Clinical Trials Register

Summary
EudraCT Number:	2013-001913-34
Sponsor's Protocol Code Number:	TP-434-008
National Competent Authority:	Estonia - SAM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-08-01
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

Estonia - SAM

A.2

EudraCT number

2013-001913-34

A.3

Full title of the trial

A Phase 3, Randomized, Double-Blind, Double-Dummy, Multicenter, Prospective Study to Assess the Efficacy and Safety of Eravacycline Compared with Ertapenem in Complicated Intra-abdominal Infections

A.3.1

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

Multicenter Study to Assess the Efficacy and Safety of a study drug, Eravacycline, Compared with an approved drug, Ertapenem, in Complicated Intra-abdominal Infections

A.4.1

Sponsor's protocol code number

TP-434-008

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01844856

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	Tetraphase Pharmaceuticals, 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	Tetraphase Pharmaceuticals, 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	PSI Company Ltd.
B.5.2	Functional name of contact point	RA BalticStates
B.5.3	Address:
B.5.3.1	Street Address	19/21 Dostoevsky St.
B.5.3.2	Town/ city	St. Petersburg
B.5.3.3	Post code	191119
B.5.3.4	Country	Russian Federation
B.5.4	Telephone number	+78123203824
B.5.5	Fax number	+78123203850
B.5.6	E-mail	RABalticStates@psi-cro.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.3.1	Product name	eravacycline
D.3.2	Product code	TP-434
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	ERAVACYCLINE
D.3.9.2	Current sponsor code	TP-434
D.3.9.4	EV Substance Code	SUB117477
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	53.0
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	Invanz
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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 concentrate 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	ERTAPENEM
D.3.9.1	CAS number	0153832-46-3
D.3.9.3	Other descriptive name	ERTAPENEM
D.3.9.4	EV Substance Code	SUB25388
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Complicated Intra-abdominal Infections

E.1.1.1

Medical condition in easily understood language

Complicated Intra-abdominal Infections

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10056570
E.1.2	Term	Intra-abdominal infection
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

Compare the clinical response at the test-of-cure (TOC) visit in the microbiological intent-to-treat (micro-ITT) population for subjects in the 2 treatment arms

E.2.2

Secondary objectives of the trial

Compare the clinical response for subjects in the 2 treatment arms at the end-of-treatment (EOT), TOC, and follow-up (FU) visits in the following populations:
- Intent-to-treat (ITT) population
-All-treated (MITT)
- Clinically evaluable (CE) population
- Micro-ITT population (for EOT and FU)
- Microbiologically evaluable (ME) population

Compare the microbiologic response in the treatment arms at the EOT and TOC visits in the following populations:
- Micro-ITT population
- ME population

Assess the safety and tolerability of eravacycline administration in the safety population

Explore pharmacokinetic (PK) parameters after eravacycline infusion including Cmax, Tmax, AUC0-12

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female subject hospitalized for cIAI with one of the following diagnoses:
a. Intra-abdominal abscess: one or more abscesses surrounding diseased or perforated viscera
b. Gastric or intestinal perforation associated with diffuse peritonitis
c. Peritonitis due to perforated viscus, or other focus of infection (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites)
d. Appendicitis with perforation, peritonitis or abscess
e. Cholecystitis with perforation or abscess
f. Intra-abdominal abscess (single or multiple), including hepatic and splenic abscesses
g. Peritonitis (local or diffuse)
Note: infections limited to the hollow viscus, such as simple cholecystitis and simple appendicitis, are not eligble. Ischemic bowel disease without perforation is not eligible. Acute suppurative cholangitis and acute necrotizing pancreatitis are not eligible.
2. At least 18 years of age (and not over 65 years of age for subjects in India)
3. Evidence of a systemic inflammatory response with at least one of the following:
a. Fever (oral, rectal tympanic or by temporal artery temperature > 100.4°F / 38°C) or hypothermia (temperature ≤ 95.9°F / 35.5°C)
b. Elevated WBC (>Upper Limit of Normal (ULN) laboratory range); or proportion of band forms of the WBC differential beyond the ULN laboratory range
c. Increased pulse (HR > 90 beats per minute)
d. Increased respiratory rate (> 20 breathes per minute)
4. Abdominal pain or flank pain (with or without rebound tenderness), or pain caused by cIAI that is referred to another anatomic area such as back or hip, or localized or diffuse abdominal wall rigidity, or mass, or ileus
5. Able to provide informed consent
6. If male: must agree to use an effective barrier method of contraception during the study and for 30 days following the last dose if sexually active with a female of childbearing potential
7. If female:
a. Not pregnant or nursing
b. If of childbearing potential, will commit to either:
i. Use at least two medically accepted, effective methods of birth control (e.g., condom, oral contraceptive, indwelling intrauterine device, hormonal implant /patch, injections, approved cervical ring) during study drug dosing and for 30 days following last study drug dose
ii. Sexual abstinence

