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Drug Trials Snapshots: NOURIANZ

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 NOURIANZ Package Insert for complete information.

NOURIANZ (istradefylline)
Nue’-ree-anz
Kyowa Kirin, Inc.
Approval date: August 27, 2019


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

NOURIANZ is a drug used to treat “off” episodes in patients with Parkinson’s disease (PD). An “off” episode is a time when a patient’s medications are not working well, leading to an increase in Parkinson’s symptoms, such as tremor and difficulty walking.

How is this drug used?

NOURIANZ is a tablet taken by mouth once daily in addition to drugs for the treatment of Parkinson’s disease that contain levodopa/carbidopa combination.

What are the benefits of this drug?

Patients treated with NOURIANZ had decreased “off” time compared to patients treated with placebo.

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

The tables below summarize the efficacy results for individual trials based on the change in percentage of daily awake “off” time for NOURIANZ and placebo treated patients.

Table 2. Change from Baseline in Daily Awake OFF Time-Trials 1 and 2

  Baseline Change from Baseline to Endpoint
 
N
(mean ± SD)
% of awake “off” hours

N
(LSMD* vs. placebo),
% awake “off” hours,
(p-value)
Trial 1
Placebo 66 37.2 ± 13.8 65 --
NOURIANZ 40 mg 129 38.4 ± 16.2 126 - 6.78 (p=0.007)
Trial 2
Placebo 113 38.7 ± 11.6 113 --
NOURIANZ 20 mg 112 39.8 ± 14.0 112 - 4.57 (p=0.025)

* LSMD: Least squares mean difference; a negative value indicates a greater reduction from baseline in “OFF” Time for NOURIANZ, relative to placebo.
SD: Standard Deviation

NOURIANZ Prescribing Information

Table 3. Change from Baseline in Daily OFF Time-Trials 3 and 4

  Baseline Change from Baseline to Endpoint

N
(mean ± SD)
hours

N
(LSMD* vs. placebo)
hours
( p-value)
Trial 3
Placebo 118 6.4 ± 2.7 118 --
NOURIANZ 20 mg 115 6.8 ± 2.9 115 -0.65 (p=0.028)
NOURIANZ 40 mg 124 6.6 ± 2.5 124 -0.92 (p=0.002)
Trial 4
Placebo 123 6.3 ± 2.5 123 --
NOURIANZ 20 mg 120 6.6 ± 2.7 120 -0.76 (p=0.006)
NOURIANZ 40 mg 123 6.0 ± 2.5 123 -0.74 (p=0.008)

* SMD: Least squares mean difference; a negative value indicates a greater reduction from baseline in “off” time for NOURIANZ, relative to placebo.
SD: Standard Deviation

NOURIANZ Prescribing Information

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

  • Sex: NOURIANZ worked similarly in men and women.
  • Race: Differences in how well the drug worked among races could not be determined.
  • Age: NOURIANZ worked similarly 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?

The tables below summarize efficacy results by demographic subgroups.

Table 4. Subgroup Analysis of Change in Percentage of Awake Time per Day Spent in the OFF State from Baseline to Endpoint by Sex -Trials 1 and 2

  NOURIANZ
LS Mean (SE)*
Placebo
LS Mean (SE)
Trial 1
Men -10.84 (1.75) -3.37 (2.42)
Women -10.15 (2.01) -6.26 (2.84)
Trial 2
Men -8.08 (1.73) -6.17 (1.71)
Women -11.17 (2.44) -3.12 (2.47)

*LS = least square; SE = standard error

FDA Review

The table below summarizes the efficacy results by sex for Trial 3 and Trial 4.

Table 5. Change from Baseline in Daily OFF Time by Sex-Trials 3 and 4

Analysis Group NOURIANZ 20mg/day
Difference from Placebo
Hours (95% CI)
NOURIANZ 40mg/day
Differences from Placebo
Hours (95% CI)
Trial 3
Men -0.26 (-1.24, 0.71) -0.32 (-1.29, 0.65)
Women -0.82 (-1.60, -0.03) -1.05 (-1.82, 0.28)
Trial 4
Men -0.41 (-1.52, 0.70) -0.94 (-1.93, 0.05)
Women -1.06 (-1.71, -0.42) -0.97 (-1.69, -0.26)

FDA Review

Table 6. Subgroup Analysis of Awake Time per Day Spent in OFF State from Baseline to Endpoint by Age Group-Trials 1 and 2

Analysis Group N NOURIANZ 20 mg/day NOURIANZ 40 mg/day
Placebo, NOURIANZ Difference from Placebo Hours
(95% CI)
Difference from Placebo Hours
(95% CI)
Trial 1
Less than 65 years 32, 71   -10.72 (-17.30, -4.14)
65 years or older 33, 55   -1.99 (-8.95,4.98)
Trial 2
Less than 65 years 64, 64 -4.91 (-9.64, -0.19)  
65 years or older 49, 48 -3.87 (-11.71, 3.98)  

