Drugs

Drug Trials Snapshots: ZINPLAVA

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 ZINPLAVA Prescribing Information for complete information.

ZINPLAVA (bezlotoxumab)
(Zin-PLAH-va)
Merck Sharp&Dohme Corp.
Approval date: October 21, 2016


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

ZINPLAVA is a drug that is used to decrease the risk of Clostridium difficile infection (CDI) from coming back in adult patients who are at high risk of CDI coming back. ZINPLAVA is used together with antibacterial drugs that are given to treat CDI.

Clostridium difficile causes inflammation of the colon and diarrhea, which can be deadly.

How is this drug used?

ZINPLAVA is given by a health care professional directly into the bloodstream through a needle in the vein. This is known as an intravenous, or IV infusion. ZINPLAVA IV infusion is given once during the treatment for CDI.

What are the benefits of this drug?

ZINPLAVA decreases the risk of CDI from coming back.

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

The table below summarizes the efficacy results for individual trials. Patients were assessed for clinical cure of the presenting CDI episode, defined as no diarrhea for 2 consecutive days following the completion of a ≤14 day SoC regimen. Patients who achieved clinical cure were then assessed for recurrence of CDI through 12 weeks following administration of the infusion of ZINPLAVA or placebo. CDI recurrence was defined as the development of a new episode of diarrhea associated with a positive stool test for toxigenic C. difficile following clinical cure of the presenting CDI episode. Sustained clinical response was defined as clinical cure of the presenting CDI episode and no CDI recurrence through 12 weeks after infusion. Table 2 contains the efficacy results for Trial 1 and Trial 2.

Table 2. Efficacy Results Through 12 Weeks after Infusion (Trial 1 and Trial 2, Full Analysis Set *)

Trial ZINPLAVA with SoC
n (%)
Placebo with SoC
n (%)
Adjusted Difference (95% CI)
1 N=386N=395 
 Sustained clinical response232 (60.1)218 (55.2)4.8 (-2.1, 11.7)
 Reasons for failure to achieve sustained clinical response:
 Clinical failure
Recurrence
87 (22.5)
67 (17.4)
68 (17.2)
109 (27.6)
 
2 N=395N=378 
 Sustained clinical response264 (66.8)197 (52.1)14.6 (7.7, 21.4)
 Reasons for failure to achieve sustained clinical response:
 Clinical failure
Recurrence
69 (17.5)
62 (15.7)
84 (22.2)
97 (25.7)
 
n (%) = Number (percentage) of subjects in the analysis population meeting the criteria for endpoint
N = Number of subjects included in the analysis population
* Full Analysis Set = a subset of all randomized subjects with exclusions for: (i) did not receive infusion of study medication; (ii) did not have a positive local stool test for toxigenic C. difficile; (iii) did not receive protocol defined standard of care therapy within a 1 day window of the infusion
SoC = Standard of Care antibacterial drugs (metronidazole or vancomycin or fidaxomicin) for CDI
 Adjusted difference of ZINPLAVA-placebo (95% confidence interval) based on Miettinen and Nurminen method stratified by SoC antibacterial drugs (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient).

ZINPLAVA Prescribing Information

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

  • Sex: ZINPLAVA worked similarly in men and women.
  • Race: ZINPLAVA worked similarly in White and non-White participants. The number of participants in other races but White was limited, therefore differences in response among other races could not be determined.
  • Age: ZINPLAVA worked similarly in participants above and below age 65.

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

Subgroup differences in Sustained clinical response rate are presented for each trial separately in the tables below.

