Drugs

Drug Trials Snapshots: XADAGO

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 XADAGO Prescribing Information for complete information.

XADAGO (safinamide)
(ZA-da-go)
Newron Pharmaceuticals
Approval date: March 21, 2017


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

XADAGO is a drug for the treatment of “off episodes” in patients with Parkinson’s disease (PD). XADAGO is to be added to drugs for the treatment of Parkinson’s disease that contain levodopa/carbidopa combination.

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?

XADAGO is a tablet taken by mouth once a day.

What are the benefits of this drug?

On average, patients taking XADAGO experienced more “ON” time, a time when Parkinson’s symptoms are reduced, without troublesome involuntary movement (dyskinesia), compared to those receiving a 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 difference in average time without any dyskinesia plus the time with non-troublesome dyskinesia

Table 2. Change in Mean Total Daily “ON” Time† in Trial 1

 NBaseline (hours)
(mean ± SD)
Change from Baseline to Endpoint
 (LSD* vs. placebo)
 (95% CI)**
 p-value
Placebo2129.3 ± 2.2--
XADAGO 50 mg
once daily
2179.4 ± 2.20.50 (0.03, 0.96)
p=0.0356
XADAGO 100 mg
once daily
2169.6 ± 2.50.53 (0.07, 1.00)
p=0.0238

† “ON” Time = “ON” Time without dyskinesia plus “ON” Time with non-troublesome dyskinesia
*LSD: Least squares difference; a positive value indicates improvement
**95% CI: 95% Confidence Interval

XADAGO Prescribing Information

Table 3. Change in Mean Total Daily “ON” Time† in Trial 2

 NBaseline (hours) (mean ± SD)Change from Baseline to Endpoint (LSD* vs. placebo) (95% CI)**p-value
Placebo2739.1 ± 2.5----
XADAGO
100 mg once daily
2709.3 ± 2.40.99 (0.58, 1.39)< 0.001

† ON time = ON time without dyskinesia plus ON time with non-troublesome dyskinesia
*LSD: Least squares difference; a positive value indicates improvement
**95% CI: 95% Confidence Interval

XADAGO Prescribing Information

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

  • Sex: XADAGO worked similarly in men and women.
  • Race: XADAGO worked similarly in White and Asian patients. The number of patients of other races was limited; therefore, differences in response could not be determined.
  • Age: XADAGO worked similarly in patients above and below age 65.

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

Subgroup analyses of the primary endpoint by sex, age and race groups are presented below for each trial separately.

Table 4. Analysis of the Primary Endpoint by Sex, MMRM, mITT population-Trial 1

SexChange from Baseline to Week 24 in total daily “on” timePlaceboXADAGO
50 mg/day
XADAGO
100 mg/day
WomenN606559
Means (SD) a1.16 (2.191)1.15 (2.419)1.35 (2.545)
LS mean b0.681.001.13
LS diff. vs. placebo (SE) b 0.32 (0.455)0.45 (0.459)
MenN152152157
Means (SD) a0.90 (2.455)1.46 (2.876)1.38 (2.669)
LS mean c0.771.471.36
LS diff. vs. placebo (SE) c 0.70 (0.283)0.59 (0.278)

LS: least squares; mITT: modified intent-to-treat; MMRM: mixed effect model repeated measures; N: number of patients in the mITT population; SD: standard deviation; SE: standard error.
a Obtained from all observations in the sex specific mITT population that were on treatment at Week 24, without imputation for missing data.
b Obtained from MMRM on all female patients in the mITT population, with treatment, center, visit, and treatment-by-center interaction as fixed effects and baseline value of the total daily “on” time as the covariate. The “on treatment” approach was used.
c Obtained from MMRM on all male patients in the mITT population, with treatment, center, visit, and treatment-by-center interaction as fixed effects and baseline value of the total daily “on” time as the covariate. The “on treatment” approach was used.