Table 7. Change from Baseline in Daily OFF Time by Age-Trials 3 and 4

Analysis Group NOURIANZ 20mg/day
Difference from Placebo
Hours (95% CI)
NOURIANZ 40mg/day
Differences from Placebo
Hours (95% CI)
Trial 3
Less than 65 years -1.02 (-1.84, -0.20) -0.69 (-1.46, 0.08)
65 years or older -0.42 (-1.25, 0.42) -1.10 (-1.96, -0.23)
Trial 4
Less than 65 years -0.45 (-1.35, 0.46) -0.24 (-1.17, 0.70)
65 years or older -0.85 (-1.62, -0.09) -1.28 (-2.01, -0.54)

FDA Review

Table 8. Subgroup Analysis of Change in Percentage of Awake Time per Day Spent in the OFF State from Baseline to Endpoint by Race-Trials 1 and 2

Analysis Group N NOURIANZ 20 mg/day NOURIANZ 40 mg/day
Placebo, NOURIANZ Difference from Placebo Hours
(95% CI)
Difference from Placebo Hours
(95% CI)
Trial 1
White 61, 121   -6.01 (-10.67, -1.35)
All Other 4, 5 -
Trial 2
White 103, 108 -4.25 (-8.36, -0.15)  
All Other 10, 4 -15.25 (-43.59, 13.08)

Subgroup analysis by race for Trials 3 and 4 was not conductedbecause all patients were Asian.

What are the possible side effects?

NOURIANZ can cause uncontrolled movement (dyskinesia), hallucinations, and unusual urges (impulse control or compulsive behaviors).

The most common side effects of NOURIANZ are uncontrolled movements, dizziness, constipation, nausea, hallucination, and insomnia.

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

The table below summarizes adverse reactions that occurred in the clinical trials.

Table 9. Adverse Reactions with an Incidence of at Least 2% in Patients Treated with NOURIANZ, and Greater than on Placebo, in Pooled Trials 1, 2, 3, and 4

Adverse Reactions NOURIANZ
20 mg/day (N=356)
%
NOURIANZ
40 mg/day (N=378)
%
Placebo N=426
%
Nervous system disorders
Dyskinesia
Dizziness

15
3

17
6

8
4
Gastrointestinal disorders
Constipation
Nausea
Diarrhea

5
4
1

6
6
2

3
5
1
Psychiatric disorders
Hallucination1
Insomnia

2
1

6
6

3
4
Metabolism and nutrition disorders
Decreased appetite

1

3

1
Investigations
Blood alkaline phosphatase
increased
Blood glucose increased
Blood urea increased


1
1
1


2
2
2


1
0
0
Respiratory, thoracic and mediastinal disorders
Upper Respiratory Tract Inflammation

1

2

0
Skin and subcutaneous tissue disorders
Rash

1

2

1

1 Includes hallucinations, hallucinations visual, hallucinations olfactory, hallucinations somatic, hallucinations auditory.

NOURIANZ Prescribing Information

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

  • Sex: The occurrence of side effects between men and women was similar.
  • Race: The occurrence of side effects was similar between White and Asian patients.
  • Age: The occurrence of side effects was similar between 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 most common adverse reactions by sex, race, and age.

Table 10. Adverse Events by Sex

  NOURIANZ 20mg NOURIANZ 40mg Placebo
  Men
N=168
n (%)
Women
N = 188
n (%)
Men
N = 197
n (%)
Women
N=181
n (%)
Men
N = 221
n (%)
Women
N = 205
n (%)
Dyskinesia 20 (12) 32 (17) 25 (13) 38 (15) 12 (5) 21 (10)
Constipation 11 (7) 8 (4) 11 (6) 10 (6) 6 (3) 7 (3)
Nausea 10 (6) 5 (3) 13 (7) 11 (6) 9 (4) 11 (5)
Dizziness 2 (1) 9 (5) 12 (6) 10 (6) 8 (4) 9 (4)
Hallucinations 3 (2) 5 (3) 9 (5) 12 (7) 10 (5) 1 (<1)
Insomnia 1 (1) 1 (1) 14 (7) 8 (4) 9 (4) 6 (3)

Clinical Trial Data

Table 11. Adverse Events by Race

  NOURIANZ 20mg NOURIANZ 40mg Placebo
  White
N = 106
n (%)
Asian
N = 242
n (%)
White
N = 124
n (%)
Asian
N = 250
n (%)
White
N = 166
n (%)
Asian
N = 251
n (%)
Dyskinesia 26 (25) 26 (11) 38 (31) 23 (9) 23 (14) 9 (4)
Nausea 8 (8) 6 (2) 16 (13) 7 (3) 13 (8) 7 (3)
Constipation 5 (5) 13 (5) 9 (7) 12 (5) 2 (1) 11 (4)
Dizziness 9 (8) 2 (1) 18 (15) 3 (1) 12 (7) 4 (2)
Hallucinations 2 (2) 6 (2) 8 (6) 13 (5) 10 (6) 1 (<1)
Insomnia 1 (1) 1 (<1) 17 (14) 4 (2) 12 (7) 3 (1)