Table 3. Sustained Clinical Response Rate by Sex, Race, and Age Subgroup (Trial 1-FAS)

 Sustained Clinical Response
ZINPLAVA with SoC
n/N (%)
Difference ZINPLAVA-placebo (95% CI)
Placebo with SoC
n/N (%)
Sex
Men92/157 (58.6)
-3.0 (-13.6, 7.6)
106/172 (61.6)
Women140/229 (61.1)
10.9 (1.8, 20.0)
112/223 (50.2)
Race
White202/338 (59.8)
4.0 (-3.3, 11.3)
204/366 (55.7)
All others30/48 (62.5)
14.2 (-8.5, 37.0)
14/29 (48.3)
Age
<65118/201 (58.7)
-4.1 (-13.7, 5.6)
123/196 (62.8)
≥65114/185 (61.6)
13.9 (4.0, 23.8)
95/199 (47.7)

FAS=full analysis set
SoC =standard of care
Adapted from FDA Statistical review

Table 4. Sustained Clinical Response Rate by Sex, Race, and Age Subgroup (Trial 2-FAS)

 CDI Recurrence
ZINPLAVA with SoC
n/N (%)
Difference ZINPLAVA-placebo (95% CI)
Placebo with SoC
n/N (%)
Sex
Men115/182 (63.2)
8.6 (-2.0, 19.2)
83/152 (54.6)
Women149/213 (70.0)
19.5 (10.5, 28.5)
114/226 (50.4)
Race
White209/311 (67.2)
14.8 (7.1, 22.4)
162/309 (52.4)
Asian41/63 (65.1)
14.2 (-3.3, 31.7)
29/57 (50.9)
All others14/21 (66.7)6/12 (50.0)
Age
<65127/190 (66.8)
10.5 (0.5, 20.4)
97/152 (56.4)
≥65137/205 (66.8)
18.3 (8.9, 27.7)
100/206 (48.5)

FAS=full analysis set
SoC =standard of care
Adapted from FDA Statistical review

What are the possible side effects?

In people with a history of congestive heart failure who receive ZINPLAVA, heart failure can occur and it can be serious.

The most common side effects are nausea, fever and headache.

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

All adverse reactions regardless of their seriousness were collected during 4 weeks post ZINPLAVA or placebo infusion; from 4 to 12 weeks only serious adverse reactions were reported.

Heart failure occurred primarily in patients with underlying congestive heart failure (CHF). In patients with a history of CHF, 12.7% (15/118) of ZINPLAVA-treated patients and 4.8% (5/104) of placebo-treated patients had the serious adverse reaction of heart failure during the 12-week study period. Additionally, in patients with a history of CHF, there were more deaths in ZINPLAVA-treated patients, 19.5% (23/118) than in placebo-treated patients, 12.5% (13/104) during the 12-week study period.

In patients with a history of CHF, ZINPLAVA should be reserved for use when the benefit outweighs the risk.

Below is the summary of the most common adverse reactions observed within 4 weeks of infusion.

Table 5. Adverse Reactions Reported Within 4 Weeks of Infusion in ≥4% of ZENPLAVA- treated Patients with CDI and at a Frequency Greater than Placebo in Trial 1 and 2 combined*



Adverse Reaction
ZINPLAVA with SoC
N=786
Placebo with SoC
N=781
%
Gastrointestinal disorders
Nausea75
General disorders and administration site conditions
Pyrexia53
Nervous system disorders
Headache43
*All patients as treated population, defined as all randomized patients who received a dose of study medication, by treatment received
Adverse reactions reported within 4 weeks of administration of ZINPLAVA
SoC = Standard of Care antibacterial drugs  (metronidazole or vancomycin or fidaxomicin) for CDI

ZINPLAVA Prescribing Information

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 occurrence of side effects was similar in White and non-White participants. The number of participants in other races but White was limited, therefore differences in side effects among other races could not be determined.
  • Age: The occurrence of side effects was similar in participants above and below age 65 enter content

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

The table below summarizes treatment emergent adverse events (TEAEs) reported within 12 weeks of infusion in ZINPLAVA and placebo treated subgroups in Trials 1 and 2 combined.

Table 6. Summary of TEAE by Subgroup (Safety Population)

 ZINPLAVA
N=786
n/N (%)
Placebo
N=781
n/N (%)
Sex
Men230/343 (67)222/326 (68)
Women318/443 (72)323/455 (71)
Age (years)
<65  270/392(69)248/372 (67)
≥65278/394 (71)297/409 (73)
Race
White452/652(69)472/682 (69)
Non-white96/134 (72)73/99 (74)

Clinical trial data

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved ZINPLAVA based on evidence from two clinical trials of 1567 participants with CDI. The trials were conducted in the United States, Canada, Europe, Asia, Africa, and Latin America.

