IGNITE4: Efficacy and Safety Study of Eravacycline Compared With Meropenem in Complicated Intra-abdominal Infections

• Sponsor: Tetraphase Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02784704
• Collaborator: (none)
• Enrollment: 500
• Locations: 54
• Arms: 2
• Actual Duration (Months): 7.2
• Patients Per Site: 9.3
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

This is a Phase 3, randomized, double-blind, double-dummy, multicenter, prospective study to assess the efficacy, safety, and pharmacokinetics (PK) of eravacycline compared with meropenem in the treatment of complicated intra-abdominal infections (cIAIs).

Condition or Disease	Intervention/Treatment	Phase
Complicated Intra-abdominal Infections; Complicated Appendicitis	Drug: Eravacycline; Drug: Meropenem; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 500 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind, Double-Dummy, Multicenter, Prospective Study to Assess the Efficacy and Safety of Eravacycline Compared With Meropenem in Complicated Intra-abdominal Infections
• Actual Study Start Date: Oct 13, 2016
• Actual Primary Completion Date: May 8, 2017
• Actual Study Completion Date: May 19, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eravacycline	Drug: Eravacycline; Other Names: TP-434 ; Drug: Placebo
Active Comparator: Meropenem	Drug: Meropenem; Other Names: Merrem ; Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population [TOC visit: 25-31 days after first dose of study drug]

   Clinical cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no additional antibacterial therapy, surgical, or radiological intervention was required. Clinical failure was defined as death related to complicated intra-abdominal infection (cIAI), persistence of clinical symptoms of cIAI, unplanned surgical or percutaneous drainage procedures for complication or recurrence of cIAI, post-surgical wound infections requiring systemic antibiotics, or initiation of rescue antibacterial drug therapy for treatment of cIAI. Indeterminate/missing was defined as an outcome that was neither a clinical cure nor clinical failure, if the investigator did not complete an assessment, if a study visit was not conducted, or if the subject died for a cause unrelated to cIAI.

Secondary Outcome Measures

1. Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the All-Treated (MITT) Population [TOC visit: 25-31 days after first dose of study drug]

   Clinical cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no additional antibacterial therapy, surgical, or radiological intervention was required. Clinical failure was defined as death related to complicated intra-abdominal infection (cIAI), persistence of clinical symptoms of cIAI, unplanned surgical or percutaneous drainage procedures for complication or recurrence of cIAI, post-surgical wound infections requiring systemic antibiotics, or initiation of rescue antibacterial drug therapy for treatment of cIAI. Indeterminate/missing was defined as an outcome that was neither a clinical cure nor clinical failure, if the investigator did not complete an assessment, if a study visit was not conducted, or if the subject died for a cause unrelated to cIAI.

2. Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Clinically Evaluable (CE) Population [TOC visit: 25-31 days after first dose of study drug]

   Clinical cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no additional antibacterial therapy, surgical, or radiological intervention was required. Clinical failure was defined as death related to complicated intra-abdominal infection (cIAI), persistence of clinical symptoms of cIAI, unplanned surgical or percutaneous drainage procedures for complication or recurrence of cIAI, post-surgical wound infections requiring systemic antibiotics, or initiation of rescue antibacterial drug therapy for treatment of cIAI.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female participant hospitalized for cIAI

• At least 18 years of age

• Evidence of a systemic inflammatory response

• Abdominal pain or flank pain (with or without rebound tenderness), or pain caused by cIAI that is referred to another anatomic area

• Able to provide informed consent

• If male: must agree to use an effective barrier method of contraception during the study and for 14 days following the last dose if sexually active with a female of childbearing potential

• If female, not pregnant or nursing or, if of childbearing potential: either will commit to use at least two medically accepted, effective methods of birth control (for example, condom, oral contraceptive, indwelling intrauterine device, hormonal implant /patch, injections, approved cervical ring) during study drug dosing and for 14 days following last study drug dose or practicing sexual abstinence

Exclusion Criteria:

• Unlikely to survive the 6-8 week study period

• Creatinine clearance of ≤50 milliliter (mL)/minute

• Presence or possible signs of significant hepatic disease

• Immunocompromised condition, including known human immunodeficiency virus (HIV) positivity, transplant recipients, and hematological malignancy

• 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

• Participation in any investigational drug or device study within 30 days prior to study entry

• Known or suspected current central nervous system (CNS) disorder that may predispose to seizures or lower seizure threshold (for example, severe cerebral arteriosclerosis, epilepsy)