Clinical Trial Data

Table 12. Adverse Events by Age

  NOURIANZ 20mg NOURIANZ 40mg Placebo
  <65
N = 164
n (%)
≥65 years
N = 192
n (%)
<65
N = 182
n (%)
≥65 years
N= 196
n (%)
<65
N = 211
n (%)
≥65 years
N = 215
n (%)
Dyskinesia 28 (17) 24 (13) 34 (19) 29 (15) 16 (8) 17 (8)
Constipation 11 (7) 8 (4) 8 (4) 13 (7) 6 (3) 7 (3)
Nausea 10 (6) 5 (3) 14 (8) 10 (5) 12 (6) 8 (4)
Dizziness 3 (2) 8 (4) 13 (7) 9 (5) 8 (4) 9 (4)
Hallucinations 2 (1) 6 (3) 7 (4) 14 (7) 5 (2) 6 (3)
Insomnia 2 (1) 0 (0) 15 (8) 7 (4) 9 (4) 6 (3)

Clinical Trial Data

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved NOURIANZ based on evidence from 4 clinical trials (Trial 1/ NCT00456586, Trial 2/NCT00199407, Trial 3/NCT00455507, Trial 4/NCT00955526) of 1,160 patients with PD whose symptoms were not well controlled while receiving their regular PD treatment. Trial 1 was conducted in the US and Canada, Trial 2 in the US, and Trials 3 and 4 in Japan.

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

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many males and females were in the clinical trials. In total, 586 (51%) males and 574 (49%) females participated in the clinical trial.

FDA Review

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

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race enrolled in the clinical trial. In total, , 743 (64%) Asian, 400 (34%) White, 9 (1%) Black or African American, and 8 (1%) Other patients participated in the clinical trials.

FDA Review

Table 1. Demographics of Trials by Race

Race Number of Patients Percentage of Patients
White 400 34%
Black or African-American 9 1%
Asian 743 64%
Other 8 1%

FDA Review

Figure 3 summarizes the percentage of patients by age group in the trials.

Figure 3. Baseline Demographics by Age

Pie chart summarizing how many individuals of certain age groups were enrolled in the clinical trial. In total, 557 patients were less than 65 years old (48%) and 603 patients were 65 years and older (52%).

FDA Review

Who participated in the trials?

The table below summarizes the demographics for the combined four clinical trials.

Table 13. Demographics for the Trial Population

Demographic Parameters All NOURIANZ
N = 734
n (%)
Placebo
N = 426
n (%)
Total
N = 1160
N (%)
Sex
Men 365 (50) 221 (52) 586 (51)
Women 369 (50) 205 (48) 574 (49)
Race
White 233 (32) 167 (39) 400 (34)
Black or African American 3 (<1) 6 (1) 9 (1)
Asian 492 (67) 251 (59) 743 (64)
Other 6 (1) 2 (<1) 8 (1)
Age Group
< 65 years 346 (47) 211 (50) 557 (48)
≥ 65 years 388 (53) 215 (50) 603 (52)
Ethnicity
Not Collected 734 (100) 426 (100) 1160 (100)
Region
United States 232 (32) 175 (41) 407 (35)
Canada 12 (2) 6 (1) 18 (2)
Japan 490 (67) 245 (58) 735 (63)

FDA Review

How were the trials designed?

There were four 12-week trials conducted in PD patients with inadequate control of their Parkinson’s symptom (“off” time) while receiving carbidopa/levodopa and other PD medications. Patients were randomly selected to receive either NOURIANZ or placebo pill once a day for 12 weeks. Neither the patients nor the health care providers knew which new treatment was being given until the trial was completed 12 weeks later.

In all trials, patients kept daily diaries of the number of hours they were awake and the number of hours of “off” time. The benefit was evaluated by measuring the change from baseline in total daily “off” time in NOURIANZ and placebo receiving patients.

How were the trials designed?

The safety and efficacy of NOURIANZ for the adjunctive treatment to levodopa/carbidopa patients with Parkinson’s disease experiencing “off” episodes was shown in four randomized, multicenter, double-blind, 12-week, placebo-controlled trials. Patients enrolled in the trials had been treated with levodopa for at least one year and were experiencing at least two hours of “off” time per day. Patients continued levodopa and other Parkinson’s Disease medications during the trials. The trials measured the change from baseline in the daily awake percentage of “off” time, or the change from baseline in total daily “off” time, based on 24-hour diaries completed by patients.

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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