Drug Trials Snapshots: PREVYMIS
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 PREVYMIS Package Insert for complete information.
PREVYMIS (letermovir)
PREH vih miss
Merck Sharp & Dome Corp
Approval date: November 8, 2017
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
PREVYMIS is a drug used to help prevent cytomegalovirus (CMV) infection and disease in adults previously exposed to CMV infection, who have received a stem cell (bone marrow) transplant.
Stem cell (bone marrow) transplant is one way of treating some blood cancers. Many transplant recipients are at high risk for CMV infection and disease because of their weakened immune system.
How is this drug used?
PREVYMIS is used once a day. PREVYMIS may be taken by mouth in the form of tablet. PREVYMIS may be given through the vein (intravenously) when patient is not able to take it by mouth. It takes one hour to receive PREVYMIS intravenously.
What are the benefits of this drug?
In the trial, PREVYMIS was better in preventing CMV infection than placebo: 38% of patients treated with PREVYMIS developed CMV infection in comparison to 61% of patients who received placebo.
What are the benefits of this drug (results of trials used to assess efficacy)?
The tables below summarize efficacy results for the clinical trial in patients previously exposed to CMV (i.e., CMV seropositive patients), who received a hematopoietic stem cell transplant (HSCT). The primary endpoint was clinically significant CMV infection through 24 weeks after transplant. Clinically significant CMV infection was defined as the occurrence of CMV end organ disease, or the need for early treatment (preemptive therapy) based on the presence of CMV viremia and the clinical condition of the subject.
Table 2: Trial P001 Efficacy Results in HSCT Recipients (NC=F Approach, FAS Population) Through Week 24
| Parameter | PREVYMIS (N=325) | Placebo (N=170) |
|---|---|---|
| Proportion of subjects who failed prophylaxis | 38% | 61% |
| Reasons for failures* | ||
| Clinically significant CMV infection by Week 24† | 18% | 42% |
| Initiation of PET based on documented CMV viremia | 16% | 40% |
| CMV end-organ disease | 2% | 2% |
| Discontinued from study before Week 24‡ | 17% | 16% |
| Missing outcome in Week 24 visit window | 3% | 3% |
| Stratum-adjusted treatment difference (PREVYMIS-Placebo)§ | ||
| Difference (95% CI) | -23.5 (-32.5, -14.6)¶ |
* The categories of failure are mutually exclusive and based on the hierarchy of categories in the order listed.
† Through Week 14, 8% of subjects in the PREVYMIS group and 39% of subjects in the placebo group experienced clinically significant CMV infection.
‡ Reasons for discontinuation included adverse event, death, lost to follow-up, physician decision, withdrawal by subject.
§ 95% CIs and p-value for the treatment differences in percent response were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (high or low risk).
¶ p-value <>
Note: FAS=Full analysis set; FAS includes randomized subjects who received at least one dose of study medication, and excludes subjects with detectable CMV DNA at baseline. Approach to handling missing values: Non-Completer=Failure (NC=F) approach. With NC=F approach, failure was defined as all subjects who developed clinically significant CMV infection or prematurely discontinued from the study or had a missing outcome through Week 24 post-transplant visit window.
PREVYMIS Prescribing Information
Were there any differences in how well the drug worked in clinical trials among sex, race and age?
- Sex: PREVYMIS worked similarly in men and women.
- Race: The majority of patients were White. The number of patients in other races was limited; therefore, differences in response among races could not be determined.
- Age: PREVYMIS 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?
The table below presents efficacy results by subgroup.
Table 3: Proporion of Subjects with Clinically Signifiant CMV Infection through Week 24 post-Transplant in Key Subgroups
| Subjects with Clinically Significant CMV Infection | |||
|---|---|---|---|
| Characteristic | PREVYMIS | Placebo | Difference in % (95%CI) |
| n/N% | n/N% | ||
| Sex | |||
| Men | 72/176 (40.9%) | 58/104 (55.8%) | -15.7 (-27.2, -3.8) |
| Women | 50/149 (33.6%) | 45/66 (68.2%) | -34.8 (-48.5, -21.2) |
| Age | |||
| < 65=""> | 100/272 (36.8%) | 85/139 (61.2%) | -24.5 (-34.4, -14.6) |
| > 65 years | 22/53 (41.5%) | 18/31 (58.1%) | -18.9 (-41.7, 3.9) |
| Race | |||
| White | 96/268 (35.8%) | 90/147 (61.2%) | -25.9 (-35.6, -16.2) |
| Asian* | 18/35 (51.4%) | 6/11 (54.5%) | -3.1 (-39.1, 32.9) |
| Black | 1/5 (20.0%) | 2/4 (50.0%) | NA |
| Other** | 7/17 (41.2%) | 5/8 (62.5%) | NA |
| Ethnicity | |||
| Hispanic* | 12/24 (50.0%) | 5/10 (50.0%) | 0.0 (-41.1, 41.1) |
| Non-Hispanic | 107/288 (37.2%) | 95/154 (61.7%) | -25.4 (-34.8, -16.0) |
| Not- reported/unknown | 3/13 (23.1%) | 3/6 (50.0%) | NA |
* The decrease in efficacy observed among Asian and Hispanic subjects in comparison to white and non-Hispanic subjects, respectively, may be due to the small number of subjects in these subgroups.