Figure 1 summarizes how many men and women were enrolled in the clinical trials.

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were in the clinical trials of the drug ZINPLAVA. In total, 669 men (43%) and 898 women (57%) participated in the clinical trials.

Clinical trial data

Figure 2 and Table 1 summarize the percentage of participants by race in the clinical trials.

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race in the ZINPLAVA clinical trials. In total, 1334 Whites (85%), 74 Blacks (5%), 127 Asians (8%), 9 American Indian or Alaska Native (1%), and 23 Multiple  (1%) participated in the clinical trial.

Clinical trial data

Table 1. Baseline Demographics by Race

RaceNumber of ParticipantsPercentage
White133485%
Black or African American745%
Asian1278%
American Indian or Alaska Native91%
Multiple231%

Clinical trial data

Figure 3 summarizes the percentage of participants by age that were enrolled in the clinical trials.

Figure 3. Baseline Demographics by Age

Pie chart summarizing how many individuals of certain age groups were enrolled in the ZINPLAVA clinical trials.  In total, 190 participants were below 40 years old (12%), 140 participants were 40 to 59 years old (26%), 671 were 60 to 79 years old (43%) and 296 were  80 and older (19%).

Who participated in the trials?

The table below summarizes demographics of participants (safety population) in clinical Trials 1 and 2 combined.

Table 7. Baseline and Demographics (Safety Population)

 ZINPLAVA
N, %
Placebo
N, %
Total
N, %
Subjects in population786 (50)781(50)1567 (100)
Sex                                    
Men343 (44)326 (42)669 (43)
Women443 (56)455 (58)898 (57)
Age (years)
Median626463
Range18-10018-9818-100
Age group (years)
<40105 (13)85 (11)190 (12)
40-59211 (27)199 (25)410 (26)
60-79327 (42)344 (44)671(43)
≥80143 (19)153 (20)296 (19)
Race
American Indian or Alaska Native5 (1)4 (1)9 (1)
Asian68 (9)59 (8)127 (8)
Black or African American46 (6)28 (4)74 (5)
Multiple15 (2)8 (1)23 (1)
White652 (83)682 (87)1334 (85)
Ethnicity
Hispanic or Latino79 (10)103 (13)182 (12)
Non-Hispanic or Latino683 (87)655 (84)1338 (85)
Not Reported/unknown24 (3)23 (3)47 (3)
Region
US311 (40)322 (41)633 (40)
Non-US475 (60)459 (59)934 (60)

FDA Clinical review

How were the trials designed?

There were two trials that evaluated the benefits and side effects of ZINPLAVA.

All participants received antibacterial drugs for the treatment of CDI.

In each trial, participants were randomly assigned to receive one infusion of either ZINPLAVA or placebo during CDI treatment. Neither the participants nor the health care providers knew which treatment was being given until after the trials were completed.

The benefit of ZINPLAVA was measured by the proportion of patients whose CDI episode went away and did not come back through 3 months after the treatment with ZINPLAVA and compared it with the proportion for patients who were treated with placebo.

In most patients, side effects were evaluated during the same three month period.

How were the trials designed?

There were two randomized, multicenter, double-blind, placebo controlled trials that evaluated the safety and efficacy of ZINPLAVA. In each trial, participants were randomized to receive either ZINPLAVA infusion or normal saline infusion (placebo arm) while receiving SoC antibacterial drugs for treatment of CDI (metronidazole, vancomycin or fidaxomicin).

The efficacy was assessed by sustained clinical response, defined as clinical cure of the presenting CDI episode and no CDI recurrence through 12 weeks after infusion. CDI recurrence was defined as the development of a new episode of diarrhea associated with a positive stool test for toxigenic C. difficile following clinical cure of the presenting CDI episode.

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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Page Last Updated: 11/10/2016
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