acknowledgements
334
This study was supported by the major research and development project of innovative drugs under the
335
auspices of Ministry of Science and Technology of China (2008ZX09312-010 and 2012ZX09303004-001).
336
We thank all the study subjects for their cooperation and the laboratory technicians for assistance in
337
performing the antimicrobial susceptibility tests.
M AN U
SC
RI PT
330
AC C
EP
TE D
338
17
ACCEPTED MANUSCRIPT 339
References
340
1.
Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the
342
Global Burden of Disease Study 2010. Lancet 2012;380:2095-128.
343
2.
RI PT
341
Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of
345
America/American Thoracic Society consensus guidelines on the management of
346
community-acquired pneumonia in adults. Clin Infect Dis 2007;44:S27-72. 3.
M AN U
347
SC
344
Peto L, Nadjm B, Horby P, Ngan TT, van Doorn R, Van Kinh N, et al. The bacterial aetiology of adult
348
community-acquired pneumonia in Asia: a systematic review. Trans R Soc Trop Med Hyg
349
2014;108:326-37.
patterns. Eur Respir J Suppl 2002;36:20s-7s.
351 5.
resistance in China. Chin J Infect Chemother 2014;14:369-78.
353 354
Hu FP, Zhu DM, Wang F, Guo Y, Yang Y, Jiang XF, et al. CHINET 2013 surveillance of bacterial
6.
EP
352
Woodhead M. Community-acquired pneumonia in Europe: causative pathogens and resistance
TE D
4.
Guo B, Wu X, Zhang Y, Shi Y, Yu J, Cao G, et al. Safety and clinical pharmacokinetics of
AC C
350
355
nemonoxacin, a novel non-fluorinated quinolone, in healthy Chinese volunteers following single and
356
multiple oral doses. Clin Drug Investig 2012;32:475-86.
357
7.
Adam HJ, Laing NM, King CR, Lulashnyk B, Hoban DJ, Zhanel GG. In vitro activity of nemonoxacin,
358
a novel nonfluorinated quinolone, against 2,440 clinical isolates. Antimicrob Agents Chemother
359
2009;53:4915-20.
360
8.
Chen YH, Liu CY, Lu JJ, King CH, Hsueh PR. In vitro activity of nemonoxacin (TG-873870), a novel
18
ACCEPTED MANUSCRIPT 361
non-fluorinated quinolone, against clinical isolates of Staphylococcus aureus, enterococci and
362
Streptococcus pneumoniae with various resistance phenotypes in Taiwan. J Antimicrob Chemother
363
2009;64:1226-29. 9.
Chen YH, Liu CY, Ko WC, Liao CH, Lu PL, Huang CH, et al. Trends in the susceptibility of
RI PT
364
methicillin-resistant Staphylococcus aureus to nine antimicrobial agents, including ceftobiprole,
366
nemonoxacin, and tyrothricin: results from the Tigecycline In Vitro Surveillance in Taiwan (TIST)
367
study, 2006-2010. Eur J Clin Microbiol Infect Dis 2014;33:233-39.
10. Lai CC, Tan CK, Lin SH, Liao CH, Chou CH, Hsu HL, et al. Comparative in vitro activities of
M AN U
368
SC
365
369
nemonoxacin, doripenem, tigecycline and 16 other antimicrobials against Nocardia brasiliensis,
370
Nocardia asteroides and unusual Nocardia species. J Antimicrob Chemother 2009;64:73-8.
371
11. Lauderdale TL, Shiau YR, Lai JF, Chen HC, King CH. Comparative in vitro activities of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, and other quinolones against clinical isolates.
373
Antimicrob Agents Chemother 2010;54:1338-42.
376
nemonoxacin, a novel non-fluorinated quinolone. J Antimicrob Chemother 2010;65:2411-15.
EP
375
12. Li CR, Li Y, Li GQ, Yang XY, Zhang WX, Lou RH, et al. In vivo antibacterial activity of
13. Chung DT, Tsai CY, Chen SJ, Chang LW, King CH, Hsu CH, et al. Multiple-dose safety, tolerability,
AC C
374
TE D
372
377
and pharmacokinetics of oral nemonoxacin (TG-873870) in healthy volunteers. Antimicrob Agents
378
Chemother 2010;54:411-17.
