Drug Trials Snapshots: XACDURO
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic 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 healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the XACDURO Prescribing Information for all of the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
XACDURO (sulbactam for injection; durlobactam for injection), co-packaged for intravenous use
Zac dur’ oh
Entasis Therapeutics, Inc.
Original Approval date: May 23, 2023
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
XACDURO is an antibacterial drug to treat adults who have hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) caused by specific bacteria called Acinetobacter baumannii-calcoaceticus complex. It should not be used to treat pneumonia, which is caused by other bacteria.
How is this drug used?
XACDURO is a drug administered by a health care professional directly into the bloodstream through a needle in the vein, known as an intravenous (IV) infusion. It is given every six hours.
Who participated in the clinical trials?
FDA approved XACDURO based on a trial (NCT03894046) of 177 hospitalized adult patients with pneumonia caused by Acinetobacter baumannii-calcoaceticus complex. The trial included patients from China, Greece, Hungary, Israel, Peru, Russia, Taiwan, and other countries. There was one patient in the trial from North America.
How were the trials designed?
XACDURO was evaluated in one clinical trial that compared XACDURO to colistin in the treatment of hospitalized adults with pneumonia caused by Acinetobacter baumannii-calcoaceticus complex infections. Both treatments were given intravenously for up to 14 days. Both groups also received an additional antibacterial drug, imipenem/cilastatin, to treat additional bacteria other than Acinetobacter baumannii-calcoaceticus complex that could potentially cause HABP/VABP. Although the clinical trial investigator knew the identity of the drugs, neither the patients nor the independent assessor knew which drugs were given until after the trial was completed. The benefit of XACDURO was measured by deaths from all causes within 28 days of treatment in patients with a confirmed infection with carbapenem-resistant A. baumannii.
How were the trials designed?
There was one randomized, active-controlled, investigator unblinded, independent assessor-blinded, non-inferiority, multi-center trial described above.
The efficacy of XACDURO was based on an assessment of whether or not it had unacceptably worse 28-day all-cause mortality than colistin in subjects who received any amount of study medication with a confirmed baseline infection with carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes how many males and females were enrolled in the clinical trial.
Figure 1. Demographics by Sex
Source: Adapted from FDA Review
Figure 2 summarizes the percentage of patients by race in the clinical trial, used to evaluate the side effects of XACDURO.
Figure 2. Baseline Demographics by Race
Source: Adapted from FDA Review
Figure 3 summarizes how many patients by age were in the clinical trial.
Figure 3. Baseline Demographics by Age
Source: Adapted from FDA Review
Figure 4 summarizes how many patients by ethnicity were in the clinical trial.
Figure 4. Baseline Demographics by Ethnicity
Source: Adapted from FDA Review
Who participated in the trials?
Table 1. Demographics Table, Efficacy Population
|
Demographic |
XACDURO |
Colistin |
Total |
|---|---|---|---|
|
Age |
|||
|
Mean (SD) |
61.6 (16.1) |
65.1 (17.0) |
63.4 (16.6) |
|
Median (min, max) |
62 (25, 91) |
66 (19, 98) |
63 (19, 98) |
|
Age group, years, n (%) |
|||
|
<65 |
36 (56.3) |
31 (48.4) |
67 (52.3) |
|
65 to 75 |
16 (25.0) |
12 (18.8) |
28 (21.9) |
|
>75 |
12 (18.8) |
21 (32.8) |
33 (25.8) |
|
Sex, n (%) |
|||
|
Male |
46 (71.9) |
49 (76.6) |
95 (74.2) |
|
Female |
18 (28.1) |
15 (23.4) |
33 (25.8) |
|
Race, n (%) |
|||
|
American Indian or Alaska Native1 |
4 (6.3) |
2 (3.1) |
6 (4.7) |
|
Asian |
23 (35.9) |
34 (53.1) |
57 (44.5) |
|
Chinese |
2 (34.4) |
29 (45.3) |
51 (39.8) |
|
Not Chinese |
1 (1.6) |
4 (6.3) |
5 (3.9) |
|
Black or African American |
0 (0.0) |
1 (1.6) |
1 (0.8) |
|
White |
36 (56.3) |
27 (42.2) |
63 (49.2) |
|
Other |
1 (1.6) |
0 (0.0) |
1 (0.8) |
|
Ethnicity, n (%) |
|||
|
Hispanic or Latino |
9 (14.1) |
9 (14.1) |
18 (14.1) |
|
Not Hispanic or Latino |
54 (84.4) |
55 (85.9) |
109 (85.2) |
|
Not reported |
1 (1.6) |
0 (0.0) |
1 (0.8) |
|
Region (a stratification factor at randomization), n (%) |
|||
|
Mainland China |
15 (23.4) |
19 (29.7) |
34 (26.6) |
|
Rest of the world |
|||
|
United States |
1 (1.6) |
0 (0.0) |
1 (0.8) |
|
Europe |
31 (48.4) |
21 (32.8) |
52 (40.6) |
|
Latin America |
9 (14.1) |
9 (14.1) |
18 (14.1) |
|
Asia-Pacific |
8 (12.5) |
15 (23.4) |
23 (18.0) |
Source: Adapted from FDA Review
1 American Indian or Alaska Native referred to a person having origins in any of the original people of North, South, or Central America and who maintained tribal affiliation or community attachment. These subjects were identified as American Indian or Alaska Native, but they were in Peru rather than the United States.