• Antibiotic-related exclusions:

1. Receipt of effective antibacterial drug therapy for cIAI for a continuous duration of >24-hours during the 72-hours preceding randomization [however, participants with documented cIAI (that is, known baseline pathogen) who have received at least 72-hours 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-hours of antibiotic therapy], or

2. Receipt of meropenem or any other carbapenem, or tigecycline for the current infection, or

3. Need for concomitant systemic antimicrobial agents effective in cIAI other than study drug

• Refusal of mechanical ventilation, dialysis or hemofiltration, cardioversion, or any other resuscitative measures and drug/fluid therapy at time of consent

• Known or suspected inflammatory bowel disease or associated visceral abscess

• The anticipated need for systemic antibiotics for a duration of more than 14 days

• 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 Test-of-Cure (TOC) visit

• Known at study entry to have cIAI caused by a pathogen(s) resistant to one of the study drugs

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Los Angeles	California	United States
2		Indianapolis	Indiana	United States
3		Las Vegas	Nevada	United States
4		Somers Point	New Jersey	United States
5		Cleveland	Ohio	United States
6		Columbus	Ohio	United States
7		Pleven		Bulgaria
8		Plovdiv		Bulgaria
9		Ruse		Bulgaria
10		Sofia		Bulgaria
11		Varna		Bulgaria
12		Jihlava		Czechia
13		Kladno		Czechia
14		Kolin		Czechia
15		Prague		Czechia
16		Tallinn		Estonia
17		Tartu		Estonia
18		Viljandi		Estonia
19		Voru		Estonia
20		Batumi		Georgia
21		Kutaisi		Georgia
22		Tbilisi		Georgia
23		Zugdidi		Georgia
24		Gyor		Hungary
25		Kaposvar		Hungary
26		Pecs		Hungary
27		Veszprem		Hungary
28		Daugavpils		Latvia
29		Liepaja		Latvia
30		Rezekne		Latvia
31		Riga		Latvia
32		Kaunas		Lithuania
33		Klaipeda		Lithuania
34		Vilnius		Lithuania
35		Bucharest		Romania
36		Cluj-Napoca		Romania
37		Craiova		Romania
38		Targu Mures		Romania
39		Timisoara		Romania
40		Arkhangelsk		Russian Federation
41		Kaluga		Russian Federation
42		Krasnodar		Russian Federation
43		Nizhny Novgorod		Russian Federation
44		St. Petersburg		Russian Federation
45		Volgograd		Russian Federation
46		Vsevolozhsk		Russian Federation
47		Dnipro		Ukraine
48		Ivano-Frankivsk		Ukraine
49		Kharkiv		Ukraine
50		Kyiv		Ukraine
51		Lviv		Ukraine
52		Odesa		Ukraine
53		Uzhhorod		Ukraine
54		Vinnytsia		Ukraine

Sponsors and Collaborators

• Tetraphase Pharmaceuticals, Inc.

Investigators

• Study Director: Chief Medical Officer, Tetraphase Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Mar 20, 2017
• Statistical Analysis Plan - Jul 12, 2017

More Information

Additional Information:

• IGNITE4: Results of a Phase 3, Randomized, Multicenter, Prospective Trial of Eravacycline vs. Meropenem in the Treatment of Complicated Intra-Abdominal Infections

Publications

None provided.

• Responsible Party: Tetraphase Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02784704
• Other Study ID Numbers: TP-434-025
• First Posted: May 27, 2016
• Last Update Posted: Jan 6, 2022
• Last Verified: Dec 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Additional relevant MeSH terms: Infections; Communicable Diseases; Appendicitis; Intraabdominal Infections; Meropenem

Study Results

Participant Flow

Recruitment Details	Subjects with a diagnosis of complicated intra-abdominal infection (cIAI) requiring surgery were recruited into this study. Subjects were recruited in 65 centers worldwide. The first subject enrolled on 13 October 2016 and the last subject completed on 19 May 2017.

