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  5. Drug Trials Snapshots: CRESEMBA (aspergillosis)
  1. Development & Approval Process (Drugs)

Drug Trials Snapshots: CRESEMBA (aspergillosis)

Drug Trials Snapshots: CRESEMBA (aspergillosis)

For the treatment of invasive aspergillosis

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 CRESEMBA Prescribing Information for complete information.

CRESEMBA (isavuconazonium sulfate)
(Crē-SEM-bah)
Astellas Pharma US, Inc.
Approval date:  March 6, 2015


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

CRESEMBA is a drug that is used to treat adults with a rare but serious fungal infection called invasive aspergillosis. This infection occurs most often in people with weak immune systems.

CRESEMBA is also used for the treatment of adults with a rare but serious fungal infection called invasive mucormycosis. This is discussed in a separate Snapshot.

How is this drug used?

CRESEMBA is 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. CRESEMBA is also available as a capsule to be taken by mouth.

What are the benefits of this drug?

The trial showed that CRESEMBA was as safe and effective in treating invasive aspergillosis as voriconazole, another drug used to treat fungal infections.  

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

The table below summarizes results for the primary endpoint for the trial.

Table 2. All-cause Mortality through Day 42

 

 

CRESEMBAVoriconazoleDifference a (95% CI)
NAll-cause
Mortality
n (%)
NAll-cause
Mortality
n (%)

Intent to Treat (ITT)

25848 (18.6)25852 (20.2)-1.0 (-8.0, 5.9)

Proven or Probable Aspergillosis

12323 (18.7)10824 (22.2)-2.7 (-13.6, 8.2)

a Adjusted treatment difference (CRESEMBA-voriconazole) by Cochran-Mantel-Haenszel method stratified by the randomization factors.
Source: CRESEMBA Package Insert, Section 14, Table 7

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

Subgroup analyses were conducted for sex, race and age.

  • Sex: CRESEMBA was similarly effective in men and women.
  • Race: The number of non-White, non-Asian patients was limited. CRESEMBA appeared to be less effective in Asians compared to Whites. However, this difference was seen in a single center in South Korea and not in all Asian patients.
  • Age: CRESEMBA was similarly effective in patients below 65 years of age and those 65 years of age and above.

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

The table below summarizes the subgroup analysis for the primary endpoint.

Table 3. Subgroup Analysis of Primary Endpoint (All-cause Mortality through Day 42)

SubgroupCRESEMBA
(N=258)
Voriconazole
(N=258)
n (%)Total, Nn (%)Total, N
Overall Response/All patients48 (18.6)25852 (20.2)258
Sex
Male27 (18.6)14536 (22.1)163
Female21 (18.6)11316 (16.8)95
Age Group (years)
<>0 0 
17-6435 (18.0)19538 (19.4)196
65-7413 (20.6)6314 (22.6)62
75 and older2 (18.2)115 (38.5)13
Race
White34 (16.1)21136 (18.8)191
Black or African
American
0101
Asian14 (31.1)4514 (21.9)64
American Indian or  
Alaska Native    
0 0 
Native Hawaiian or
Other Pacific Islander
0 0 
Other0111
Missing01
Ethnicity
Hispanic or Latino4 (18.2)222 (22.2)9
Not Hispanic or Latino44 (18.6)23649 (19.8)248
Missing0 11
Region
United States5 (17.2)294 (16.0)25
Rest of World43 (18.8)22948 (20.6)233
Canada0113
South America3 (17.7)174 (28.6)14
Europe15 (13.0)11526 (22.2)117
Asia20 (25.6)7817 (18.5)92
Africa3 (30.0)1003
Mexico2201
Australia/New Zealand0603

Source: From Clinical Reviewer

To explore the observed higher difference in mortality in Asians, the following analysis by country was performed. South Korea appeared to be an outlier.

Figure 4. Difference in All-cause Mortality at 42 days by Country in the Trial

Chart summarizing an observed higher difference in mortality in Asians upon following analysis by country was performed.

Source: Statistical Review, Figure 3

According to the Clinical and Statistical Reviews, the apparent higher mortality difference in the Asian population was highly influenced by the results in the enrolled population in South Korea. An analysis was performed excluding the South Korean sites, and Asians had a similar mortality as other groups and there was not a difference in mortality between isavuconazonium sulfate and voriconazole.  The reason for the difference at the South Korean sites is not clear.  The disease severity of South Korean patients was similar to other patients in the trial.