Abbreviations: SD, standard deviation
What are the benefits of this drug?
In patients with pneumonia caused by Acinetobacter bacteria, the use of XACDURO resulted in survival similar to colistin (an antibacterial drug to treat Acinetobacter infections). Of those who received XACDURO, 19% died compared to 32% treated with colistin.
What are the benefits of this drug (results of trials used to assess efficacy)?
The efficacy of XACDURO was established based on a primary endpoint of 28-day all-cause mortality in the patients who received any amount of study medication with a confirmed baseline infection with carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRABC) microbiologically modified intent to treat (m-MITT) population. Table 2 summarizes efficacy results for patients evaluated in the clinical trial of XACDURO.
Table 2. All-Cause Mortality at Day 28, CRABC m-MITT Population
|
Trial endpoint |
XACDURO |
Colistin |
Treatment Difference (95% CI)a |
|---|---|---|---|
|
Day 28 all-cause mortality |
12/63 (19.0%) |
20/62 (32.3%) |
-13.2% (-30.0%, 3.5%) |
Source: Adapted from XACDURO Prescribing Information
a The 95% CI (2-sided) was computed using a continuity-corrected z statistic.
Abbreviations: CI, confidence interval; CRABC, carbapenem-resistant Acinetobacter balumannii-calcoaceticus complex; m-MITT, microbiologically modified intent-to-treat
Were there any differences in how well the drug worked in clinical trials among sex, race and age?
- Sex: Clinical studies of XACDURO did not include enough patients to determine whether the drug works differently in males and females.
- Race: The majority of patients were White. The number of patients in other races were limited. Differences in how well the drug worked among races could not be determined.
- Age: Clinical studies of XACDURO did not include enough patients aged 65 years and older to determine whether they respond differently than younger patients.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Subgroup analyses for the primary endpoint are presented in Table 3.
Table 3. Subgroup Analyses of 28-Day All-Cause Mortality in the CRABC m-MITT Population Excluding Subjects Who Withdrew Consent Prior to Assessment of Survival Status at Day 28
|
Subgroup |
XACDURO |
Colistin |
Treatment Difference |
|---|---|---|---|
|
Age, years |
|||
|
<65 |
3/36 (8.3) |
7/29 (24.1) |
-15.8 (-36.9, 5.3) |
|
≥65 |
9/27 (33.3) |
13/33 (39.4) |
-6.1 (-33.8, 21.7) |
|
65 to 75 |
6/16 (37.5) |
2/12 (16.7) |
20.8 (-18.2, 59.9) |
|
>75 |
3/11 (27.3) |
11/21 (52.4) |
-25.1 (-65.9, 15.7) |
|
Gender |
|||
|
Male |
8/45 (17.8) |
18/47 (38.3) |
-20.5 (-40.5, -0.5) |
|
Female |
4/18 (22.2) |
2/15 (13.3) |
8.9 (-23.0, 40.8) |
|
Race |
|||
|
Asian |
6/22 (27.3) |
9/33 (27.3) |
0.0 (-27.8, 27.8) |
|
White |
6/36 (16.7) |
9/26 (34.6) |
-18.0 (-43.2, 7.3) |
|
Other |
0/5 (0) |
2/3 (66.7) |
-66.7 (-100, 13.3) |
Source: Adapted from FDA Review
Other included American Indian or Alaska Native, Black or African American, other, and not reported
Abbreviations: CI, confidence interval; CRABC, carbapenem-resistant Acinetobacter balumannii-calcoaceticus complex; m-MITT, microbiologically modified intent-to-treat; N, number of patients in treatment arm; n, number of patients meeting criteria; Ns, total number of patients for each specific subgroup and were assigned to that specific arm
What are the possible side effects?