** Other race: 1 Native Hawaiin/Pacific Islander in the letermovir arm; the remainig others represent subjects with multiple races.
Adapted from Clinical Review
What are the possible side effects?
The most common side effects of PREVYMIS are nausea, diarrhea, vomiting, swelling of the legs and arms, cough, headache, fatigue and stomach pain.
What are the possible side effects (results of trials used to assess safety)?
Below is the summary of the most common adverse reactions with frequency of 10% or greater and at a frequency at least 2% greater than placebo that were observed in the controlled trial.
Table 4: Trial P001 All Grade Adverse Events Reported in ≥ 10% of PREVYMIS -Treated HSCT Recipients at a Frequency at least 2% Greater than Placebo
| Adverse Events | PREVYMIS (N=373) |
Placebo (N=192) |
|---|---|---|
| Nausea | 27% | 23% |
| Diarrhea | 26% | 24% |
| Vomiting | 19% | 14% |
| Peripheral Edema | 14% | 9% |
| Cough | 14% | 10% |
| Headache | 14% | 9% |
| Fatigue | 13% | 11% |
| Abdominal Pain | 12% | 9% |
PREVYMIS Prescribing Information
Were there any differences in side effects among sex, race and age?
- Sex: The risk of side effects was similar in men and women.
- Race: The majority of patients were White. The number of patients in other races was limited; therefore, differences in side effects among races could not be determined.
- Age: The risk of side effects was similar in 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?
The tables below summarize the frequency of all adverse events for the safety population by subgroup.
Table 5: Common Adverse Events that Occurred with a > 3% Difference Between Sexes in the PREVYMIS Arm
| Preferred Term | PREVYMIS | PLACEBO | ||
|---|---|---|---|---|
| Female N=162 n (%) |
Male N=211 n (%) |
Female N=76 n (%) |
Male N=116 n (%) |
|
| Diarrhea | 39(24.1%) | 58(27.5%) | 15(19.7%) | 32(27.6%) |
| Nausea | 47(29.0%) | 52(24.6%) | 18(23.7%) | 27(23.3%) |
| Pyrexia | 29(17.9%) | 48(22.7%) | 15(19.7%) | 28(24.1%) |
| Vomiting | 36(22.2%) | 33(15.6%) | 14(18.4%) | 12(10.3%) |
| Cough | 30(18.5%) | 23(10.9%) | 5(6.6%) | 15(12.9%) |
| Peripheral edema | 18(11.1%) | 36(17.1%) | 9(11.8%) | 8(7.8%) |
| Acute kidney injury | 11(6.8%) | 23(10.9%) | 4(5.3%) | 6(5.2%) |
| Insomnia | 11(6.8%) | 23(10.9%) | 4(5.3%) | 6(5.2%) |
| Erythema | 19(11.7%) | 14(6.6%) | 3(3.9%) | 8(6.9%) |
| Dyspnea | 8(4.9%) | 22(10.4%) | 2(2.6%) | 4(3.4%) |
Adapted from Clinical Review
Table 6: Common Adverse Events with a > 2% Higher Frequency in PREVYMIS Patients > 65 Years of Age Compared to PREVYMIS Subjects < 65="" years="" of="">
| Preferred Term | PREVYMIS | PLACEBO | ||
|---|---|---|---|---|
| Age < 65="" years=""> N=317 n (%) |
Age> 65 Years N=317 n (%) |
Age < 65="" years=""> N=317 n (%) |
Age> 65 Years N=317 n (%) |
|
| Diarrhea | 79(24.9%) | 18(32.1%) | 41(25.6%) | 6(18.8%) |
| Peripheral edema | 43(13.6%) | 11(19.6%) | 13(8.1%) | 5(15.6%) |
| Fatigue | 40(12.6%) | 10(17.9%) | 18(11.3%) | 3(9.4%) |
| Decreased appetite | 28(8.8%) | 10(17.9%) | 17(10.6%) | 5(15.6%) |
| Acute kidney Injury | 26(8.2%) | 10(17.9%) | 17(10.6%) | 8(25.0%) |
| Increased creatinine | 29(9.1%) | 7(12.5%) | 13(8.1%) | 0(0.0%) |
Adapted from Clinical Review
WHO WAS IN THE CLINICAL TRIALS?
Who participated in the clinical trials?