What are the possible side effects?

The most common side effects are nausea, vomiting, diarrhea, headache, abnormal liver blood tests, low potassium levels in the blood, constipation, shortness of breath, cough, and swelling of the arms and legs.

CRESEMBA may also cause serious side effects, including liver problems, infusion reactions, and severe allergic and skin reactions.

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

Table 4. Treatment-Emergent Adverse Reactions in the Clinical Trial with an Incidence of at least 10% in CRESEMBA-treated Patients

Adverse EventCRESEMBA
(N=257)
n (%)
Voriconazole
(N=259)
n (%)
Nausea71 (27.6)78 (30.1)
Vomiting64 (24.9)73 (28.2)
Diarrhea61 (23.7)60 (23.2)
Hypokalemia49 (19.1)58 (22.4)
Elevated liver laboratory tests44 (17.1)63 (24.3)
Dyspnea44 (17.1)35 (13.5)
Abdominal pain43 (16.7)59 (22.8)
Headache43 (16.7)38 (14.7)
Peripheral edema39 (15.2)47 (17.8)
Constipation36 (14)54 (20.8)
Insomnia27 (10.5)25 (9.7)
Fatigue27 (10.5)18 (6.9)
Back pain26 (10.1)19 (7.3)
Renal failure26 (10.1)21 (8.1)

Source: Extracted from CRESEMBA Package Insert, Section 6, Table 2

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

Subgroup analyses were conducted for sex, race and age.

  • Sex: The risk of overall side effects was similar in men and women.
  • Race: The number of non-White, non-Asian patients was limited. The risk of overall of side effects was similar in Whites and Asians.
  • Age: The risk of overall side effects was similar in patients 65 years and below and those above 65 years. Certain side effects—called serious adverse events1—were seen more frequently in patients above 65 years.

1 Serious adverse event was defined as any event that resulted in one of the following: death, life-threatening event, required hospitalization or extended a current hospital stay, persistent or significant disability/incapacity, or congenital anomaly or birth defect.

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

Tables 5, 6 and 7 summarize treatment-emergent adverse events (TEAEs) by age, sex, and race.

Table 5. Incidence of TEAEs by Age (Safety Population)

 

≤65 years of age>65 years of age
CRESEMBA
N=201
n (%)
Voriconazole
N=201
n (%)
CRESEMBA
N=56
n (%)
Voriconazole
N=58
n (%)

All TEAEs

192 (95.5)197 (98)55 (98.2)58 (100)

Serious TEAEs

99 (49.3)116 (57.7)35 (62.5)33 (56.9)

TEAEs Leading to Discontinuation of Study Drug

29 (14.4)44 (21.9)8 (14.3)15 (25.9)

TEAEs Leading to Death

47 (23.4)55 (27.4)15 (26.8)17 (29.3)

Source: Clinical Review, Table 82

Table 6. Incidence of TEAEs by Sex (Safety Population)

 MalesFemales
CRESEMBA
N=145
n (%)
Voriconazole
N=163
n (%)
CRESEMBA
N=112
n (%)
Voriconazole
N=96
n (%)
All TEAEs139 (95.9)161 (98.8)108 (96.4)94 (97.9)
Serious TEAEs75 (51.7)93 (57.1)59 (52.7)56 (58.3)
TEAEs Leading to Discontinuation of Study Drug19 (13.1)43 (26.4)18 (16.1)16 (16.7)
TEAEs Leading to Death30 (20.7)44 (27)32 (28.6)28 (29.2)

Source: Clinical Review, Table 83

Table 7. Incidence of TEAEs by Race (Safety Population)

   WhiteAsian
CRESEMBA
N=211
n (%)
Voriconazole
N=191
n (%)
CRESEMBA
N=44
n (%)
Voriconazole
N=65
n (%)
All TEAEs204 (96.7)189 (98.6)41 (93.2)63 (96.9)
Serious TEAEs110 (52.1)112 (58.6)22 (50)34 (52.3)
TEAEs Leading to Discontinuation of Study Drug27 (12.8)47 (24.6)10 (22.7)12 (18.5)
TEAEs Leading to Death45 (21.3)57 (29.8)17 (38.6)13 (20)

Source: Clinical Review, Table 84

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved CRESEMBA based on evidence from a clinical trial of 516 patients believed or confirmed to have invasive aspergillosis. The trial was conducted at 102 centers in 12 countries, including those in North America, South America, Europe, Asia, and Africa.