XACDURO may cause serious and life-threatening allergic reactions and severe diarrhea caused by Clostridioides difficile. Common side effects that were associated with the use of XACDURO include liver test abnormalities, diarrhea, anemia, and hypokalemia (low potassium).
What are the possible side effects (results of trials used to assess safety)?
Table 4 summarizes the most common adverse events observed in the trial.
Table 4. Selected Adverse Reactions Occurring at a Frequency of >5% in the Trial, Safety Population
|
Adverse Reaction |
XACDURO |
Colistin |
|---|---|---|
|
Any adverse reaction |
80 (88) |
81 (94) |
|
Liver test abnormalities1 |
17 (19) |
18 (21) |
|
Diarrhea |
15 (17) |
9 (11) |
|
Anemia |
12 (13) |
12 (14) |
|
Hypokalemia |
11 (12) |
9 (11) |
|
Arrhythmia |
8 (9) |
8 (9) |
|
Acute kidney injury2 |
5 (6) |
31 (36) |
|
Thrombocytopenia |
5 (6) |
3 (4) |
|
Constipation |
5 (6) |
5 (6) |
Source: XACDURO Prescribing Information
1 Liver test abnormalities includes the following adverse reactions: liver function test abnormal, hepatic function abnormal, increased transaminases, ALT increased, and AST increased.
2 Acute kidney injury includes the following adverse reactions: renal impairment, blood Cr increased, toxic nephropathy, renal failure, and acute kidney injury.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; Cr, creatinine
Were there any differences in side effects of the clinical trials among sex, race, and age?
- Sex: The occurrence of side effects was similar between males and females.
- Race: The majority of the patients were White and Asian. The number of patients in other races was limited. Differences in side effects among races could not be determined.
- Age: The occurrence of side effects was similar between 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?
Table 5 summarizes the incidence of treatment-emergent adverse events by subgroups.
Table 5. Summary of Incidence of TEAEs by Subgroup, Safety Population
|
Subgroup |
XACDURO |
Colistin |
|---|---|---|
|
Sex |
||
|
Female |
20/24 (83) |
21/22 (96) |
|
Male |
61/67 (91) |
60/64 (94) |
|
Age group, years |
||
|
18 to 64 |
37/42 (88) |
33/37 (89) |
|
65 to 75 |
30/32 (94) |
18/18 (100) |
|
>75 |
14/17 (82) |
30/31 (97) |
|
Age group ≥65, years |
||
|
≥65 |
44/49 (90) |
48/49 (98) |
|
Race |
||
|
American Indian or Alaska Native |
5/5 (100) |
2/2 (100) |
|
Asian |
31/33 (94) |
43/44 (98) |
|
Black or African American |
0/0 (NA) |
1/1 (100) |
|
Other |
5/5 (100) |
0/0 (NA) |
|
White |
40/48 (83) |
35/39 (90) |
|
Ethnicity |
||
|
Hispanic or Latino |
14/15 (93) |
7/9 (78) |
|
Not Hispanic or Latino |
66/75 (88) |
74/77 (96) |
|
Not reported |
1/1 (100) |
0/0 (NA) |
|
Is in United States |
||
|
United States |
1/1 (100) |
0/0 (NA) |
|
Non-United States |
80/90 (89) |
81/86 (94) |
Source: Adapted from FDA Review
Abbreviations: N, number of patients in treatment arm; n, number of patients meeting criteria; NA, not applicable; Ns, total number of patients for each specific subgroup and were assigned to that specific arm; TEAE, treatment-emergent adverse event
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 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.
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