Adapted from FDA Statistical review

Table 5. Analysis of the Primary Endpoint by Sex, ANCOVA, LOCF, mITT population-Trial 2

SexChange from Baseline to Week 24 in total daily “on” timePlaceboXADAGO
50-100 mg/day
WomenN111100
Means (SD) a0.59 (2.415)1.71 (2.615)
LS mean b0.451.84
LS diff. vs. placebo (SE) b 1.39 (0.330)
MenN162168
Means (SD) a0.50 (2.457)1.28 (2.915)
LS mean c0.641.35
LS diff. vs. placebo (SE) c 0.71 (0.269)

ANCOVA: analysis of covariance; LOCF: last observation carried forward; LS: least squares; mITT: modified intent-to-treat; N: number of patients in the mITT population; SD: standard deviation; SE: standard error.
a Obtained from all observations in the gender specific mITT population that were on treatment at Week 24, with LOCF imputation for missing data.
b Obtained from ANCOVA model on all female patients in the mITT population, with treatment and region effects and baseline value of the total daily “on” time as the covariate. The “on treatment” approach and the LOCF method were used.
c Obtained from ANCOVA model on all male patients in the mITT population, with treatment and region effects and baseline value of the total daily “on” time as the covariate. The “on treatment” approach and the LOCF method were used.

Adapted from FDA Statistical review

Table 6. Analysis of the Primary Endpoint by Age, MMRM, mITT population-Trial 1

AgeChange from Baseline to Week 24 in total daily “on” timePlaceboXADAGO
50 mg/day
XADAGO
100 mg/day
< 65 yearsN143142144
Means (SD) a1.01 (2.488)1.50 (2.799)1.35 (2.538)
LS mean b0.771.381.31
LS diff. vs. placebo (SE) b 0.60 (0.290)0.53 (0.290)
≥ 65 yearsN697572
Means (SD) a0.90 (2.183)1.09 (2.642)1.42 (2.837)
LS mean c0.791.281.30
LS diff. vs. placebo (SE) c 0.49 (0.438)0.50 (0.440)

LS: least squares; mITT: modified intent-to-treat; MMRM: mixed effect model repeated measures; N: number of patients in the mITT population; SD: standard deviation; SE: standard error.
a Obtained from all observations in the age group specific mITT population that were on treatment at Week 24, without imputation for missing data.
b Obtained from MMRM on all patients < 65 years in the mITT population, with treatment, center, visit and treatment-by-center interaction as fixed effects and baseline value of the total daily “on” time as the covariate. The “on treatment” approach was used.
c Obtained from MMRM on all patients ≥ 65 years in the mITT population, with treatment, center, visit and treatment-by-center interaction as fixed effects and baseline value of the total daily “on” time as the covariate. The “on treatment” approach was used.

Adapted from FDA Statistical review

Table 7. Analysis of the Primary Endpoint by Age, ANCOVA, LOCF, mITT population-Trial 2

AgeChange from Baseline to Week 24 in total daily “on” timePlaceboXADAGO
50-100 mg/day
< 65 yearsN156157
Means (SD) a0.60 (2.461)1.41 (2.883)
LS mean b0.501.45
LS diff. vs. placebo (SE) b 0.96 (0.271)
≥ 65 yearsN117111
Means (SD) a0.44 (2.409)1.48 (2.714)
LS mean c0.501.57
LS diff. vs. placebo (SE) c 1.08 (0.323)

ANCOVA: analysis of covariance; LOCF: last observation carried forward; LS: least squares; mITT: modified intent-to-treat; N: number of patients in the mITT population; SD: standard deviation; SE: standard error.
a Obtained from all observations in the age group specific mITT population that were on treatment at Week 24, with LOCF imputation for missing data.
b Obtained from ANCOVA model on all patients < 65 years in the mITT population, with treatment and region effects and baseline value of the total daily “on” time as the covariate. The “on treatment” approach and the LOCF method were used.
c Obtained from ANCOVA model on all patients ≥ 65 years in the mITT population, with treatment and region effects and baseline value of the total daily “on” time as the covariate. The “on treatment” approach and the LOCF method were used.