And either
8A. Meets All Inclusion Criteria for Pre-operative Enrollment:
-Has a sonogram or radiographic imaging result congruent with the diagnosis of cIAI, AND
-Acute surgical or percutaneous intervention (open laparotomy, laparoscopic surgery, or percutaneous drainage of an abscess) is foreseen within 48-h
8B. Meets All Inclusion Criteria for Intra-operative/Post-operative Enrollment:
-Visual confirmation of cIAI (presence of pus within the abdominal cavity), AND
-Surgical intervention includes open laparotomy, laparoscopic surgery, or percutaneous draining of an abscess, AND
- Intervention is adequate (i.e., a procedure in which all communications between the gastrointestinal (GI) tract and the peritoneal cavity are closed, no necrotic intestine is left, and all infected collections are drained at the procedure)

E.4

Principal exclusion criteria

1. Considered unlikely to survive the 6-8 week study period
Any rapidly-progressing disease or immediately life-threatening illness, including acute hepatic failure, respiratory failure and septic shock
Requirement for vasopressors (prior to enrollment) at therapeutic dosages (i.e., dopamine > 5 μg/kg/min, any dose of norepinephrine, epinephrine or phenylephrine) to maintain a systolic blood pressure ≥ 90 mm Hg or a mean
arterial pressure ≥ 70 mm Hg following adequate fluid resuscitation
2. Renal failure as defined as:
a. Threefold increase of serum creatinine to a known previous value OR
b. Decrease in estimated glomerular filtration rate to < 75% of a known previous value OR
c. Urine output of < 0.3 mL/kg per h for > 24-h OR
d. Anuria for > 12-h OR
e. Serum creatinine of > 4 mg/dL (353.6 μmol/L) with an acute rise of 0.5 mg/dL (42.2 μmol/L) compared with a previous value or
f. Creatinine clearance of < 50 mL/min as estimated by the Cockcroft-Gault equation, OR = (140-age [years]
* body weight [kg] * 0.85 [if female] / 72 * serum creatinine [mg/dL]
g. Requires peritoneal dialysis, hemodialysis or hemofiltration
3. Presence or possible signs of significant hepatic disease:
a. Alanine aminotransferase or aspartate aminotransferase > 3 x ULN; > 5 x ULN for patients with hepatic abscess or
b. Total bilirubin > 3 x ULN, unless isolated hyperbilirubinemia is directly related to the acute process or
c. Alkaline phosphatase > 3 x ULN or
d. Subjects with diagnosis of hepatic failure
4. Immunocompromised condition, including known HIV positivity (requiring anti-retroviral therapy or with CD4 count <300), AIDS, organ (bone marrow) transplant recipients, and hematological malignancy.
Immunosuppressive therapy, including use of high-dose corticosteroids (e.g., > 40 mg prednisone or equivalent per day for greater than 2 weeks)
5. History of moderate or severe hypersensitivity reactions to tetracyclines, carbapenems, β-lactam antibiotics or to any of the excipients contained in the study drug formulations
6. Participation in any investigational drug or device study within 30 days prior to study entry
7. Known or suspected current central nervous system (CNS) disorder that may predispose to seizures or lower seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy)
8. Previously received eravacycline in a clinical trial
9. Antibiotic-related exclusions:
a. Receipt of effective antibacterial drug therapy for cIAI for a continuous duration of > 24-h during the 72-h preceding enrollment (however, subjects with documented cIAI (i.e., known baseline pathogen) who have received at least 72-h of antibiotic therapy and are considered treatment failures may be
enrolled. Treatment failure is defined as persistent fever and/or clinical symptoms; or the development of a new intra-abdominal abscess after ≥ 72-h of antibiotic therapy), or
b. Receipt of ertapenem or any other carbapenem, or tigecycline for the current infection or
c. Need for concomitant systemic antimicrobial agents other than study drug
10. Refusal of mechanical ventilation, dialysis or hemofiltration, cardioversion or any other resuscitative measures and drug/fluid therapy at time of consent
11. Known or suspected inflammatory bowel disease or associated visceral abscess
12. The anticipated need for systemic antibiotics for a duration of more than 14 days
13. Systemic malignancy that required chemotherapy, immunotherapy, radiation therapy or antineoplastic therapy within the previous 3 months or that is anticipated to begin prior to the TOC visit
14. Known at study entry to have cIAI caused by a pathogen(s) resistant to one of the study drugs

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of this study will be the clinical response at the Test-of-cure visit in the micro-ITT population.

E.5.1.1

Timepoint(s) of evaluation of this end point

The test-of-cure (TOC) visit

E.5.2

Secondary end point(s)

The secondary endpoints of the study are:
 Clinical response at the EOT, TOC, and FU visits
 Microbiologic response for subjects in the 2 treatment arms at the EOT and TOC visits

E.5.2.1

Timepoint(s) of evaluation of this end point

The End of Trial, Test-of-cure and Follow Up visits

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

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Argentina

Bulgaria

Czech Republic

Estonia

France

Germany

India

Latvia

Lithuania

Romania

Russian Federation

South Africa

Ukraine

United Kingdom

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

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:

483

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Subjects must be able to provide informed consent however if they are incapable of giving consent personally, for example if they are blind or illiterate, then the option for a legal representative or a witness to sign is available.

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

295

F.4.2.2

In the whole clinical trial

536

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)

Post-operative treatment for subjects who completed his/her participation in the trial is not different from the standard treatment for patients with complicated intra-abdominal infection

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

2013-08-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-08-26

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