379
14. Lin L, Chang LW, Tsai CY, Hsu CH, Chung DT, Aronstein WS, et al. Dose escalation study of the
380
safety, tolerability, and pharmacokinetics of nemonoxacin (TG-873870), a novel potent
381
broad-spectrum nonfluorinated quinolone, in healthy volunteers. Antimicrob Agents Chemother
382
2010;54:405-10.
19
ACCEPTED MANUSCRIPT 383
15. Van Rensburg DJ, Perng RP, Mitha IH, Bester AJ, Kasumba J, Wu RG, et al. Efficacy and safety of
384
nemonoxacin versus levofloxacin for community-acquired pneumonia. Antimicrob Agents Chemother
385
2010;54:4098-106.
387 388
16. Lai CC, Lee KY, Lin SW, Chen YH, Kuo HY, Hung CC, et al. Nemonoxacin (TG-873870) for
RI PT
386
treatment of community-acquired pneumonia. Expert Rev Anti Infect Ther 2014;12:401-17. 17. Poole RM. Nemonoxacin: first global approval. Drugs 2014;74:1445-53.
AC C
EP
TE D
M AN U
SC
389
20
ACCEPTED MANUSCRIPT 390
Table 1 Clinical response at the test of cure visit. Nemonoxacin 500 mg
Nemonoxacin 750 mg
Levofloxacin 500 mg
N (%)
N (%)
N (%)
56 (93.3)
48 (87.3)
4 (6.7)
7 (12.7)
0
1
Clinical failure Unevaluable
Clinical cure
51 (89.5)
Clinical failure
6 (10.5)
Unevaluable
TE D EP 21
46 (88.5) 6 (11.5) 0
44 (89.8)
39 (88.6)
5 (10.2)
5 (11.4)
1
1
* Unevaluable cases were not included in the denominator.
AC C
391
0
M AN U
Per protocol set
SC
Clinical cure
RI PT
Full analysis set
ACCEPTED MANUSCRIPT
Table 2 Clinical efficacy and treatment difference of the three groups at the test of cure visit. Levofloxacin 500 mg N (%)
Nemonoxacin 500 mg N (%)
Treatment
P value (95% CI)
4.9%
Per protocol set
40 (88.9)
53 (93.0)
4.1%
0.851 (-7.23%, 15.42%)
EP
TE D
Treatment difference = nemonoxacin group - levofloxacin group.
0.569 (-5.86%, 15.61%)
M AN U
56 (93.3)
AC C
393
46 (88.5)
SC
difference Full analysis set
RI PT
392
22
N (%)
Nemonoxacin 750 mg Treatment
P value (95% CI)
difference
48 (87.3)
-1.2%
0.71 (-13.56%, 11.18%)
46 (93.9)
5.0%
0.62 (-6.39%, 16.36%)
ACCEPTED MANUSCRIPT 394
Table 3 Logistic regression analysis of the efficacy of nemonoxacin treatments compared with
395
levofloxacin at the test of cure visit. Nemonoxacin 500 mg 95% CI
Wald χ2
P
OR
95% CI
Wald χ2
Full analysis set
1.83
(0.49, 6.86)
0.7947
0.3727
0.89
(0.28, 2.86)
0.0354
0.8508
Per protocol set
1.66
(0.42, 6.57)
0.5155
0.4728
1.92
(0.43, 8.53)
0.7297
0.3930
EP
TE D
M AN U
SC
OR, the ratio between nemonoxacin treatment and levofloxacin in terms of clinical efficacy rate.
23
P
RI PT
OR
AC C
396
Nemonoxacin 750 mg
ACCEPTED MANUSCRIPT
397
Table 4 Clinical efficacy at test of cure visit by primary baseline pathogens in full analysis set. Number of isolates
Nemonoxacin 500 mg
Nemonoxacin 750 mg
RI PT
Pathogens n1/n2 (%)
a
n1/n2 (%)
n1/n2 (%)
4/4 (100)
3/4 (75.0)
2/2 (100)
0/0
2/2 (100)
3/4 (75.0)
a
Typical pathogen
Levofloxacin 500 mg a
S. pneumoniae
11
2/2 (100)
S. aureus
4
2/2 (100)
H. influenzae
9
3/3 (100)
H. parainfluenzae
9
2/3 (66.7)
3/4 (75.0)
2/2 (100)
K. pneumoniae
16
4/4 (100)
2/3 (66.7)
7/9 (77.8)
M. pneumoniae
29
7/7 (100)
13/14 (92.9)
8/8 (100)
L. pneumophila
3
2/2 (100)
0/0
1/1 (100)
C. pneumoniae
1
0/0
1/1 (100)
0/0
SC
M AN U
c
b
EP
TE D
Atypical pathogen only
a
n1: the number of strains actually or presumably eradicated; n2, total number of evaluable strains.