Table 8. Analysis of the Primary Endpoint by Race, MMRM, mITT population-Trial 1

RaceChange from Baseline to Week 24 in total daily “on” timePlaceboXADAGO
50 mg/day
XADAGO
100 mg/day
AsianN171176173
Means (SD) a1.07 (2.371)1.54 (2.702)1.49 (2.606)
LS mean b0.851.491.39
LS diff. vs. placebo (SE) b 0.64 (0.252)0.54 (0.250)
WhiteN414143
Means (SD) a0.61 (2.421)0.71 (2.860)0.90 (2.713)
LS mean c0.410.560.93
LS diff. vs. placebo (SE) c 0.15 (0.603)0.53 (0.609)

LS: least squares; mITT: modified intent-to-treat; MMRM: mixed effect model repeated measures; N: number of patients in the mITT population; SD: standard deviation; SE: standard error.
a Obtained from all observations in the race specific mITT population that were on treatment at Week 24, without imputation for missing data.
b Obtained from MMRM on all Asian patients in the mITT population, with treatment, center, visit, and treatment-by-center interaction as fixed effects and baseline value of the total daily “on” time as the covariate. The “on treatment” approach was used.
c Obtained from MMRM on all White patients in the mITT population, with treatment, center, visit, and treatment-by-center interaction as fixed effects and baseline value of the total daily “on” time as the covariate. The “on treatment” approach was used.

Adapted from FDA Statistical review

Table 9. Analysis of the Primary Endpoint by Race, ANCOVA, LOCF, mITT population-Trial 2

RaceChange from Baseline to Week 24 in total daily “on” timePlaceboXADAGO
50-100 mg/day
AsianN8587
Means (SD) a0.71 (2.267)1.20 (2.749)
LS mean b1.202.03
LS diff. vs. placebo (SE) b 0.83 (0.323)
WhiteN186178
Means (SD) a0.45 (2.523)1.55 (2.862)
LS mean c0.501.60
LS diff. vs. placebo (SE) c 1.10 (0.266)

ANCOVA: analysis of covariance; LOCF: last observation carried forward; LS: least squares; mITT: modified intent-to-treat; N: number of patients in the mITT population; SD: standard deviation; SE: standard error.
a Obtained from all observations in the race specific mITT population that were on treatment at Week 24, with LOCF imputation for missing data.
b Obtained from ANCOVA model on all Asian patients in the mITT population, with treatment and region effects and baseline value of the total daily “on” time as the covariate. The “on treatment” approach and the LOCF method were used.
c Obtained from ANCOVA model on all White patients in the mITT population, with treatment and region effects and baseline value of the total daily “on” time as the covariate. The “on treatment” approach and the LOCF method were used.

Adapted from FDA Statistical review

What are the possible side effects?

When taken with certain other medications, XADAGO may cause a serious, life- threatening condition called serotonin syndrome. Other serious side effects include an increase in blood pressure, falling asleep during activities of daily living (watching television, driving a car, etc.), hallucinations (seeing or hearing things that are not real), behavioral problems, and confusion.

The most common side effects are uncontrolled involuntary movements (dyskinesia), fall, nausea, and difficulty sleeping.

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

The table below summarizes common adverse reactions during clinical trials based on Safety population defined as all patients from Trials 1 and 2 who received at least one dose of the drug.

Table 10. Percentage of Patients with Adverse Reactions with an Incidence ≥ 2% in the XADAGO 100 mg/day Group and Greater than Placebo in Trials 1 and 2

 XADAGO
50 mg/day
(N = 223)
XADAGO
100 mg/day
(N = 498)
Placebo
 
(N = 497)
Adverse Reaction(%)(%)(%)
Dyskinesia21179
Fall464
Nausea364
Insomnia142
Orthostatic hypotension221
Anxiety221
Cough221
Dyspepsia021

XADAGO Prescribing Information

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

  • Sex: The occurrence of some side effects was higher in women than in men.
  • Race: The occurrence of side effects was similar between White and Asian patients. The number of patients in other races was limited; therefore, differences in side effects among other races could not be determined.
  • Age: The occurrence of side effects was similar in patients above and below age 65.

