Drugs

Drug Trial Snapshot: XERAVA

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the XERAVA Package Insert for complete information.

XERAVA (eravacycline)
zuh-RAH-vah
Tetraphase Pharmaceuticals, Inc.
Approval date:August 27, 2018


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

XERAVA is a drug for the treatment of complicated intra-abdominal infections caused by bacteria in patients 18 years and older. It should be used only when the infection is caused by bacteria that are sensitive to XERAVA.

Complicated intra-abdominal infections are serious infections that extend beyond the digestive organs into the intra-abdominal cavity and require treatment in the hospital.

How is this drug used?

A healthcare provider injects XERAVA directly into the bloodstream through a needle in the vein. This is known as an intravenous, or IV infusion. It takes about 60 minutes to receive an XERAVA infusion.

XERAVA is given once every 12 hours for a total of 4 to 14 days.

The amount of drug used depends on the patient’s weight.

What are the benefits of this drug?

The benefit of XERAVA in patients with complicated intra-abdominal infections was similar to ertapenem and meropenem (medications used to treat complicated intra-abdominal infections).

What are the benefits of this drug (results of trials used to assess efficacy)?

The table below summarizes efficacy results for the evaluated patients in Trials 1 and 2. The main trial endpoint was clinical cure defined as complete resolution or significant improvement of signs or symptoms of the index infection at the test of cure (TOC) visit 25 to 31 days after randomization.

Table 2. Clinical Cure Rates at TOC in Trials 1 and 2, Microbiologic Intent-to-Treat (micro-ITT) Population

 

Trial 1

Trial 2

XERAVAa
(N=220)
n (%)


Ertapenemb
(N=226)
n (%)

XERAVAa
(N=195)
n (%)

Meropenemc
(N=205)
n (%)

Clinical cure

191 (86.8)

198 (87.6)

177 (90.8)

187 (91.2)

Difference (95% CI)d

-0.80
(-7.1, 5.5)

-0.5
(-6.3, 5.3)

Prescribing Information

Abbreviations: CI = confidence interval; IV= intravenous; micro-ITT = all randomized subjects who had baseline bacterial pathogens that caused cIAI and against at least one of which the investigational drug has in vitro antibacterial activity; N = number of subjects in the micro-ITT population; n = number within a specific category with a clinical cure based on the Surgical Adjudication Committee assessment (if available); TOC = Test of Cure.

a XERAVA dose equals 1 mg/kg every 12 hours

b Ertapenem dose equals 1 g every 24 hours

c Meropenem dose equals 1 g every 8 hours

d Treatment Difference = Difference in clinical cure rates (eravacycline minus ertapenem or meropenem). Confidence intervals are calculated using the unadjusted Miettinen-Nurminen method.

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

  • Sex: XERAVA  worked similarly in men and women.
  • Race: The majority of patients in the trial were White. Differences in how well the drug worked among races could not be determined because of the small number of patients in other races.
  • Age: XERAVA worked similarly in patients younger and older than 65 years of age.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

The table below summarizes efficacy results by sex, race, and age.

Table 3. Clinical Cure Rates by Sex, Race, and Age

 

Trial 1

Trial 2

Subgroup

XERAVA
(N=220)

Ertapenem (N=226)

Difference     (95% CI)

XERAVA
(N=195)

Meropenem (N=205)

Difference
 (95% CI)

Sex

Male

107/126
 (84.9)

117/132
(88.6)

-3.7
(-12.3, 4.7)

98/109
( 89.9)

95/105
(90.5)

-0.6
(-8.9, 7.9)

Female

84/94
(89.4)

81/94
(86.2)

3.2
(-6.5, 13.0)

79/86
(91.9)

92/100
(92.0)

-0.1
(-8.9, 8.1)

Race1

White

186/214
(86.9)

190/215
(88.4)

-1.5
(-7.8, 4.9)

176/194
(90.7)

187/205
(91.2)

-0.5
(-6.4, 5.3)

Other

4/5
(80.0)

8/11
(72.7)

7.3
(-42.7, 45.2)

1/1
(100)

0

n.e.

Age

< 65 years

132/149
(88.6)

142/159
(89.3)

-0.7
(-8.0, 6.4)

136/148
(91.9)

134/145
( 92.4)

-0.5
(-7.0, 6.0)

≥ 65 years

59/71
(83.1)

56/67
(83.6)

-0.5
(-13.2, 12.4)

41/47
(87.2)

53/60
(88.3)

-1.1
(-15.1, 11.7)

FDA Review

1 One XERAVA patient in Trial 1 had missing race information and was not included.

Note: n.e. denotes "not estimable"

What are the possible side effects?

XERAVA may cause serious side effects, including severe allergic reactions, and a severe form of diarrhea caused by Clostridium difficile bacterium.

XERAVA like other antibacterial medications called tetracyclines may stain teeth, and cause thinning of the outer protective layer of teeth and decreased bone growth in the children up to 8 years old.

