Clinical Trials Register

Summary
EudraCT Number:	2014-000914-76
Sponsor's Protocol Code Number:	1409R2121
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-01-06
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Bulgarian Drug Agency

A.2

EudraCT number

2014-000914-76

A.3

Full title of the trial

A Multicenter, Double-blind, Randomized, Clinical Study to Assess the Efficacy and Safety of Intravenous S-649266 in Complicated Urinary Tract Infections with or without Pyelonephritis or Acute Uncomplicated Pyelonephritis Caused by Gram-Negative Pathogens in Hospitalized Adults in Comparison with Intravenous Imipenem/Cilastatin

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A randomized study in hospitalised patients with complicated urinary tract infections caused by Gram-negative bacteria to compare the efficacy and safety of S-649266 to Imipenem/Cilastin, both administered by intravenous infusion

A.4.1

Sponsor's protocol code number

1409R2121

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Shionogi Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Shionogi Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Medpace UK
B.5.2	Functional name of contact point	Guido Moesker
B.5.3	Address:
B.5.3.1	Street Address	Wallace House, 17-21 Maxwell Place
B.5.3.2	Town/ city	Sterling
B.5.3.3	Post code	FK8 1JU
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+441786 460 415 4415
B.5.6	E-mail	g.moesker@medpace.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	S-649266
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.3	Other descriptive name	S-649266
D.3.9.4	EV Substance Code	SUB131099
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Tienam
D.2.1.1.2	Name of the Marketing Authorisation holder	MSD SHARP & DOHME DE ESPANA, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Imipenem
D.3.9.1	CAS number	74431-23-5
D.3.9.3	Other descriptive name	IMIPENEM MONOHYDRATE
D.3.9.4	EV Substance Code	SUB21472
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cilastatin
D.3.9.3	Other descriptive name	CILASTATIN SODIUM
D.3.9.4	EV Substance Code	SUB01295MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Complicated Urinary Tract Infections with or without Pyelonephritis or Acute Uncomplicated Pyelonephritis caused by Gram-negative Pathogens

E.1.1.1

Medical condition in easily understood language

Complicated Urinary Tract Infections caused by Gram-negative pathogens

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	HLT
E.1.2	Classification code	10046577
E.1.2	Term	Urinary tract infections
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare the composite outcome of clinical cure and microbiologic eradication of S-649266 with those of imipenem/cilastatin (IPM/CS) in a patient population at risk for multidrug resistant (MDR) Gram-negative pathogens originating from complicated urinary tract infection (cUTI) with or without pyelonephritis or acute uncomplicated pyelonephritis at the test of cure (TOC) (approximately 7 days following the end of treatment (EOT); (EOT is defined as the last day of study drug treatment).

E.2.2

Secondary objectives of the trial

● To assess the safety of S-649266 in a patient population with the potential to have MDR bacterial infections.
● To compare the clinical and microbiologic responses of S-649266 with IPM/CS in a patient population at risk for MDR Gram-negative pathogens at early assessment (EA), EOT, and at Follow-Up (FUP) as defined in the Acceptable Time Windows
● To assess microbiologic response per pathogen at EA, EOT, TOC, and FUP.
● To assess microbiologic response per patient at EA, EOT, TOC, and FUP.
● To assess clinical response per pathogen at EA, EOT, TOC, and FUP.
● To assess clinical response per patient at EA, EOT, TOC, and FUP.
● To determine plasma and urine drug concentrations at specified times post dose in a population of patients with acute infection.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Hospitalized patients who have a clinical diagnosis of either cUTI with or without pyelonephritis or acute uncomplicated pyelonephritis, and who have provided written informed consent or informed consent provided by legal guardian. (Note: Country specific rules and local Ethics Committee approval for legal guardian informed consent will determine whether or not a patient unable to comprehend or sign the informed consent is allowed to be enrolled in the study).
The specific clinical diagnosis will include:

cUTI with a history of at least one of the following:
•Indwelling urinary catheter or recent instrumentation of the urinary tract (within 14 days prior to screening)
•Urinary retention caused by benign prostatic hypertrophy
• Urine retention of at least 100 millileters (mL) or more of residual urine after voiding (neurogenic bladder)
•Obstructive uropathy (nephrolithiasis, fibrosis, etc.)
•Azotemia caused by intrinsic renal disease (BUN and creatinine values greater than normal laboratory values)
OR
Pyelonephritis and normal urinary tract anatomy, ie, acute uncomplicated pyelonephritis

