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Drug Trials Snapshot: ZEMDRI

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that support 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 ZEMDRI Prescribing Information for complete information.

ZEMDRI (plazomicin)
zem' dree
Achaogen, Inc.
Approval date: June 25, 2018


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

ZEMDRI is used to treat adults who have a complicated urinary tract infection (abbreviated as cUTI) including infection of the kidneys (pyelonephritis) caused by specific bacteria. It should be used only when few or no other treatment options are available.

How is this drug used?

ZEMDRI is a drug administered by a health care professional directly into the bloodstream through a needle in the vein. This is known as an intravenous, or IV, infusion. It is given every 24 hours for 4-7 days.

What are the benefits of this drug?

On Day 5 of IV treatment with ZEMDRI, 88% of patients were cured or had improved signs and symptoms of cUTI and had decreased the number of bacteria in their urine. This was similar to the cure rates for patients who received another antibacterial drug, meropenem (91%).

Because cUTI can come back, many patients continued with oral antibacterial drugs to complete the treatment for cUTI. The benefit was also evaluated after this treatment was completed (about 7-10 days later after total treatment was finished) and it showed that 82% of patients who were initially treated with ZEMDRI were cured from cUTI in comparison to 70% of patients who were initially treated with meropenem.

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

The efficacy of ZEMDRI was established based on success at Day 5 of IV treatment and at the TOC visit. At Day 5, this success was defined as both a clinical outcome of cure or improvement and a microbiologic outcome of eradication (all uropathogens which were at >105/mL at baseline were to be reduced to <104 cfu/ml="" with="" treatment).="" at="" the="" test="" of="" cure="" (toc)="" visit="" (approximately="" 7-10="" days="" after="" completion="" of="" iv="" treatment)="" clinical="" response="" was="" defined="" as="" both="" a="" clinical="" outcome="" of="" cure="" and="" a="" microbiological="" outcome="" of="" eradication.="" efficacy="" was="" assessed="" in="" the="" microbiological="" modified="" intent="" to="" treat="" population="" (m-mitt),="" which="" was="" a="" subset="" of="" all="" randomized="" patients="" who="" received="" any="" dose="" of="" study="" drug="" and="" had="" at="" least="" one="" qualified="" baseline="" pathogen="" (from="" a="" baseline="" urine="" culture),="" against="" which="" plazomicin="" and="" meropenem="" had="" antibacterial="">

Table 2. Composite Cure Rates in cUTI Patients (m MITT Population)

Analysis Visit ZEMDRI
n/N (%)
Meropenem
n/N (%)
Treatment Difference a
(95% CI)
Day 5 168/191 (88.0) 180/197 (91.4) -3.4 (-10.0, 3.1)
Clinical cure or improvement   171/191 (89.5)   182/197 (92.4)  
Microbiological eradication   188/191 (98.4)   193/197 (98.0)  
TOC 156/191 (81.7) 138/197 (70.1) 11.6 (2.7, 20.3)
Clinical Cure 170/191 (89.0) 178/197 (90.4)  
Microbiological eradication   171/191 (89.5)   147/197 (74.6)  

Abbreviations: CI=confidence interval; TOC=test-of-cure; CI=95% confidence interval based on Newcombe method with continuity correction.
a Treatment difference is ZEMDRI – meropenem.

ZEMDRI Prescribing Information

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

  • Sex: ZEMDRI worked similarly in men and women.
  • Race: Almost all patients were White. The number of patients in other races was limited. Differences in how well the drug worked among races could not be determined.
  • Age: ZEMDRI worked similarly in patients below and above 65 years of age.

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

Subgroup analysis at Day 5 and the TOC (test of cure) time points for composite endpoint (Clinical cure and Microbiological Eradication) are presented in the tables below.

Table 3. Subgroup Analyses for the Composite Response at Day 5, mMITT Population

Subgroup
Population
Risk
difference
95% CI lower bound 95% CI upper bound
Sex, n (%)
Men, 183 (47.2) -1 -12 9.4
Women, 205 (52.8) -6.1 -14.7 2.5
Age
< 65="" years,="" 196=""> -0.6 -9.1 8.2
>= 65 years, 192 (49.5) -6.9 -17.6 3.5

Table 4. Subgroup Analyses for the Composite Response at TOC, mMITT Population

Subgroup
Population
Risk
difference
95% CI lower bound 95% CI upper bound
Sex, n(%)
Men, 183 (47.2) 8.7 -5.1 21.7
Women, 205 (52.8) 13.6 1.6 25.4
Age, n(%)
< 65="" years,="" 196=""> 17.5 5.7 29
>= 65 years, 192 (49.5) 4.7 -8.9 17.9

Adapted from FDA Statistical review

What are the possible side effects?

ZEMDRI may cause serious and life threatening allergic reactions and severe diarrhea caused by C. difficile.

Common side effects that were associated with the use of ZEMDRI include decreased kidney function, diarrhea, headache, nausea, vomiting and change in blood pressure.

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

Table 5 summarizes the most common adverse events observed in the trial.