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

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were enrolled in the CRESEMBA clinical trial.  In total, 308 men (60%) and 208 women (40%) participated in the clinical trial.

Source: From Clinical Reviewer

Figure 2 summarizes how many patients by race were in the clinical trial.

Figure 2. Baseline Demographics by Race

Bar chart summarizing the percentage of patients by race enrolled in the CRESEMBA clinical trial. In total, 402 White (78%), 2 Black (0.4%), 109 Asian (21%), 2 identified as Other (0.4%), and 1 patient where data was missing (0.2%) participated in the clinical trial.

Source: From Clinical Reviewer

Table 1. Baseline Demographics by Race

RaceNumber of PatientsPercentage (%)
White40278
Black or African American20.4
Asian10921
Other20.4
Missing10.2

Source: From Clinical Reviewer

The figure below summarizes the ages of patients in the clinical trial.

Figure 3. Baseline Demographics by Age

Pie chart summarizing how many individuals of certain age groups were enrolled in the CRESEMBA clinical trial.  In total, 391 were between 17 and 64 years (76%), 101 were between 65 and 74 years (19%), and 24 were over the age of 75 (5%).

Source: From Clinical Reviewer

Who participated in the trials?

The table below summarizes baseline demographics for the clinical trial. The efficacy and safety populations were similar.

Table 8. Baseline Demographics in the Clinical Trial

Demographic ParameterCRESEMBA
(N=258)
n (%)
Voriconazole
(N=258)
n (%)
Sex
Male145 (56.2)163 (63.2)
Female113 (43.8)95 (36.8)
Age (years)
Mean (SD)51.1 (16.2)51.1 (15.8)
Median5453.5
Min, Max17, 8218,87
Age Group (years)
17 - 64195 (75.6)196 (76.0)
65 and older63 (24.4)62 (24.0)
Race 
White211 (81.8)191 (74.3)
Black or African American1 (0.4)1 (0.4)
Asian45 (17.4)64 (24.9)
American Indian or Alaskan Native00
Native Hawaiian or Other Pacific Islander00
Other1 (0.4)1 (0.4)
Missing01 (0.4)
Ethnicity
Hispanic or Latino22 (8.5)9 (3.5)
Not Hispanic or Latino236 (91.5)248 (96.5)
Missing01 (0.4)
Region  
United States29 (11.2)25 (9.7)
Rest of World229 (88.8)233 (90.3)
Canada1 (0.4)3 (1.2)
South America17 (6.6)14 (5.4)
Europe115 (44.6)117 (45.4)
Asia78 (30.2)92 (35.7)
Africa10 (3.9)3 (1.2)
Mexico2 (0.8)1 (1.4)
Australia/New Zealand6 (2.3)3 (1.2)

Source: From Clinical Reviewer

How were the trials designed?

CRESEMBA was approved by the FDA based on a trial of 516 patients. Patients were randomly assigned to treatment with either CRESEMBA or voriconazole. Neither the patients nor the health care professionals knew which patients received CRESEMBA and which patients received voriconazole. The trial was designed to evaluate whether CRESEMBA works as well as voriconazole for the treatment of invasive aspergillosis.

How were the trials designed?

The trial was a randomized, double-blind, non-inferiority, active-controlled trial which evaluated the safety and efficacy of CRESEMBA versus voriconazole for primary treatment of invasive fungal disease caused by Aspergillus species or other filamentous fungi. Eligible patients had proven, probable, or possible invasive fungal infections per European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria. Patients were stratified by history of allogeneic bone marrow transplant, uncontrolled malignancy at baseline, and by geographic region.

Patients randomized to receive CRESEMBA treatment were administered an IV loading dose of CRESEMBA every 8 hours for the first 48 hours. Beginning on day 3, patients received intravenous or oral therapy of CRESEMBA once daily. Patients randomized to receive voriconazole treatment were administered voriconazole intravenously for the first 48 hours. Therapy could then be switched to an oral formulation of voriconazole. The protocol-defined maximum treatment duration was 84 days, and the primary efficacy endpoint was all-cause mortality through Day 42.

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

MEDICAL REVIEW

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