AND
All patients must have at least two of the following signs or symptoms:
•Chills or rigors or warmth associated with fever (temperature greater than or equal to 38 degrees Celsius)
•Flank pain (pyelonephritis) or suprapubic/pelvic pain (cUTI)
•Nausea or vomiting
•Dysuria, urinary frequency, or urinary urgency
•Costo-vertebral angle tenderness on physical examination

AND
Urinalysis evidence of pyuria demonstrated by:
•Dipstick analysis positive for leukocyte esterase
•Or ≥10 WBCs per μL in unspun urine, or ≥10 WBCs per high power field in spun urine)
2. Patients who had a positive urine culture obtained within 48 hours prior to randomization containing ≥ 100000CFU/mL of a Gram-negative uropathogen likely to be susceptible to imipenem are eligible for this study (Note: patients may be enrolled prior to the results of the urine culture being available)
3. Patients, who have been treated previously with an empiric antibiotic other than the study medications, but failed treatment, both clinically and microbiologically, are eligible for the study if they have an identified uropathogen which is non-susceptible to the empiric treatment and is a Gram-negative uropathogen likely to be susceptible to imipenem (or alternative carbapenem antibiotic).
4. Female patients can participate if they are surgically sterile or have completed menopause, or if they are capable of having children, are not pregnant or nursing and they agree not to attempt pregnancy from the screening until end of study (EOS) (approximately 28 days following EOT) or according to country specific requirements, whichever is longer.

E.4

Principal exclusion criteria

1. Have a history of hypersensitivity reactions to carbapenems, cephalosporins, penicillins, or other β-lactam antibiotics
2. Patient's urine culture at study entry isolates more than 2 uropathogens, regardless of colony count, or patient has a confirmed fungal UTI.
3. Patients with asymptomatic bacteriuria, the presence of ≥100000CFU/mL of a uropathogen and pyuria but without local or systemic symptoms
4. Patient is receiving hemodialysis or peritoneal dialysis. Impairment of renal function with an estimated CrCl < 21 mL/min, requirement for peritoneal dialysis, hemodialysis or hemofiltration, or oliguria (< 20 mL/h urine output over 24 hours).

E.5 End points

E.5.1

Primary end point(s)

Clinical and microbiologic response: Clinical cure in clinical outcomes (resolution of the signs and symptoms of cUTI or return to pre-infection baseline if known) and Eradication in microbiological outcomes (microbiological success) at the Test of Cure (TOC).

E.5.1.1

Timepoint(s) of evaluation of this end point

Test of cure (TOC) - EOT + 7 days

E.5.2

Secondary end point(s)

Microbiologic response per pathogen and patient at EA, EOT, TOC, and FUP
Clinical response per patient and pathogen at EA, EOT, TOC, and FUP
Pharmacokinetic and safety profile

E.5.2.1

Timepoint(s) of evaluation of this end point

Early assessment (EA) - Day 4
End of treatment (EOT) - last day of study drug ie up to 14 days
Test of cure (TOC) - EOT + 7 days
Follow-up (FUP) - EOT + 14 days

PK Days 3-5: plasma-prior to, just before the end and 2 hours post infusion; urine-2 and 6 hours after the start of infusion

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Bulgaria

Chile

Colombia

Croatia

Czech Republic

Ecuador

Georgia

Germany

Guatemala

Hungary

Italy

Japan

Latvia

Peru

Poland

Romania

Russian Federation

Spain

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last Visit Last Subject (LVLS)

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

202

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

248

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

384

F.4.2.2

In the whole clinical trial

450

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After participation in the trial, patients will be treated with the current standard therapy.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-02-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-12-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-08-16

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