Arm/Group Title	Eravacycline	Meropenem
Arm/Group Description	Eravacycline 1.0mg/kg q12h	Meropenem 1g q8h
Period Title: Overall Study
STARTED	250	250
Treated	250	249
COMPLETED	237	241
NOT COMPLETED	13	9

Baseline Characteristics

Arm/Group Title	Eravacycline	Meropenem	Total
Arm/Group Description	Eravacycline 1.0 mg/kg q12h	Meropenem 1 g q8h	Total of all reporting groups
Overall Participants	250	249	499
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	180 72%	174 69.9%	354 70.9%
>=65 years	70 28%	75 30.1%	145 29.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.1 (17.69)	52.8 (18.24)	52.4 (17.931)
Sex: Female, Male (Count of Participants)
Female	111 44.4%	120 48.2%	231 46.3%
Male	139 55.6%	129 51.8%	268 53.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 1.6%	0 0%	4 0.8%
Not Hispanic or Latino	239 95.6%	238 95.6%	477 95.6%
Unknown or Not Reported	7 2.8%	11 4.4%	18 3.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 0.4%	0 0%	1 0.2%
White	249 99.6%	249 100%	498 99.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Latvia	34 13.6%	33 13.3%	67 13.4%
Romania	23 9.2%	34 13.7%	57 11.4%
Hungary	10 4%	20 8%	30 6%
United States	8 3.2%	4 1.6%	12 2.4%
Czechia	13 5.2%	16 6.4%	29 5.8%
Ukraine	39 15.6%	43 17.3%	82 16.4%
Georgia	8 3.2%	16 6.4%	24 4.8%
Bulgaria	52 20.8%	41 16.5%	93 18.6%
Lithuania	22 8.8%	18 7.2%	40 8%
Estonia	20 8%	11 4.4%	31 6.2%
Russia	21 8.4%	13 5.2%	34 6.8%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population
Description	Clinical cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no additional antibacterial therapy, surgical, or radiological intervention was required. Clinical failure was defined as death related to complicated intra-abdominal infection (cIAI), persistence of clinical symptoms of cIAI, unplanned surgical or percutaneous drainage procedures for complication or recurrence of cIAI, post-surgical wound infections requiring systemic antibiotics, or initiation of rescue antibacterial drug therapy for treatment of cIAI. Indeterminate/missing was defined as an outcome that was neither a clinical cure nor clinical failure, if the investigator did not complete an assessment, if a study visit was not conducted, or if the subject died for a cause unrelated to cIAI.
Time Frame	TOC visit: 25-31 days after first dose of study drug

Outcome Measure Data

Analysis Population Description

Microbiological Intent-to-Treat Population: all randomized subjects who have at least one baseline bacterial pathogen that causes cIAI and against which the investigational drug has in vitro antibacterial activity.

Arm/Group Title	Eravacycline	Meropenem
Arm/Group Description	Eravacycline 1.0mg/kg q12h	Meropenem 1g q8h
Measure Participants	195	205
Clinical Cure	177 70.8%	187 75.1%
Clinical Failure	7 2.8%	7 2.8%
Indeterminate/missing	11 4.4%	11 4.4%

2. Secondary Outcome

Title	Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the All-Treated (MITT) Population
Description	Clinical cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no additional antibacterial therapy, surgical, or radiological intervention was required. Clinical failure was defined as death related to complicated intra-abdominal infection (cIAI), persistence of clinical symptoms of cIAI, unplanned surgical or percutaneous drainage procedures for complication or recurrence of cIAI, post-surgical wound infections requiring systemic antibiotics, or initiation of rescue antibacterial drug therapy for treatment of cIAI. Indeterminate/missing was defined as an outcome that was neither a clinical cure nor clinical failure, if the investigator did not complete an assessment, if a study visit was not conducted, or if the subject died for a cause unrelated to cIAI.
Time Frame	TOC visit: 25-31 days after first dose of study drug

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat Population: all randomized subjects who receive any amount of study drug.

Arm/Group Title	Eravacycline	Meropenem
Arm/Group Description	Eravacycline 1.0 mg/kg q12h	Meropenem 1.0g q8h
Measure Participants	250	249
Clinical Cure	231 92.4%	228 91.6%
Clinical Failure	7 2.8%	9 3.6%
Indeterminate/missing	12 4.8%	12 4.8%

3. Secondary Outcome

Title	Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Clinically Evaluable (CE) Population
Description	Clinical cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no additional antibacterial therapy, surgical, or radiological intervention was required. Clinical failure was defined as death related to complicated intra-abdominal infection (cIAI), persistence of clinical symptoms of cIAI, unplanned surgical or percutaneous drainage procedures for complication or recurrence of cIAI, post-surgical wound infections requiring systemic antibiotics, or initiation of rescue antibacterial drug therapy for treatment of cIAI.
Time Frame	TOC visit: 25-31 days after first dose of study drug

Outcome Measure Data

Analysis Population Description

Clinically Evaluable: all randomized subjects who meet key inclusion/exclusion criteria and follow other important components of the trial

Arm/Group Title	Eravacycline	Meropenem
Arm/Group Description	Eravacycline 1.0 mg/kg q12h	Meropenem 1.0g q8h
Measure Participants	225	231
Clinical Cure	218 87.2%	222 89.2%
Clinical Failure	7 2.8%	9 3.6%

Adverse Events

Time Frame	52 days
Adverse Event Reporting Description	All serious adverse events by preferred term, Safety Population
Arm/Group Title	Eravacycline		Meropenem
Arm/Group Description	Eravacycline 1 mg/kg q12h		Meropenem 1 g q8h
All Cause Mortality
	Eravacycline		Meropenem
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/250 (1.6%)		1/249 (0.4%)
Serious Adverse Events
	Eravacycline		Meropenem
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/250 (6%)		16/249 (6.4%)
Blood and lymphatic system disorders
Splenic hematoma	0/250 (0%)		1/249 (0.4%)
Cardiac disorders
Atrial fibrillation	0/250 (0%)		1/249 (0.4%)
Cardiac arrest	0/250 (0%)		1/249 (0.4%)
Myocardial infarction	0/250 (0%)		1/249 (0.4%)
Gastrointestinal disorders
Gastrointestinal inflammation	1/250 (0.4%)		0/249 (0%)
Large intestine perforation	1/250 (0.4%)		0/249 (0%)
Melaena	1/250 (0.4%)		0/249 (0%)
Pancreatitis acute	1/250 (0.4%)		0/249 (0%)
Duodenal ulcer	0/250 (0%)		1/249 (0.4%)
Duodenal ulcer haemorrhage	0/250 (0%)		1/249 (0.4%)
Ileus	0/250 (0%)		1/249 (0.4%)
Intestinal fistula	0/250 (0%)		1/249 (0.4%)
General disorders
Pyrexia	0/250 (0%)		1/249 (0.4%)
Hepatobiliary disorders
Cholecystitis acute	0/250 (0%)		1/249 (0.4%)
Infections and infestations
Pneumonia	2/250 (0.8%)		1/249 (0.4%)
Abdominal abscess	0/250 (0%)		0/249 (0%)
Peritonitis	0/250 (0%)		1/249 (0.4%)
Sepsis	0/250 (0%)		1/249 (0.4%)
Injury, poisoning and procedural complications
Abdominal wound dehiscence	1/250 (0.4%)		0/249 (0%)
Wound dehiscence	1/250 (0.4%)		0/249 (0%)
Suture related complication	0/250 (0%)		1/249 (0.4%)
Wound decomposition	0/250 (0%)		1/249 (0.4%)
Metabolism and nutrition disorders
Dehydration	1/250 (0.4%)		0/249 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	1/250 (0.4%)		0/249 (0%)
Neuroendocrine tumor	1/250 (0.4%)		0/249 (0%)
Gallbladder cancer	0/250 (0%)		1/249 (0.4%)
Renal and urinary disorders
Ureteric rupture	1/250 (0.4%)		0/249 (0%)
Renal failure	0/250 (0%)		1/249 (0.4%)
Reproductive system and breast disorders
Pelvic fluid collection	0/250 (0%)		1/249 (0.4%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/250 (0.4%)		0/249 (0%)
hydrothorax	1/250 (0.4%)		0/249 (0%)
Pulmonary embolism	1/250 (0.4%)		1/249 (0.4%)
Respiratory failure	1/250 (0.4%)		1/249 (0.4%)
Vascular disorders
Hypotension	0/250 (0%)		1/249 (0.4%)
Other (Not Including Serious) Adverse Events
	Eravacycline		Meropenem
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/250 (11.6%)		8/249 (3.2%)
Gastrointestinal disorders
Nausea	12/250 (4.8%)		2/249 (0.8%)
Vomiting	9/250 (3.6%)		5/249 (2%)
General disorders
Infusion site phlebitis	8/250 (3.2%)		1/249 (0.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Publications should include input from the PI, his/her colleagues, other PIs in the trial and the Sponsor's personnel; such input should be reflected in the authorship. Agreement of order of authors should be established before writing a manuscript. The PI interested in participating in writing the manuscript should contact the Sponsor. The PI shall not make any publication without the Sponsor's prior written approval, which may be withheld or granted by the Sponsor, in it's sole discretion.