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

The table below summarizes “dyskinesia” adverse reaction in the Safety population defined as all patients who received at least at least one dose of the drug.

Table 11. Subgroup Analysis of Adverse Reaction “Dyskinesia”

Demographic SubgroupXADAGO
N=721
x/n* (%)
Placebo
N=497
x/n* (%)
Overall134/721 (17)44/497 (9)
Sex
Men84/491 (17)30/323 (9)
Women50/230 (22)14/174 (8)
Age Group
<65 years92/454 (20)33/307 (11)
>= 65 years42/267 (16)11 /190 (6)
Race
White46/271 (17)18/230 (8)
Asian88/447 (20)26/265 (10)
Black or African American0/3 (0)0/2 (0)

Clinical trial data

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved XADAGO based on evidence from two clinical trials of 1218 patients with PD whose symptoms were not well controlled while receiving their regular PD treatment. The trials were conducted in 178 centers in North America, Europe, Asia and Latin America.

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

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were in the clinical trials of the drug XADAGO. In total,  814 men (67%) and 404 women (33%) participated in the clinical trials

Clinical trial data

Figure 2 summarizes 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 in the clinical trials. In total, 501 Whites (41%), 5 Black or African Americans  (less than 1%), and 712 Asians (59%), participated in the clinical trials.

Clinical trial data

Table 1. Baseline Demographics by Race

RaceNumber of PatientsPercentage
Asian71259
White50141
Black or African American5less than 1

Clinical trial data

Figure 3 summarizes the percentage of patients by age that were enrolled in the clinical trials.

Figure 3. Baseline Demographics by Age

Pie chart summarizing how many individuals of certain age groups participated in the clinical trials. In total, 761 (62%) patients were younger than 65 years and 457 participants were 65 and older (38 %).

Clinical trial data

Who participated in the trials?

The table below summarizes demographics of all randomized patients in clinical Trials 1 and 2 combined.

Table 12. Baseline and Demographics (Randomized Population)

 XADAGO
N=721
Placebo
N=497
Total
N=1218
Age (years)
Min, Max35, 8030, 7930, 80
Median616161
Age Group, n (%)
<65 years454 (63)307 (62)761 (62)
≥ 65 years267 (37)190 (38)457 (38)
Sex, n (%)
Men491 (68)323 (65)814 (67)
Women230 (32)174 (35)404 (33)
Race, n (%)
White271 (38)230 (46)501 (41)
Asian447 (62)265 (53)712 (58)
Black or African American3 (<1)2 (<1)5 (<1)
Ethnicity, n (%)
Hispanic or Latino12 (2)9 (2)21 (2)
Non-Hispanic or Latino709 (98)488 (98)1197 (98)
Geographic Region, n (%)
North America51 (7)51 (10)102 (8)
Western Europe126 (18)117 (24)243 (20)
Other544 (76)329 (66)873 (72)

Clinical trial data

How were the trials designed?

There were two 24-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 XADAGO or placebo pill once a day for 24 weeks. Neither the patients nor the health care providers knew which new treatment was being given until the trial was completed 24 weeks later.

In both trials, the benefit was evaluated by measuring the change from baseline in total daily “ON” time in XADAGO and placebo receiving patients. “ON” time was defined as time without any dyskinesia plus the time with non-troublesome dyskinesia and was based on the 18-hour diaries completed by patients for at least 3 days before each of the scheduled visits.

How were the trials designed?

Two double-blind, placebo-controlled, multi-national, 24-week trials (Trials 1 and 2) were conducted in PD patients experiencing “OFF” time during treatment with carbidopa/levodopa and other PD medications.

In both trials, the primary measure of effectiveness was the change from baseline in total daily “ON” time without troublesome dyskinesia (i.e., “ON” time without dyskinesia plus “ON” time with non-troublesome dyskinesia), based on the 18-hour diaries completed by patients for at least 3 days before each of the scheduled visits.

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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