The most common side effects are infusion-site reactions, nausea, and vomiting.

What are the possible side effects (results of trials used to assess safety)?

The table below summarizes adverse reactions in patients with complicated intra-abdominal infections (Trials 1 and 2)

Table 4. Selected Adverse Reactions Reported in ≥ 1 % of Patients Receiving XERAVA in Trials 1 and 2

Adverse Reactions

XERAVAa
N=520
n (%)

Comparatorsb
N=517
n (%)

Infusion site reactionsc

40 (7.7)

10 (1.9)

Nausea

34(6.5)

3 (0.6)

Vomiting

19 (3.7)

13 (2.5)

Diarrhea

12 (2.3)

8 (1.5)

Hypotension

7 (1.3)

2 (0.4)

Wound dehiscence

7 (1.2)

1 (0.2)

XERAVA Prescribing Information

Abbreviations: IV = intravenous

a XERAVA dose equals 1 mg/kg every 12 hours

b Comparators include Ertapenem 1 g every 24 hours IV and Meropenem 1 g every 8 hours IV.

c Infusion site reaction includes: catheter/vessel puncture site pain, infusion site extravasation, infusion site hypoaesthesia, infusion/injection site phlebitis, infusion site thrombosis, injection site/vessel puncture site erythema, phlebitis, phlebitis superficial, thrombophlebitis, and vessel puncture site swelling.

Were there any differences in side effects among sex, race and age?

  • Sex: The occurrence of side effects was similar in men and women.
  • Race: The majority of patients in the trial were White. Differences in the occurrence of side effects among races could not be determined because of the small number of patients in other races.
  • Age: The occurrence of side effects was similar in patients younger and older than 65 years of age.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

The table below summarizes the occurrence of the most common adverse reaction, infusion site reactions, by subgroup.

Table 5. Pooled Subgroup Analysis of Infusion Site Reactions (Trials 1 and 2)

Demographic Characteristic

XERAVA
n/N (%)

Comparators
n/N (%)

Sex

 Male

24/295 (8)

5/292 (2)

 Female

16/225 (7)

5/225 (2)

Race

 White

40/512 (8)

10/506 (2)

 Other

0/8 (0)

0/11 (0)

Age Group

< 65 years

28/362 (8)

8/366 (2)

> 65 years

12/158(8)

2/151 (1)

Clinical Trial Data

WHO WAS IN THE STUDIES?

Who participated in the clinical trials?

The FDA approved XERAVA based on evidence primarily from two clinical trials (Trial 1/NCT01844856 and Trial 2/NCT02784704) of 1037 patients with complicated intra-abdominal infections. The trials were conducted in Europe, South Africa, and the United States.

The safety population is presented below. Demographics of the patients who provided data for evaluation of benefit (efficacy population) are presented in Table 7, under the MORE INFO section.

Figure 1 summarizes how many men and women were in the clinical trials used to evaluate safety.

Figure 1. Baseline Demographics by Sex (safety population)

Pie chart summarizing how many males and females were in the clinical trials. In total, 587 males (57%) and 450 (43%) females participated in the clinical trials.

FDA Review

Figure 2 summarizes the percentage of patients by race in the clinical trials used to evaluate safety.

Figure 2. Baseline Demographics by Race (safety population)

Pie chart summarizing the percentage of patients by race enrolled in the clinical trials. In total, 1018 White (98%), and 19 Other patients (2%) participated in the clinical trial.

* Other includes Black or African American, Asian, Other, and Missing

FDA Review

Table 1. Demographics of Safety Trials by Race (safety population)

Race

Number of Patients

Percentage of Patients

White

1018

98%

Black or African American

5

Less than 1

Asian

4

Less than 1

Other

9

Less than 1

Missing

1

Less than 1

Clinical Trial Data

Figure 3 summarizes the percentage of patients by race in the clinical trials used to evaluate safety.

Figure 3. Baseline Demographics by Age (safety population)

Pie charts summarizing how many individuals of certain age groups were enrolled in the clinical trials. In total, 728 patients (70%) were less than 65years old, 309 patients (30%) were 65 years and ol

FDA Review

Who participated in the trials?

The table below summarizes demographics of all patients who received XERAVA or the comparator in the clinical trials (safety population).

Table 6. Demographic Characteristics (safety population)

Demographic
Parameters

Trial 1

Trial 2

Pooled Trials

XERAVA
N=270

Ertapenem
N=268

XERAVA
N=250

Meropenem
N=249

XERAVA
N=520

Comparator
N=517

Sex, n (%)

 Male

156 (57.8)

163 (60.8)

139 (55.6)

129 (51.8)

295 (56.7)

292 (56.5)

 Female

114 (42.2)

105 (39.2)

111 (44.4)

120 (48.2)

225 (43.3)

225 (43.5)

Race, n (%)

 White

263 (97.4)

257 (95.9)

249 (99.6)

249 (100)

512 (98.5)

506 (97.9)

 Other

6 (2.2)

11 (4.1)

1 (0.4)

