Armodafinil (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a mouse carcinogenicity study, armodafinil (R-modafinil) was administered at oral doses of up to 300 mg/kg/day in males and 100 mg/kg/day in females for approximately two years, no tumorigenic effects were observed.

In a rat carcinogenicity study modafinil (a mixture of R- and S-modafinil) was administered at oral doses of up to 60 mg/kg/day for two years; no tumorigenic effects were observed.

At the highest doses studied in mouse and rat, the plasma armodafinil exposures (AUC) were less than that in humans at the MRHD of armodafinil (250 mg/day).

Mutagenesis

Armodafinil was negative in an in vitro bacterial reverse mutation assay and in an in vitro chromosomal aberration assay in human lymphocytes.

Modafinil was negative in a series of in vitro (i.e., bacterial reverse mutation, mouse lymphoma tk, chromosomal aberration in human lymphocytes, cell transformation in BALB/3T3 mouse embryo cells) or in vivo (mouse bone marrow micronucleus) assays.

Impairment of Fertility

A fertility and early embryonic development (to implantation) study was not conducted with armodafinil alone.

Oral administration of modafinil (doses of up to 480 mg/kg/day) to male and female rats prior to and throughout mating, and continuing in females through day 7 of gestation produced an increase in the time to mate at the highest dose; no effects were observed on other fertility or reproductive parameters. The no-effect dose of 240 mg/kg/day was associated with a plasma armodafinil AUC less than that in humans at the MRHD of armodafinil.

14 CLINICAL STUDIES

14.1 Obstructive Sleep Apnea (OSA)

The effectiveness of armodafinil in improving wakefulness in patients with excessive sleepiness associated with OSA was established in two 12-week, multi-center, placebo-controlled, parallel-group, double-blind clinical studies of outpatients who met the criteria for OSA. The criteria include either: 1) excessive sleepiness or insomnia, plus frequent episodes of impaired breathing during sleep, and associated features such as loud snoring, morning headaches or dry mouth upon awakening; or 2) excessive sleepiness or insomnia; and polysomnography demonstrating one of the following: more than five obstructive apneas, each greater than 10 seconds in duration, per hour of sleep; and one or more of the following: frequent arousals from sleep associated with the apneas, bradytachycardia, or arterial oxygen desaturation in association with the apneas. In addition, for entry into these studies, all patients were required to have excessive sleepiness as demonstrated by a score ≥10 on the Epworth Sleepiness Scale (ESS), despite treatment with continuous positive airway pressure (CPAP). Evidence that CPAP was effective in reducing episodes of apnea/hypopnea was required along with documentation of CPAP use.

Patients were required to be compliant with CPAP, defined as CPAP use ≥4 hours/night on ≥70% of nights. CPAP use continued throughout the study. In both studies, the primary measures of effectiveness were 1) sleep latency, as assessed by the Maintenance of Wakefulness Test (MWT) and 2) the change in the patient’s overall disease status, as measured by the Clinical Global Impression of Change (CGI-C) at the final visit. For a successful trial both measures had to show statistically significant improvement.

The MWT measures latency (in minutes) to sleep onset. An extended MWT was performed with test sessions at 2 hour intervals between 9AM and 7PM. The primary analysis was the average of the sleep latencies from the first four test sessions (9AM to 3PM). For each test session, the subject was asked to attempt to remain awake without using extraordinary measures. Each test session was terminated after 30 minutes if no sleep occurred or immediately after sleep onset. The CGI-C is a 7-point scale, centered at No Change , and ranging from Very Much Worse to Very Much Improved. Evaluators were not given any specific guidance about the criteria they were to apply when rating patients.

In the first study, a total of 395 patients with OSA were randomized to receive armodafinil 150 mg/day, armodafinil 250 mg/day or matching placebo. Patients treated with armodafinil showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT at final visit. A statistically significant greater number of patients treated with armodafinil showed improvement in overall clinical condition as rated by the CGI-C scale at final visit. The average sleep latencies (in minutes) in the MWT at baseline for the trials are shown in Table 3 below, along with the average change from baseline on the MWT at final visit. The percentages of patients who showed any degree of improvement on the CGI-C in the clinical trials are shown in Table 4 below. The two doses of armodafinil produced statistically significant effects of similar magnitudes on the MWT, and also on the CGI-C.

In the second study, 263 patients with OSA were randomized to either armodafinil 150 mg/day or placebo. Patients treated with armodafinil showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients as measured by the MWT (Table 3). A statistically significant greater number of patients treated with armodafinil showed improvement in overall clinical condition as rated by the CGI-C scale (Table 4).

Nighttime sleep measured with polysomnography was not affected by the use of armodafinil in either study.