The FDA approved PREVYMIS based on evidence from one clinical trial of 565 patients, who had been previously exposed to CMV, and underwent a recent stem cell transplant. The trial was conducted at 67 sites in the following 20 countries: Austria, Belgium, Brazil, Canada, Finland, France, Germany, Italy, Japan, Republic of Korea, Lithuania, New Zealand, Peru, Poland, Romania, Spain, Sweden, Turkey, United Kingdom, and the United States.
Figure 1 summarizes how many men and women were enrolled in the clinical trial.
Figure 1. Baseline Demographics by Sex
FDA Clinical Review
Figure 2 and Table 1 summarize the percentage of patients by race enrolled in the clinical trial.
Figure 2. Baseline Demographics by Race
FDA Clinical Review
Table 1. Demographics of Trials by Race
| Race | Number of Patients | Percentage |
|---|---|---|
| White | 462 | 82 |
| Black or African American | 12 | 2 |
| Asian | 58 | 10 |
| Native Hawaiian or Pacific Islander | 1 | less than 1 |
| Other | 31 | 6 |
| Not reported | 1 | less than 1 |
FDA Clinical Review
Figure 3 summarizes the percentage of patients by age in the clinical trials.
Figure 3. Baseline Demographics by Age
FDA Clinical Review
Who participated in the trials?
The table below summarizes demographics of patients enrolled in the clinical trial.
Table 7: Patient Demographics
| PREVYMS N = 373 n (%) |
Placebo N = 192 n (%) |
Total N = 565 n (%) |
|
|---|---|---|---|
| SEX | |||
| Men | 211 (56.6) | 116 (60.4) | 327 (57.9) |
| Women | 162 (43.4) | 76 (39.6) | 238 (42.1) |
| AGE (YEARS) | |||
| Mean (SD) | 50.8 (13.4) | 50.8 (14.8) | 50.8 (13.9) |
| Median | 53 | 54 | 54 |
| Min, Max | 18, 75 | 19, 78 | 18, 78 |
| AGE GROUP | |||
| >= 18 <=> | 60 (16.1) | 33 (17.2) | 93 (16.5) |
| >= 36 <=> | 103 (27.6) | 49 (25.5) | 152 (26.9) |
| >= 51 <=> | 154 (41.3) | 78 (40.6) | 232 (41.1) |
| >= 65 <=> | 55 (14.7) | 30 (15.6) | 85 (15.0) |
| >= 75 | 1 (0.3) | 2 (1.0) | 3 (0.5) |
| RACE | |||
| White | 301 (80.7) | 161 (83.9) | 462 (81.8) |
| Black or African American | 8 (2.1) | 4 (2.1) | 12 (2.1) |
| Asian | 40 (10.7) | 18 (9.4) | 58 (10.3) |
| Native Hawaiian or Pacific Islander | 1 (0.3) | 0 (0.0) | 1 (0.2) |
| Other | 22 (5.9) | 9 (4.7) | 31 (5.5) |
| Missing Race | 1 (0.3) | 0 (0.0) | 1 (0.2) |
| ETHNICITY | |||
| Hispanic | 30 (8.0) | 10 (5.2) | 40 (7.1) |
| Non-Hispanic | 337 (90.3) | 177 (92.2) | 514 (91.0) |
| Missing Ethnicity | 6 (1.6) | 5 (2.6) | 11 (1.9) |
| REGION | |||
| Asia-Pacific | 37 (9.9) | 16 (8.3) | 53 (9.4) |
| Europe | 185 (49.6) | 97 (50.5) | 282 (49.9) |
| Latin America | 7 (1.9) | 2 (1.0) | 9 (1.6) |
| North America | 144 (38.6) | 77 (40.1) | 221 (39.1) |
FDA Clinical Review
How were the trials designed?
FDA approved PREVYMIS based on evidence from one clinical trial of 565 patients, who received stem cell (bone marrow) transplant as a part of cancer treatment. Patients were previously exposed to CMV.
Following transplant, patients randomly received either PREVYMIS or placebo (by mouth or intravenously) for 14 weeks. Neither patients nor healthcare providers knew which treatment was being given until after the trial was completed.
The trial measured the proportion of patients who developed CMV infection through Week 24 post-transplant.
How were the trials designed?
The safety and efficacy of PREVYMIS were assessed in a multicenter, double-blind, placebo-controlled trial. Adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT) were randomized (2:1) to receive either PREVYMIS at a dose of 480 mg once daily adjusted to 240 mg when co-administered with cyclosporine, or placebo. Treatment started 0-28 days after transplant and continued through 14 weeks after transplant. Study drug was administered by mouth or intravenously (in patients who were unable to take oral therapy).
The primary efficacy outcome was clinically significant CMV infection through 24 weeks after transplant. Clinically significant CMV infection was defined as the occurrence of CMV end organ disease, or the need for early treatment (preemptive therapy) based on the presence of CMV viremia and the clinical condition of the subject.
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