Drug Trials Snapshots: KORSUVA
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic 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 healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the KORSUVA Prescribing Information for all of the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
KORSUVA (Difelikefalin)
(kor soo' vah)
Cara Therapeutics, Inc.
Approval date: August 23, 2021
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
KORSUVA is an opioid receptor agonist for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD).
How is this drug used?
KORSUVA is given in the vein (intravenous) at the end of each dialysis treatment.
Who participated in the clinical trials?
The FDA approved KORSUVA based on evidence from two clinical trials of 851 patients undergoing hemodialysis who had moderate-to-severe pruritus. The trials were conducted in 80 sites in the United States and 95 sites globally (Japan, Canada, and Europe).
What are the benefits of this drug?
More participants achieved reduction in itch after treatment with KORSUVA in comparison to those treated with placebo.
What are the benefits of this drug (results of trials used to assess efficacy)?
Table 1 below summarizes efficacy results for the clinical trials based on the primary efficacy endpoint defined as the proportion of subjects achieving a 4-point or greater improvement (reduction) from baseline in the weekly mean of the daily 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS).
Table 1. Efficacy Results of Subjects With Moderate-to-Severe CKD-aP Undergoing HD at Week 12 (Trials 1 & 2)
| Parameter | Trial 1 | Trial 2 | ||
|---|---|---|---|---|
| KORSUVA 0.5 µg/kg 3 Times Weekly N=189 |
Placebo N=189 |
KORSUVA 0.5 µg/kg 3 Times Weekly N=237 |
Placebo N=236 |
|
| Percentage of subjects with ≥4‑point improvement from baseline in WI‑NRS score | 40% | 21% | 37% | 26% |
| Difference from placebo (95% CI) | 19% (9%, 28%) | 12% (3%, 20%) | ||
Source: Adapted from FDA Review
Abbreviations: CKD-aP, chronic kidney disease-associated pruritus; HD, hemodialysis; WI-NRS, Worst Itching Intensity Numerical Rating Scale
Figure 1. Percentage of Subjects With Moderate-to-Severe CKD-aP Undergoing HD With a ≥4-point Improvement From Baseline on the WI-NRS in Trial 1 and Trial 2
Source: KORSUVA Prescribing Information
Abbreviations: CKD-aP, chronic kidney disease-associated pruritus; HD, hemodialysis; WI-NRS, Worst Itching Intensity Numerical Rating Scale
Itch reduction was seen by Week 4 and sustained through Week 12.
Were there any differences in how well the drug worked in clinical trials among sex, race and age?
- Sex: KORSUVA worked similarly in males and females.
- Race: KORSUVA worked similarly in White and Black participants. The number of participants of other races was small; therefore, differences in response among all races could not be determined.
- Age: KORSUVA worked similarly in different age groups in patients younger and older than 65 years of age.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Table 2 and Table 3 below summarize efficacy results at Week 12 by age, sex, and race.
Table 2. Results for ≥4-Point Improvement in WI-NRS From Baseline at Week 12 by Age, Sex, and Race - Trial 1
| Subgroups (n [K], n [P]) | KORSUVA N=189 | Placebo N=189 |
Difference (95% CI) |
|---|---|---|---|
| Age, years | |||
| <65 (135, 137) | 41% | 19% | 22% (12%, 33%) |
| ≥65 (54, 52) | 36% | 26% | 10% (-8%, 28%) |
| Sex | |||
| Male (112, 119) | 40% | 19% | 21% (9%, 33%) |
| Female (77, 70) | 39% | 25% | 14% (-1%, 29%) |
| Race | |||
| White (91, 93) | 41% | 20% | 21% (8%, 34%) |
| Black or African American (82, 76) | 43% | 22% | 21% (6%, 36%) |
Source: Adapted from FDA Review
Intent-to-Treat (ITT) population: all randomized subjects. Missing data were imputed using multiple imputation (MI). Combined analysis used the separate interim and post-interim results to generate an adjusted overall estimate using the Cui, Hung, and Wang methodology.