14.2 Narcolepsy

The effectiveness of armodafinil in improving wakefulness in patients with excessive sleepiness associated with narcolepsy was established in one 12-week, multi-center, placebo‑controlled, parallel-group, double‑blind study of outpatients who met the criteria for narcolepsy. A total of 196 patients were randomized to receive armodafinil 150 or 250 mg/day, or matching placebo. The criteria for narcolepsy include either: 1) recurrent daytime naps or lapses into sleep that occur almost daily for at least three months, plus sudden bilateral loss of postural muscle tone in association with intense emotion (cataplexy); or 2) a complaint of excessive sleepiness or sudden muscle weakness with associated features: sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleep episode; and polysomnography demonstrating one of the following: sleep latency less than 10 minutes or rapid eye movement (REM) sleep latency less than 20 minutes and a Multiple Sleep Latency Test (MSLT) that demonstrates a mean sleep latency of less than 5 minutes and two or more sleep onset REM periods and no medical or mental disorder accounts for the symptoms. For entry into these studies, all patients were required to have objectively documented excessive daytime sleepiness, via MSLT with a sleep latency of 6 minutes or less and the absence of any other clinically significant active medical or psychiatric disorder. The MSLT, an objective polysomnographic assessment of the patient’s ability to fall asleep in an unstimulating environment, measured latency (in minutes) to sleep onset averaged over 4 test sessions at 2-hour intervals. For each test session, the subject was told to lie quietly and attempt to sleep. Each test session was terminated after 20 minutes if no sleep occurred or immediately after sleep onset.

The primary measures of effectiveness were: 1) sleep latency as assessed by the Maintenance of Wakefulness Test (MWT); and 2) the change in the patient’s overall disease status, as measured by the CGI-C at the final visit [see Clinical Studies (14.1) for a description of these measures]. Each MWT test session was terminated after 20 minutes if no sleep occurred or immediately after sleep onset in this study.

Patients treated with armodafinil showed a statistically significantly enhanced ability to remain awake on the MWT at each dose compared to placebo at final visit [Table 3 ]. A statistically significant greater number of patients treated with armodafinil at each dose showed improvement in overall clinical condition as rated by the CGI-C scale at final visit [Table 4 ].

The two doses of armodafinil produced statistically significant effects of similar magnitudes on the CGI-C. Although a statistically significant effect on the MWT was observed for each dose, the magnitude of effect was observed to be greater for the higher dose.

Nighttime sleep measured with polysomnography was not affected by the use of armodafinil.

14.3 Shift Work Disorder (SWD)

The effectiveness of armodafinil in improving wakefulness in patients with excessive sleepiness associated with SWD was demonstrated in a 12-week, multi-center, double-blind, placebo-controlled, parallel-group clinical trial. A total of 254 patients with chronic SWD were randomized to receive armodafinil 150 mg/day or placebo. All patients met the criteria for chronic SWD. The criteria include: 1) either, a) a primary complaint of excessive sleepiness or insomnia which is temporally associated with a work period (usually night work) that occurs during the habitual sleep phase, or b) polysomnography and the MSLT demonstrate loss of a normal sleep-wake pattern (i.e., disturbed chronobiological rhythmicity); and 2) no other medical or mental disorder accounts for the symptoms; and 3) the symptoms do not meet criteria for any other sleep disorder producing insomnia or excessive sleepiness (e.g., time zone change [jet lag] syndrome).

It should be noted that not all patients with a complaint of sleepiness who are also engaged in shift work meet the criteria for the diagnosis of SWD. In the clinical trial, only patients who were symptomatic for at least 3 months were enrolled.

Enrolled patients were also required to work a minimum of 5 night shifts per month, have excessive sleepiness at the time of their night shifts (MSLT score ≤6 minutes), and have daytime insomnia documented by a daytime polysomnogram.

The primary measures of effectiveness were: 1) sleep latency, as assessed by the Multiple Sleep Latency Test (MSLT) performed during a simulated night shift at the final visit; and 2) the change in the patient’s overall disease status, as measured by the CGI-C at the final visit [see Clinical Studies (14.1) for a description of these measures].

Patients treated with armodafinil showed a statistically significant prolongation in the time to sleep onset compared to placebo-treated patients, as measured by the nighttime MSLT at final visit (Table 3). A statistically significant greater number of patients treated with armodafinil showed improvement in overall clinical condition as rated by the CGI-C scale at final visit (Table 4).

Daytime sleep measured with polysomnography was not affected by the use of armodafinil.

Table 3: Average Baseline Sleep Latency and Change from Baseline at Final Visit (MWT and MSLT in minutes)
Disorder Measure Armodafinil 150 mg * Armodafinil 250 mg * Placebo
*
Significantly different than placebo for all trials (p<0.05)

Baseline

Change from Baseline

Baseline

Change from Baseline

Baseline

Change from Baseline

OSA I

MWT

21.5

1.7

23.3

2.2

23.2

-1.7

OSA II

MWT

23.7

2.3

23.3

-1.3

Narcolepsy

MWT

12.1

1.3

9.5

2.6

12.5

-1.9

SWD

MSLT

2.3

3.1

2.4

0.4

Table 4: Clinical Global Impression of Change (CGI-C) (Percent of Patients Who Improved at Final Visit)
Disorder Armodafinil 150 mg * Armodafinil 250 mg * Placebo
*
Significantly different than placebo for all trials (p<0.05)

OSA I

71%

74%

37%

OSA II

71%

53%

Narcolepsy

69%

73%

33%

SWD

79%

59%

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