399
b
There were five S. pneumoniae isolates at the end of treatment. One strain was unevaluable because the subject received acetylspiramycin before the test of cure
400
visit.
401
c
AC C
398
Of the 4 S. aureus isolates, 3 were methicillin-resistant, including 2 in nemonoxacin 500 mg group and 1 in nemonoxacin 750 mg group.
24
ACCEPTED MANUSCRIPT
402
Table 5 Bacteriological efficacy at the test of cure visit by treatment group. Nemonoxacin 750 mg
N (%) Bacteriological full analysis seta
SC
RI PT
Nemonoxacin 500 mg
Levofloxacin 500 mg
N (%)
N (%)
15 (83.3)
16 (80.0)
15 (83.3)
Bacteriological failurec
3 (16.7)
3 (16.7)
4 (20.0)
0
1
0
14 (82.4)
15 (93.8)
13 (81.3)
3 (17.7)
1 (6.2)
3 (18.7)
1
0
M AN U
Bacteriological successb
Unevaluable
Bacteriological failure
0
AC C
Unevaluable
EP
Bacteriological success
TE D
Bacteriological per protocol set
403
a
Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila were not included.
404
b
Bacteriological success included eradication and presumed eradication.
405
c
Bacteriological failure included persistence, presumed persistence and partial eradication.
25
ACCEPTED MANUSCRIPT
Table 6 In vitro susceptibilities of primary baseline isolates to the study drugs. Nemonoxacin
Levofloxacin
Bacteria (n)
MIC50 (mg/L)
MIC90 (mg/L)
0.125
0.25
0.03-1
0.25
0.5
S. aureusb (4)
0.06-1
K. pneumoniae (19)
0.06-＞32
0.5
0.008-1
0.06
M AN U
TE D
taken. b
32
0.06-＞32
0.125
＞32
1
0.008-1
0.06
1
Thirteen S. pneumoniae strains were isolated in all randomized groups and two of those were excluded from BFAS because of wrong drugs
MIC50 and MIC90 were not calculated because of few strains.
EP
a
0.125-32
AC C
410
MIC range (mg/L)
0.015-1
408 409
MIC90 (mg/L)
S. pneumoniae (13)a
H. influenzae and H. parainfluenzae (16) 407
MIC50 (mg/L)
SC
MIC range (mg/L)
RI PT
406
26
ACCEPTED MANUSCRIPT
Table 7 Summary of the most common treatment-related adverse events (≥ 2% in any one group) by system organ and preferred term.
System organ class and preferred term
(N = 62) n (%)
Subjects with any treatment-related adverse event
19 (30.6) 1 (1.6)
M AN U
Nausea
Levofloxacin 500 mg
(N = 59)
(N = 56)
n (%)
n (%)
21 (35.6)
14 (25.0)
SC
Digestive system
Nemonoxacin 750 mg
RI PT
Nemonoxacin 500 mg
6 (10.2)
1 (1.8)
Vomiting
0
4 (6.8)
2 (3.6)
Stomach upset
0
2 (3.4)
1 (1.8)
Leukopenia
4 (6.5)
6 (10.2)
4 (7.1)
Neutropenia
2 (3.2)
2 (3.4)
2 (3.6)
2 (3.2)
1 (1.7)
0
1 (1.6)
2 (3.4)
1 (1.8)
0
3 (5.1)
0
3 (4.8)
0
1 (1.8)
0
1 (1.7)
2 (3.6)
2 (3.2)
3 (5.1)
1 (1.8)
2 (3.2)
0
0
Percentage of neutrophils increased Metabolic and nutritional Abnormal liver function Elevated alanine aminotransferase Elevated urinary protein Cardiovascular system QT interval prolongation Bundle branch block
EP
Percentage of eosinophils increased
TE D
Blood and lymphatic system
AC C
411
27
ACCEPTED MANUSCRIPT FIGURE LEGEND
412
Figure 1. Patient disposition flow chart. NEMO, nemonoxacin; LEVO, levofloxacin; SS,
414
safety set; FAS, full analysis set; PPS, per protocol set; BFAS, bacteriological full analysis set;
415
BPPS, bacteriological per protocol set.
AC C
EP
TE D
M AN U
SC
RI PT
413
28
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT