IGNITE1: Efficacy and Safety Study of Eravacycline Compared With Ertapenem in Complicated Intra-abdominal Infections

• Sponsor: Tetraphase Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01844856
• Collaborator: (none)
• Enrollment: 541
• Locations: 69
• Arms: 2
• Duration (Months): 12
• Patients Per Site: 7.8
• Patients Per Site Per Month: 0.7

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 of eravacycline compared with ertapenem in the treatment of adult complicated intra-abdominal infections (cIAI).

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 541 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 Ertapenem in Complicated Intra-abdominal Infections
• Study Start Date: Aug 1, 2013
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eravacycline, 1.0 mg/kg q12h Eravacycline was administered intravenously (IV) at a dose of 1.0 milligram per kilogram of body weight (mg/kg) every 12 hours (q12h) for a minimum of 4 days and a maximum of 14 days. Eravacycline treatment was to be stopped when symptoms of complicated intra-abdominal infection (cIAI) resolved, there was treatment failure, or the maximum allowed number of infusion days was reached.	Drug: Eravacycline; Other Names: TP-434 ; Drug: Placebo; Administered IV to maintain the blind.
Active Comparator: Ertapenem, 1.0 g q24h Ertapenem was administered IV at a dose of 1.0 gram (g) every 24 hours (q24h) for a minimum of 4 days and a maximum of 14 days. Ertapenem treatment was to be stopped when symptoms of cIAI resolved, there was treatment failure, or the maximum allowed number of infusion days was reached.	Drug: Ertapenem; Other Names: Invanz ; Drug: Placebo; Administered IV to maintain the blind.

Outcome Measures

Primary Outcome Measures

1. Clinical Response of Eravacycline and Ertapenem Treatment Arms at the Test-of-cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population [TOC visit: 25-31 days after the first dose of study drug]

   Clinical response was classified as cure (complete resolution or significant improvement of signs and symptoms of the index infection), failure (death related to complicated intra-abdominal infection [cIAI], unplanned surgical procedures or percutaneous drainage procedures, persisting or recurrent infection within the abdomen, postsurgical wound infection, or administration of effective concomitant antibacterial therapy), or indeterminate (outcome was neither cure nor failure, or assessment was not available). Participants who were failures at the End-of-Treatment (EOT) visit (within 24 hours of last dose) were considered failures at the TOC visit. The number of participants with a clinical response classification of cure, failure, or indeterminate is presented.

Secondary Outcome Measures

1. Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Modified Intent-to-treat (MITT) Population at the TOC Visit [TOC visit: 25-31 days after first dose]

   Clinical response was classified as cure (complete resolution or significant improvement of signs and symptoms of the index infection), failure (death related to complicated intra-abdominal infection [cIAI], unplanned surgical procedures or percutaneous drainage procedures, persisting or recurrent infection within the abdomen, postsurgical wound infection, or administration of effective concomitant antibacterial therapy), or indeterminate (outcome was neither cure nor failure, or assessment was not available). Participants who were failures at the EOT visit (within 24 hours of last dose) were considered failures at the TOC visit. The number of participants with a clinical response classification of cure, failure, or indeterminate is presented.

2. Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Clinically Evaluable (CE) Population at the TOC Visit [TOC visit: 25-31 days after first dose]

   Clinical response was classified as cure (complete resolution or significant improvement of signs and symptoms of the index infection), failure (death related to complicated intra-abdominal infection [cIAI], unplanned surgical procedures or percutaneous drainage procedures, persisting or recurrent infection within the abdomen, postsurgical wound infection, or administration of effective concomitant antibacterial therapy), or indeterminate (outcome was neither cure nor failure, or assessment was not available). Participants who were failures at the EOT visit (within 24 hours of last dose) were considered failures at the TOC visit. The number of participants with a clinical response classification of cure, failure, or indeterminate is presented.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Male or female participant hospitalized for cIAI

2. At least 18 years of age (and not over 65 years of age for participant in India)

3. Evidence of a systemic inflammatory response

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

5. Able to provide informed consent

6. If male: must agree to use an effective barrier method of contraception during the study and for 90 days following the last dose if sexually active with a female of childbearing potential

7. 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 90 days following last study drug dose or practicing sexual abstinence

Exclusion Criteria:

1. Unlikely to survive the 6-8 week study period

2. Renal failure

3. Presence or possible signs of hepatic disease

4. Immunocompromised condition, including known human immunodeficiency virus (HIV) positivity (requiring anti-retroviral therapy or with CD4 count <300), acquired immune deficiency syndrome (AIDS), organ (bone marrow) transplant recipients, and hematological malignancy. Immunosuppressive therapy, including use of high-dose corticosteroids (for example, >40 mg prednisone or equivalent per day for greater than 2 weeks)

5. History of hypersensitivity reactions to tetracyclines, carbapenems, β-lactam antibiotics or to 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 disorder that may predispose to seizures or lower seizure threshold

8. Previously received eravacycline in a clinical trial

9. Antibiotic-related exclusions:

10. Receipt of effective antibacterial drug therapy for cIAI for a continuous duration of >24 hours during the 72-hour preceding enrollment (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

11. Receipt of ertapenem or any other carbapenem, or tigecycline for the current infection or

12. Need for concomitant systemic antimicrobial agents other than study drug

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

14. Known or suspected inflammatory bowel disease or associated visceral abscess

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

16. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Florence	Alabama	United States
2		Mobile	Alabama	United States
3		Glendale	California	United States
4		La Mesa	California	United States
5		Los Angeles	California	United States
6		Torrance	California	United States
7		Aurora	Illinois	United States
8		Carmel	Indiana	United States
9		Boston	Massachusetts	United States
10		Springfield	Massachusetts	United States
11		Minneapolis	Minnesota	United States
12		Las Vegas	Nevada	United States
13		Camden	New Jersey	United States
14		Teaneck	New Jersey	United States
15		Cleveland	Ohio	United States
16		Columbus	Ohio	United States
17		Weston	Ohio	United States
18		Houston	Texas	United States
19		Seattle	Washington	United States
20		Cordoba		Argentina
21		Pleven		Bulgaria
22		Plovdiv		Bulgaria
23		Rousse		Bulgaria
24		Sofia		Bulgaria
25		Varna		Bulgaria
26		Brno		Czechia
27		Kladno		Czechia
28		Melnik		Czechia
29		Olomouc		Czechia
30		Prague		Czechia
31		Usti nad Labem		Czechia
32		Kohtla-Jarve		Estonia
33		Tallinn		Estonia
34		Tartu		Estonia
35		Paris		France
36		Heidelberg		Germany
37		Luebeck		Germany
38		Magdeburg		Germany
39		Daugavpils		Latvia
40		Liepaja		Latvia
41		Riga		Latvia
42		Kaunas		Lithuania
43		Klaipeda		Lithuania
44		Siauliai		Lithuania
45		Vilnius		Lithuania
46		Bucharest		Romania
47		Cluj-Napoca		Romania
48		Craiova		Romania
49		Timisoara		Romania
50		Kaluga		Russian Federation
51		Kemerovo		Russian Federation
52		Moscow		Russian Federation
53		Nizhny Novgorod		Russian Federation
54		Smolensk		Russian Federation
55		St. Petersburg		Russian Federation
56		Tomsk		Russian Federation
57		Volgograd		Russian Federation
58		Vsevolozhsk		Russian Federation
59		Benoni		South Africa
60		Johannesburg		South Africa
61		Pretoria		South Africa
62		Worcester		South Africa
63		Dnipropetrovsk		Ukraine
64		Ivano-Frankivsk		Ukraine
65		Kharkiv		Ukraine
66		Kyiv		Ukraine
67		Odesa		Ukraine
68		Uzhhorod		Ukraine
69		Zaporizhia		Ukraine

Sponsors and Collaborators

• Tetraphase Pharmaceuticals, Inc.

Investigators

• Study Director: Patrick T Horn, MD, PhD, Tetraphase Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Tetraphase Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01844856
• Other Study ID Numbers: TP-434-008
• First Posted: May 1, 2013
• Last Update Posted: Jan 11, 2022
• Last Verified: Dec 1, 2021

• Additional relevant MeSH terms: Infections; Communicable Diseases; Intraabdominal Infections; Ertapenem

Study Results

Participant Flow

Arm/Group Title	Eravacycline, 1.0 mg/kg q12h	Ertapenem, 1.0 g q24h
Arm/Group Description	Eravacycline was administered intravenously (IV) at a dose of 1.0 milligrams per kilogram of body weight (mg/kg) every 12 hours (q12h) for a minimum of 4 days and a maximum of 14 days.	Ertapenem was administered IV at a dose of 1.0 grams (g) every 24 hours (q24h) for a minimum of 4 days and a maximum of 14 days.
Period Title: Overall Study
STARTED	270	271
Received at Least 1 Dose of Study Drug	270	268
COMPLETED	246	255
NOT COMPLETED	24	16

Baseline Characteristics

Arm/Group Title	Eravacycline, 1.0 mg/kg q12h	Ertapenem, 1.0 g q24h	Total
Arm/Group Description	Eravacycline was administered IV at a dose of 1.0 mg/kg q12h for a minimum of 4 days and a maximum of 14 days.	Ertapenem was administered IV at a dose of 1.0 g q24h for a minimum of 4 days and a maximum of 14 days.	Total of all reporting groups
Overall Participants	270	271	541
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.8 (16.92)	54.8 (16.09)	54.8 (16.49)
Sex: Female, Male (Count of Participants)
Female	114 42.2%	108 39.9%	222 41%
Male	156 57.8%	163 60.1%	319 59%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 3%	9 3.3%	17 3.1%
Not Hispanic or Latino	261 96.7%	262 96.7%	523 96.7%
Unknown or Not Reported	1 0.4%	0 0%	1 0.2%
Race/Ethnicity, Customized (participants) [Number]
White	263 97.4%	260 95.9%	523 96.7%
Black or African American	1 0.4%	3 1.1%	4 0.7%
Asian	1 0.4%	3 1.1%	4 0.7%
Other Race	4 1.5%	5 1.8%	9 1.7%
Unknown or Not Reported	1 0.4%	0 0%	1 0.2%
Region of Enrollment (participants) [Number]
Russian Federation	28 10.4%	24 8.9%	52 9.6%
Romania	42 15.6%	42 15.5%	84 15.5%
United States	18 6.7%	20 7.4%	38 7%
Ukraine	38 14.1%	38 14%	76 14%
Czech Republic	14 5.2%	17 6.3%	31 5.7%
Latvia	25 9.3%	23 8.5%	48 8.9%
South Africa	0 0%	1 0.4%	1 0.2%
Bulgaria	45 16.7%	44 16.2%	89 16.5%
Lithuania	26 9.6%	26 9.6%	52 9.6%
Germany	2 0.7%	2 0.7%	4 0.7%
Estonia	32 11.9%	34 12.5%	66 12.2%

Outcome Measures

1. Primary Outcome

Title	Clinical Response of Eravacycline and Ertapenem Treatment Arms at the Test-of-cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population
Description	Clinical response was classified as cure (complete resolution or significant improvement of signs and symptoms of the index infection), failure (death related to complicated intra-abdominal infection [cIAI], unplanned surgical procedures or percutaneous drainage procedures, persisting or recurrent infection within the abdomen, postsurgical wound infection, or administration of effective concomitant antibacterial therapy), or indeterminate (outcome was neither cure nor failure, or assessment was not available). Participants who were failures at the End-of-Treatment (EOT) visit (within 24 hours of last dose) were considered failures at the TOC visit. The number of participants with a clinical response classification of cure, failure, or indeterminate is presented.
Time Frame	TOC visit: 25-31 days after the first dose of study drug

Outcome Measure Data

Analysis Population Description

All randomized participants who had baseline bacterial pathogens that cause cIAI and against at least one of which the investigational drug has in vitro antibacterial activity (micro-ITT population).

Arm/Group Title	Eravacycline, 1.0 mg/kg q12h	Ertapenem, 1.0 g q24h
Arm/Group Description	Eravacycline was administered IV at a dose of 1.0 mg/kg q12h for a minimum of 4 days and a maximum of 14 days.	Ertapenem was administered IV at a dose of 1.0 g q24h for a minimum of 4 days and a maximum of 14 days.
Measure Participants	220	226
Cure	191 70.7%	198 73.1%
Failure	19 7%	11 4.1%
Indeterminate	10 3.7%	17 6.3%

2. Secondary Outcome

Title	Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Modified Intent-to-treat (MITT) Population at the TOC Visit
Description	Clinical response was classified as cure (complete resolution or significant improvement of signs and symptoms of the index infection), failure (death related to complicated intra-abdominal infection [cIAI], unplanned surgical procedures or percutaneous drainage procedures, persisting or recurrent infection within the abdomen, postsurgical wound infection, or administration of effective concomitant antibacterial therapy), or indeterminate (outcome was neither cure nor failure, or assessment was not available). Participants who were failures at the EOT visit (within 24 hours of last dose) were considered failures at the TOC visit. The number of participants with a clinical response classification of cure, failure, or indeterminate is presented.
Time Frame	TOC visit: 25-31 days after first dose

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug (MITT population).

Arm/Group Title	Eravacycline, 1.0 mg/kg q12h	Ertapenem, 1.0 g q24h
Arm/Group Description	Eravacycline was administered IV at a dose of 1.0 mg/kg q12h for a minimum of 4 days and a maximum of 14 days.	Ertapenem was administered IV at a dose of 1.0 g q24h for a minimum of 4 days and a maximum of 14 days.
Measure Participants	270	268
Cure	235 87%	238 87.8%
Failure	19 7%	15 5.5%
Indeterminate	16 5.9%	15 5.5%

3. Secondary Outcome

Title	Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Clinically Evaluable (CE) Population at the TOC Visit
Description	Clinical response was classified as cure (complete resolution or significant improvement of signs and symptoms of the index infection), failure (death related to complicated intra-abdominal infection [cIAI], unplanned surgical procedures or percutaneous drainage procedures, persisting or recurrent infection within the abdomen, postsurgical wound infection, or administration of effective concomitant antibacterial therapy), or indeterminate (outcome was neither cure nor failure, or assessment was not available). Participants who were failures at the EOT visit (within 24 hours of last dose) were considered failures at the TOC visit. The number of participants with a clinical response classification of cure, failure, or indeterminate is presented.
Time Frame	TOC visit: 25-31 days after first dose

Outcome Measure Data

Analysis Population Description

All randomized participants who had no major protocol deviations (CE population).

Arm/Group Title	Eravacycline, 1.0 mg/kg q12h	Ertapenem, 1.0 g q24h
Arm/Group Description	Eravacycline was administered IV at a dose of 1.0 mg/kg q12h for a minimum of 4 days and a maximum of 14 days.	Ertapenem was administered IV at a dose of 1.0 g q24h for a minimum of 4 days and a maximum of 14 days.
Measure Participants	239	238
Cure	222 82.2%	225 83%
Failure	17 6.3%	13 4.8%
Indeterminate	0 0%	0 0%

Adverse Events

Arm/Group Title	Eravacycline, 1.0 mg/kg q12h		Ertapenem, 1.0 g q24h
Arm/Group Description	Eravacycline was administered IV at a dose of 1.0 mg/kg q12h for a minimum of 4 days and a maximum of 14 days.		Ertapenem was administered IV at a dose of 1.0 g q24h for a minimum of 4 days and a maximum of 14 days.
All Cause Mortality
	Eravacycline, 1.0 mg/kg q12h		Ertapenem, 1.0 g q24h
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Eravacycline, 1.0 mg/kg q12h		Ertapenem, 1.0 g q24h
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/270 (6.3%)		16/268 (6%)
Cardiac disorders
Atrial fibrillation	0/270 (0%)		1/268 (0.4%)
Cardiopulmonary failure	0/270 (0%)		1/268 (0.4%)
Pulseless electrical activity	0/270 (0%)		1/268 (0.4%)
Supraventricular tachycardia	0/270 (0%)		1/268 (0.4%)
Gastrointestinal disorders
Abdominal compartment syndrome	0/270 (0%)		1/268 (0.4%)
Colonic fistula	0/270 (0%)		1/268 (0.4%)
Diverticular perforation	1/270 (0.4%)		0/268 (0%)
Duodenal ulcer haemorrhage	1/270 (0.4%)		1/268 (0.4%)
Ileus	1/270 (0.4%)		0/268 (0%)
Intestinal fistula	1/270 (0.4%)		0/268 (0%)
Oesophageal fistula	1/270 (0.4%)		0/268 (0%)
Pancreatitis necrotising	1/270 (0.4%)		0/268 (0%)
General disorders
Multi-organ failure	1/270 (0.4%)		0/268 (0%)
Infections and infestations
Abdominal abscess	1/270 (0.4%)		2/268 (0.7%)
Empyema	1/270 (0.4%)		0/268 (0%)
Haematoma infection	1/270 (0.4%)		0/268 (0%)
Liver abscess	1/270 (0.4%)		1/268 (0.4%)
Peritoneal abscess	0/270 (0%)		1/268 (0.4%)
Peritonitis	1/270 (0.4%)		0/268 (0%)
Pneumonia	2/270 (0.7%)		1/268 (0.4%)
Sepsis	0/270 (0%)		1/268 (0.4%)
Septic shock	0/270 (0%)		1/268 (0.4%)
Injury, poisoning and procedural complications
Abdominal wound dehiscence	1/270 (0.4%)		0/268 (0%)
Gastrointestinal stoma complication	0/270 (0%)		1/268 (0.4%)
Splenic rupture	1/270 (0.4%)		0/268 (0%)
Wound dehiscence	2/270 (0.7%)		1/268 (0.4%)
Wound evisceration	1/270 (0.4%)		0/268 (0%)
Nervous system disorders
Cerebrovascular accident	1/270 (0.4%)		0/268 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/270 (0%)		1/268 (0.4%)
Acute respiratory failure	1/270 (0.4%)		0/268 (0%)
Pleural effusion	1/270 (0.4%)		0/268 (0%)
Pulmonary artery thrombosis	0/270 (0%)		1/268 (0.4%)
Pulmonary embolism	0/270 (0%)		2/268 (0.7%)
Respiratory disorder	0/270 (0%)		1/268 (0.4%)
Respiratory failure	0/270 (0%)		1/268 (0.4%)
Surgical and medical procedures
Biliary drainage	1/270 (0.4%)		0/268 (0%)
Vascular disorders
Deep vein thrombosis	1/270 (0.4%)		0/268 (0%)
Other (Not Including Serious) Adverse Events
	Eravacycline, 1.0 mg/kg q12h		Ertapenem, 1.0 g q24h
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/270 (15.9%)		28/268 (10.4%)
Blood and lymphatic system disorders
Anaemia	7/270 (2.6%)		9/268 (3.4%)
Gastrointestinal disorders
Nausea	22/270 (8.1%)		2/268 (0.7%)
Vomiting	11/270 (4.1%)		9/268 (3.4%)
General disorders
Pyrexia	6/270 (2.2%)		8/268 (3%)
Vascular disorders
Phlebitis	8/270 (3%)		1/268 (0.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

At least 60 days prior to submitting or presenting a manuscript, poster, presentation, abstract or other materials relating to the Trial, the PI shall provide to Sponsor all such manuscripts and materials, and Sponsor shall have 60 days to review and comment. If requested, the PI shall remove confidential information prior to submitting or presenting the materials, and shall delay publication or presentation for up to 90 days to allow Sponsor to protect its interests in any such materials.