Table 5. Incidence (%) of Adverse Reactions Occurring in 1% or More of cUTI Adult Patients Treated With ZEMDRI

Adverse Reactions ZEMDRI
(N=303)
n (%)
Meropenem a
(N=301)
n (%)
Decreased Renal Function b 11 (3.6) 4 (1.3)
Diarrhea 7 (2.3) 5 (1.7)
Hypertension 7 (2.3) 7 (2.3)
Headache 4 (1.3) 9 (3.0)
Nausea 4 (1.3) 4 (1.3)
Vomiting 4 (1.3) 3 (1.0)
Hypotension 3 (1.0) 2 (0.7)

a 1 g IV every 8 hours.
b Combined term that corresponds to adverse reactions associated with renal function

ZEMDRI Prescribing Information

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

  • Sex: The occurrence of side effects was similar between men and women.
  • Race: Almost all patients were White. 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 higher in patients above 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 incidence of treatment-emergent adverse events (adverse events that occurred while patient was receiving study drug treatment) by subgroup.

Table 6. Summary of Incidence of Treatment-Emergent Adverse Events by Subgroup (Safety Population)

Subgroup ZEMDRI
N=303
Meropenem
N=301
n (%) Total, N n (%) Total, N
Overall 59 (19.5) 303 65 (21.6) 301
SEX
    Men 27 (20.3) 133 22 (14.4) 153
    Women 32 (18.8) 170 43 (29.1) 148
AGE (years)
    <> 22 (13.3) 166 38 (24.1) 158
    >= 65 37 (27) 137 27 (18.9) 143

Clinical trial data

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

FDA approved ZEMDRI based on the trial (NCT02486627) of 604 patients with cUTI. The trial included patients from the Europe, United States and Mexico.

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

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were in the clinical trial.  In total, 286 men (47%) and 318 women (53%) participated in the clinical trial.

FDA Review

Figure 2 and Table 1 summarize the percentage of patients by race in the clinical trial.

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race in the clinical trial. In total, 601 White (99%), and 3 Other (1%), participated in the clinical trial.

FDA Review

Table 1. Baseline Demographics by Race

Race Number of Patients Percentage (%)
White 601 99
Other 3 1

FDA Review

Figure 3 summarizes by age how many patients were in the clinical trial.

Figure 3. Baseline Demographics by Age

Pie chart summarizing how many individuals of certain age groups were in the clinical trial.  In total, 324 participants were below 65 years old (54%) and 280 participants were 65 and older (46%).

FDA Review

Who participated in the trials?

The table below summarizes baseline demographic information for the safety population.

Table 7. Demographic and Baseline Characteristics (Safety Population)

Demographic Parameters ZEMDRI
N=303
n (%)
Meropenem
N=301
n (%)
TOTAL 
N=604 
n (%)
Sex
Men 133 (43.9) 153 (50.8) 286 (47.4)
Women 170 (55.1) 148 (49.2) 318 (52.6)
Race
White 301 (99.3) 300 (99.3) 601 (99.5)
Other 2 (0.7) 1 (0.3) 3 (0.5)
Age (years)
Median (min, max) 62 64 63
Age Group
< 65=""> 166 (54.8) 158 (52.5) 324 (53.6)
>= 65 years 137 (45.2) 143 (47.5) 280 (46.4)
Ethnicity
Hispanic or Latino 2 (0.7) 4 (1.3) 6 (1)
Not Hispanic or Latino 298 (98.3) 295 (98) 593 (98.2)
Not reported 3 (0.9) 2 (0.7) 5 (0.8)
Region
USA 2 (0.7) 1 (0.3) 3 (0.5)
Rest of World 301 (99.3) 300 (99.6) 601 (99.5)

FDA Review

How were the trials designed?

In the clinical trial, approximately half of the patients with cUTI were chosen at random to receive ZEMDRI, and the other half was given another antibacterial drug called meropenem. Both treatments were given intravenously for 4-7 days and neither the patients nor the health care professionals knew which drugs were given until after the study was complete. After at least 4 days of IV treatment with ZEMDRI or meropenem, patients could be switched to an oral antibacterial drug to complete the treatment for cUTI.

The benefit of ZEMDRI was measured by the proportion of patients who achieved cure or improvement in their symptoms related to cUTI and a negative urine culture test in comparison to meropenem.

How were the trials designed?

There was one randomized, active-controlled, double blind, non-inferiority, multi center trial comparing ZEMDRI to meropenem in the treatment of adults with cUTI. Medications were given intravenously for 4 to 7 days. A switch to levofloxacin or other approved oral treatment was allowed after a minimum of 4 and maximum of 7 days of IV therapy.

The efficacy of ZEMDRI was based on non-inferiority assessment of the primary-endpoint defined as a success on Day 5 which required both a clinical outcome of cure or improvement and a microbiologic outcome of eradication (all baseline uropathogens at >105/mL are to be reduced to <104>

The efficacy was assessed also on Composite cure at the Test of Cure (TOC) visit (Day 17 ± 2 from the first dose of study drug) defined as resolution of clinical cUTI symptoms and a microbiological outcome of eradication.

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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