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=386 | N=395 | |||
| Sustained clinical response | 232 (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=395 | N=378 | |||
| Sustained clinical response | 264 (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 | ||
| Men | 92/157 (58.6) -3.0 (-13.6, 7.6) | 106/172 (61.6) |
| Women | 140/229 (61.1) 10.9 (1.8, 20.0) | 112/223 (50.2) |
| Race | ||
| White | 202/338 (59.8) 4.0 (-3.3, 11.3) | 204/366 (55.7) |
| All others | 30/48 (62.5) 14.2 (-8.5, 37.0) | 14/29 (48.3) |
| Age | ||
| > | 118/201 (58.7) -4.1 (-13.7, 5.6) | 123/196 (62.8) |
| ≥65 | 114/185 (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 | |||
| Men | 115/182 (63.2) 8.6 (-2.0, 19.2) | 83/152 (54.6) | |
| Women | 149/213 (70.0) 19.5 (10.5, 28.5) | 114/226 (50.4) | |
| Race | |||
| White | 209/311 (67.2) 14.8 (7.1, 22.4) | 162/309 (52.4) | |
| Asian | 41/63 (65.1) 14.2 (-3.3, 31.7) | 29/57 (50.9) | |
| All others | 14/21 (66.7) | 6/12 (50.0) | |
| Age | |||
| > | 127/190 (66.8) 10.5 (0.5, 20.4) | 97/152 (56.4) | |
| ≥65 | 137/205 (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 | ||
| Nausea | 7 | 5 |
| General disorders and administration site conditions | ||
| Pyrexia | 5 | 3 |
| Nervous system disorders | ||
| Headache | 4 | 3 |
| *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 | |||
| Men | 230/343 (67) | 222/326 (68) | |
| Women | 318/443 (72) | 323/455 (71) | |
| Age (years) | |||
| 65> | 270/392(69) | 248/372 (67) | |
| ≥65 | 278/394 (71) | 297/409 (73) | |
| Race | |||
| White | 452/652(69) | 472/682 (69) | |
| Non-white | 96/134 (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
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
Clinical trial data
Table 1. Baseline Demographics by Race
| Race | Number of Participants | Percentage |
|---|---|---|
| White | 1334 | 85% |
| Black or African American | 74 | 5% |
| Asian | 127 | 8% |
| American Indian or Alaska Native | 9 | 1% |
| Multiple | 23 | 1% |
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
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 population | 786 (50) | 781(50) | 1567 (100) |
| Sex | |||
| Men | 343 (44) | 326 (42) | 669 (43) |
| Women | 443 (56) | 455 (58) | 898 (57) |
| Age (years) | |||
| Median | 62 | 64 | 63 |
| Range | 18-100 | 18-98 | 18-100 |
| Age group (years) | |||
| > | 105 (13) | 85 (11) | 190 (12) |
| 40-59 | 211 (27) | 199 (25) | 410 (26) |
| 60-79 | 327 (42) | 344 (44) | 671(43) |
| ≥80 | 143 (19) | 153 (20) | 296 (19) |
| Race | |||
| American Indian or Alaska Native | 5 (1) | 4 (1) | 9 (1) |
| Asian | 68 (9) | 59 (8) | 127 (8) |
| Black or African American | 46 (6) | 28 (4) | 74 (5) |
| Multiple | 15 (2) | 8 (1) | 23 (1) |
| White | 652 (83) | 682 (87) | 1334 (85) |
| Ethnicity | |||
| Hispanic or Latino | 79 (10) | 103 (13) | 182 (12) |
| Non-Hispanic or Latino | 683 (87) | 655 (84) | 1338 (85) |
| Not Reported/unknown | 24 (3) | 23 (3) | 47 (3) |
| Region | |||
| US | 311 (40) | 322 (41) | 633 (40) |
| Non-US | 475 (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.