Abbreviations: K, Korsuva; P, placebo; WI-NRS, Worst Itching Intensity Numerical Rating Scale
Table 3. Results for ≥4-Point Improvement in WI-NRS From Baseline at Week 12 by Age, Sex, and Race - Trial 2
| Subgroups (n[K], n [P]) | KORSUVA N=237 |
Placebo N=236 |
Difference (95% CI) |
|---|---|---|---|
| Age | |||
| < 65 (147, 153) | 38% | 27% | 11% (0%, 22%) |
| ≥ 65 (90, 83) | 37% | 24% | 12% (-2%, 26%) |
| Sex | |||
| Male (137, 139) | 28% | 24% | 4% (-7%, 15%) |
| Female (100, 97) | 50% | 29% | 21% (7%, 35%) |
| Race | |||
| White (164, 169) | 39% | 26% | 12% (2%, 23%) |
| Black or African American (53, 38) | 40% | 27% | 12% (-9%, 34%) |
Source: Adapted from FDA Review
Intent-to-Treat (ITT) population: all randomized subjects. Missing data were imputed using multiple imputation (MI). Combined analysis used the separate interim and post-interim results to generate an adjusted overall estimate using the Cui, Hung, and Wang methodology.
Abbreviations: K, Korsuva; P, placebo; WI-NRS, Worst Itching Intensity Numerical Rating Scale
What are the possible side effects?
KORSUVA may cause serious side effects including high potassium levels in the blood.
Concomitant use of centrally acting depressant medications, sedating antihistamines and opioid analgesics may increase the likelihood of dizziness, somnolence, mental status changes, and gait disturbances, including falls.
Dizziness, somnolence, and mental status changes have occurred in patients taking KORSUVA. KORSUVA may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car and operating machinery.
The most common adverse reactions leading to discontinuation were dizziness, mental status change, nausea, and headache.
What are the possible side effects (results of trials used to assess safety)?
Table 4 below summarizes adverse reactions that occurred in clinical trials. Presented is the safety population that includes all participants who used the treatment at least once according to the approved dose regimen.
Table 4. Adverse Reactions in ≥2% of KORSUVA-Treated Subjects With Moderate-to-Severe CKD-aP Undergoing HD and ≥1% Higher Than Placebo in Trials 1 and 2
Source: Adapted from FDA Review
Abbreviations: CKD-aP, chronic kidney disease-associated pruritus; HD, hemodialysis
Were there any differences in side effects among sex, race and age?
- Sex: The risk of side effects was similar in females and males.
- Race: The risk of side effects was similar in White and Black participants. The number of participants in other races was small; therefore, differences in side effects among races could not be determined.
- Age: The incidence of somnolence was higher in KORSUVA-treated subjects 65 years of age and older (7.0%) than in KORSUVA-treated subjects less than 65 years of age (2.8%).
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
Table 5. Incidence of TEAE Occurring in ≥2% of KORSUVA Subjects and With ≥1% Higher Incidence Than Placebo by Age, Sex, and Race in the Primary Safety Pool
| Subgroup | Numbers of Subjects in Treatment Groups | |
|---|---|---|
| Placebo | KORSUVA 0.5 µg/kg | |
| <65 years | N=289 | N=281 |
| Subjects with any event, n (%) | 180 (62.3%) | 196 (69.8%) |
| >65 years | N=135 | N=143 |
| Subjects with any event, n (%) | 97 (71.9%) | 106 (74.1%) |
| Male | N=257 | N=247 |
| Subjects with any event, n (%) | 160 (62.3%) | 165 (66.8%) |
| Female | N=167 | N=177 |
| Subjects with any event, n (%) | 117 (70.1%) | 137 (77.4%) |
| White | N=262 | N=253 |
| Subjects with any event, n (%) | 162 (61.8%) | 164 (64.8%) |
| Black or African American | N=113 | N=135 |
| Subjects with any event, n (%) | 80 (70.8%) | 106 (78.5%) |
| Other | N=49 | N=36 |
| Subjects with any event, n (%) | 35 (71.4%) | 32 (88.9%) |
Source: Adapted from FDA Review
Abbreviations: TEAE, treatment-emergent adverse events
DEMOGRAPHICS SNAPSHOT
Figure 2 below summarizes how many patients by sex were in the combined trials used to evaluate efficacy of KORSUVA.
Figure 2. Baseline Demographics by Sex (Trials 1 and 2)
Source: Adapted from FDA review
Figure 3 summarizes the percentage of patients by race enrolled in the combined clinical trials used to evaluate the efficacy of KORSUVA.
Figure 3. Baseline Demographics by Race (Trials 1 and 2)
Source: Adapted from FDA review
Figure 4 summarizes the percentage of patients by age enrolled in the combined clinical trials used to evaluate the efficacy of KORSUVA.