0

7 (1.3)

11 (2.1)

 Missing

1 (0.4)

0

0

0

1 (0.2)

0

Age Group, n (%)

  < 65 years

182 (67.4)

193 (72.0)

180 (72.0)

173 (69.5)

362 (69.6)

366 (70.8)

  > 65 years

88 (32.6)

75 (28.0)

70 (28.0)

76 (30.5)

158 (30.4)

151 (29.2)

Age (years)

 Mean (SD)

54.8 (16.9)

54.8 (16.1)

52.1 (17.7)

52.8 (18.2)

53.5 (17.3)

53.8 (17.2)

 Min, Max

19, 93

20, 87

18, 88

19, 87

18, 93

19, 87

Ethnicity, n (%)

 Hispanic

8 (3.0)

8 (3.0)

4 (1.6)

0

12 (2.3)

8 (1.5)

 Not Hispanic

261 (96.7)

260 (97.0)

239 (95.6)

238 (95.6)

500 (96.2)

498 (96.3)

 Unknown/
Not Reported

1 (0.4)

0

7 (2.8)

11 (4.4)

8 (1.5)

11 (2.1)

Region, n (%)

 Europe

252 (93.3)

248 (92.5)

242 (96.8)

245 (98.4)

494 (95.0)

493 (95.4)

 United States

18 (6.7)

19 (7.1)

8 (3.2)

4 (1.6)

26 (5.0)

23 (4.4)

 South Africa

0

1 (0.4)

0

0

0

1 (0.2)

FDA Review

The table below summarizes demographics of all patients in the microbiologic intent- to- treat population (efficacy population).

Table 7. Demographic Characteristics (efficacy population)

 

Trial 1

Trial 2

Demographic Parameters

XERAVA
(N=220)

Ertapenem
(N=226)

XERAVA
(N=195)

Meropenem
(N=205)

Sex, n (%)

Male

126 (57)

132 (58)

109 (56)

105 (51)

Female

94 (43)

94 (42)

86 (44)

100 (49)

Race, n (%)

White

214 (97)

215 (95)

194 (99)

205 (100)

Non-white

5 (2)

11 (5)

1 (1)

0

Missing/Unknown

1 (0)

0

0

0

Age Group, n (%)

< 65 years

149 (68)

159 (70)

148 (76)

145 (71)

≥ 65 years

71 (32)

67 (30)

47 (24)

60 (29)

Age (years)

Mean (SD)

54.9 (17.1)

55.4 (16.2)

50.3 (17.7)

52.3 (18.3)

Median

57

57

53

54

Min, max

19, 86

20, 87

18, 84

19, 87

Ethnicity, n (%)

Hispanic

6 (3)

8 (4)

3 (2)

0

Not Hispanic

213 (97)

218 (96)

186 (95)

195 (95)

Missing/Unknown

1 (0)

0

6 (3)

10 (5)

Region, n (%)  

United States

15 (7)

17 (8)

6 (3)

2 (1)

Russia/Ukraine/Georgia

55 (25)

48 (21)

58 (30)

60 (29)

    Rest of Europe   (including  South Africa)

150 (68)

161 (71)

131 (67)

143 (70)

FDA Review

How were the trials designed?

The benefit and side effects of XERAVA were evaluated in two clinical trials. The trials enrolled adult patients hospitalized with complicated intra-abdominal infections that required surgery or drainage.

In Trial 1, patients were assigned to XERAVA every 12 hours by intravenous infusion or ertapenem (a medication to treat complicated intra-abdominal infections) every 24 hours by intravenous infusion. In Trial 2, patients were assigned to XERAVA every 12 hours by intravenous infusion or meropenem (a medication to treat complicated intra-abdominal infections) every 8 hours by intravenous infusion. Treatment was for 4 to 14 days. Neither the patients nor the investigators knew which treatment was being given until after the trial was completed.

Patients were evaluated for clinical cure 25 to 31 days after treatment assignment. Clinical cure meant that either signs and symptoms of the infection were absent or that signs and symptoms of the infection were significantly improved. The benefit of XERAVA was assessed by comparing the clinical cure in patients treated with XERAVA to the clinical cure in patients treated with ertapenem or meropenem.

How were the trials designed?

The efficacy and safety of XERAVA were established in two randomized, double-blind, double-dummy, active-controlled trials. The trials enrolled hospitalized adults with complicated intra-abdominal infections that required surgery or drainage. Infections included appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation, and peritonitis. Trial 1 compared XERAVA (1 mg/kg intravenous every 12 hours) with ertapenem (1 g every 24 hours) as the active comparator for 4 to 14 days of treatment. Trial 2 compared XERAVA (1 mg/kg intravenous every 12 hours) with meropenem (1 g every 8 hours) as the active comparator for 4 to 14 days of treatment.

The primary efficacy endpoint was the clinical cure defined as complete resolution or significant improvement of signs or symptoms of the index infection at the test of cure (TOC) visit 25 to 31 days after randomization.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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