SYNOPSIS
Name of Sponsor/Company
Name of Finished ProductName of Active Ingredient
Title of Study
Investigators
Study Centre(s)Publication (reference)
Studied Period
Phase of Development
Objectives

Methodology
Number of Patients(planned and analyzed)

Daiichi Sankyo Co., Ltd.
CRAVIT ® INTRAVENOUS DRIP INFUSION
Levofloxacin
Phase III clinical study of DR-3355 injection in patients with surgicalinfection
8 sites
None
Date of obtaining first consent: August, 2012
Date of last observation: December, 2013
Phase 3
The aim of this open-labeled study is to evaluate efficacy and safetyof DR-3355 injection at a dose of 500 mg once-daily in patients withsurgical infection. Additionally, the efficacy and the safety areevaluated after switching from DR-3355 injection to levofloxacin oralagent.
Open-label, multicentre study
Planned: 30 patients
Registered: 22 patients
Analyzed:
Valid for analysis of clinical efficacy
Valid for analysis of bacteriological efficacy
Valid for analysis of PK
Valid for analysis of safety

Diagnosis and Main Criteria
for Inclusion

18 patients
16 patients
6 patients
22 patients

Diagnosis:
1) Secondary infection after injury, burn, or operation
2) Acute cholecystitis, acute cholangitis
Inclusion:a) Patients with age of 20 or older at the time of obtaining
informed consentsb) Inpatientsc) Patients who need the treatment using injectiond) Patients who satisfied the below criteria at the start of therapy,
and provided proper specimen for cultivation of pathogenic
bacteria before the start of therapy or within 24 hours from thestart of therapy
1) Secondary infection after injury, burn, or operation
Patients who have at least one item in systemic inflammation and 2
or more items in local findings, and receive initial treatment thistime<Systemic inflammation>
Fever, increased WBC count, marked left shift, increased CRP
level, increased pulse rate, or increased respiration rate
<Local findings>
Redness, spontaneous pain/tenderness, pulsation, local warmth,swelling/induration, or discharge of pus/effusion
2) Biliary infection
Patients who satisfied No.1 or 2, and 3, and below criteria of acutecholecystitis or cholangitis, and receive initial treatment this time
1. Patients scheduled for surgery, percutaneous drainage, or biliary
drainage, or done.2. Patients confirmed bile or purulent fluid from indwelling drain
3. Malfunctioning gastrointestinal tract (ex. nausea/vomiting,hypoactive bowel sound, obstruction to the discharge of intestinal
tract gas, symptoms of ileus)<Acute cholecystitis>
At least one item in A, one or more item in B, and CA) Fever, increased WBC count, increased CRP level
B) RUQ mass/pain/tenderness or Murphy’s signC) Imaging findings characteristic of acute cholecystitis

Test Product, Dose andMode of Administration,
Batch Number

Duration of Treatment

Reference Therapy, Doseand Mode ofAdministration, Batch
NumberCriteria for Evaluation

Statistical Method
Summary - Conclusion<Acute cholangitis>
All items in A, or at least one item in A and all items in B
A) Fever, abdominal pain (RUQ or upper abdominal), jaundiceB) Increased serum ALP, or γ-GT levels; increased WBC count, orincreased CRP level; biliary dilatation, or evidence of an etiology(stricture, stone, etc) on imaging findings
Test product (batch number):
DR-3355inj (D3355I0H11T01A)
Oral levofloxacin (D3355F0S11T01A)
Dosage and administration:
Intravenous administration of DR-3355inj at 500 mg, once daily
Oral administration of levofloxacin at 500 mg, once daily
Three to fourteen days
DR-3355inj at 500 mg as a single daily dose by the intravenous
route for at least three days.
Intravenous therapy could be followed by levofloxacin by the oralroute at a single, daily dose of 500 mg to complete a 14-day courseof therapy. The timing of the switch to oral therapy should be doneat the discretion of the physician and in accordance with clinicalresponse.
None

Primary endpoint:
Clinical efficacy at the test of cure
Secondary endpoint:
Bacteriological efficacy at the test of cureThe point estimate of the efficacy rate and the two-sided 95%
confidence interval were calculated by diagnosis.
Efficacy summary:
The primary endpoint was the clinical efficacy rate at the test ofcure in PPS. The efficacy rate was 90.0 % (9/10) in patients withsecondary infection after injury, burn, or operation. All fivepatients with acute cholecystitis and three patients with acutecholangitis were judged as cure.
The bacteriological efficacy rate at the test of cure inPPS(bacterial) was 90.0% (9/10) in patients with secondary
infection after injury, burn, or operation. The bacteriologicalefficacy in three patients with acute cholecystitis and three patientswith acute cholangitis was all judged as eradication. All
causative organisms disappeared in seventeen strains of secondary
infection after injury, burn, or operation, four strains of acutecholecystitis, and four strains of acute cholangitis at the test ofDate of Reportcure.
The mean drug concentration two hours after a single treatment ofDR-3355 injection at 500 mg in 2 patients with acute cholecystitis
was 19.2 μg/mL in bile, 9.6 μg/mL in plasma, and the bile/plasma
ratio was 1.97. The mean drug concentration two hours after asingle treatment of DR-3355 injection at 500 mg in 4 patients withacute cholangitis was 12.0 μg/mL in bile, 6.8 μg/mL in plasma, andthe bile/plasma ratio was 1.82.
Safety summary:
The incidence of adverse events was 63.6% (14/22) up to the testof cure. The events which occurred in two patients werevomiting, dermatitis contact, injection site erythema, or injection
site pain. The incidence of adverse events was 54.5% (12/22) up
to the end of intravenous treatment. The severity ofschizophrenia in a patient was moderate, and the other adverse
events were mild. There was not adverse event that led towithdrawal.
Incidence of adverse drug reactions was 13.6% (3/22) up to the testof cure, and 9.1% (2/22) up to the end of intravenous treatment.
Conclusion:
From these results, DR-3355inj (including switch therapy tolevofloxacin oral agent) is useful for treatment of secondary
infection after injury, burn, or operation, acute cholecystitis, andacute cholangitis, and there is no important problem in the safety.
July 3, 2014