Figure 4. Baseline Demographics by Age (Trials 1 and 2)
Source: Adapted from FDA review
Who participated in the trials?
Table 6 below summarizes demographics for the randomized population (ITT population) in the pooled clinical trials.
Table 6. Demographics (Trials 1 and 2)
| Demographic Subgroup | KORSUVA N=426 |
Placebo N=425 |
Total N=851 |
|---|---|---|---|
| Age (years) | |||
| Mean (SD) | 59 (12) | 58 (14) | 59 (13) |
| Median | 60 | 59 | 59 |
| Min, max | 22, 90 | 24, 88 | 22, 90 |
| Age category | |||
| <65 | 282 (66) | 290 (68) | 572 (67) |
| ≥65 | 144 (34) | 135 (32) | 279 (33) |
| Sex, n (%) | |||
| Male | 249 (58) | 258 (61) | 507 (60) |
| Female | 177 (42) | 167 (39) | 344 (40) |
| Race, n (%) | |||
| White | 255 (60) | 262 (62) | 517 (61) |
| Black or African American | 135 (32) | 114 (27) | 249 (29) |
| Asian | 18 (4) | 27 (6) | 45 (5) |
| Other | 18 (4) | 22 (5) | 40 (5) |
| Ethnicity, n (%) | |||
| Hispanic or Latino | 133 (31) | 136 (32) | 269 (32) |
| Not Hispanic or Latino | 287 (67) | 287 (68) | 574 (67) |
| Not reported | 2 (<1) | 2 (<1) | 4 (<1) |
| Unknown | 4 (1) | 0 (0) | 4 (<1) |
| Region, n (%) | |||
| United States | 335 (79) | 322 (76) | 657 (77) |
| Eastern Europe | 54 (13) | 60 (14) | 114 (13) |
| Western Europe | 29 (7) | 31 (7) | 60 (7) |
| Asia | 8 (2) | 12 (3) | 20 (2) |
Source: Adapted from FDA review
How were the trials designed?
KORSUVA was evaluated in two clinical trials (Trials 1 [NCT03422653] and Trial 2 [NCT03636269]) of 851 patients with moderate-to-severe pruritus and on hemodialysis for chronic kidney failure. In the two trials, participants received treatment with either KORUVA or placebo injections after every hemodialysis, three times a week for 12 weeks. Neither the participants nor the health care providers knew which treatment was being given until after the trials were completed.
Participants who completed the initial treatment were eligible to enter the open-label part of the study. Participants who were on placebo, were then given KORSUVA and followed for up to 52 weeks.
In each trial, participants were evaluated for improvement of pruritus based on the proportion of participants achieving a 4-point or greater improvement in the weekly mean of the daily 24-hour Worst Itch Intensity Numerical Rating Scale (WI-NRS) at Week 12.
How were the trials designed?
The efficacy of KORSUVA was evaluated in two randomized, multicenter, double-blind, placebo-controlled trials (Trial 1 [NCT03422653] and Trial 2 [NCT03636269]) that enrolled a total of 851 subjects 18 years of age and older undergoing HD who had moderate-to-severe pruritus. In both trials, subjects received intravenous bolus injections of KORSUVA 0.5 µg per kilogram of dry body weight into the venous line of the hemodialysis circuit at the end of each hemodialysis session or placebo three times per week for 12 weeks. In both trials, a 7-day run-in period prior to randomization was used to confirm that each subject had moderate-to-severe pruritus and to establish a baseline itch intensity, as measured by the patient-reported daily 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS) scores (0 “no itch” to 10 “worst itch imaginable”).
The mean (SD) baseline WI-NRS score was 7.1 (1.5) in Trial 1 and 7.2 (1.4) in Trial 2. At baseline in Trial 1, 61% of subjects were male, 49% were White, 42% were Black or African American, the mean age was 57 years (range 22 to 88 years), and 40% of subjects were using prior anti-pruritic medications (including sedating antihistamines) and continued the use throughout the trial. At baseline in Trial 2, 58% of subjects were male, 70% were White, 19% were Black or African American, the mean age was 60 years (range 23 to 90 years), and 36% of subjects were using prior anti-pruritic medications (including sedating antihistamines) and continued the use throughout the trial.
In each trial, efficacy was assessed based on the proportion of subjects achieving a 4-point or greater improvement (reduction) from baseline in the weekly mean of the daily 24-hour WI-NRS score at Week 12.
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