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Cognitive and Behavioral Neurology :... Sep 2012Examine the efficacy of armodafinil in improving cognition in patients with multiple sclerosis (MS). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Examine the efficacy of armodafinil in improving cognition in patients with multiple sclerosis (MS).
BACKGROUND
Many patients with MS experience cognitive difficulties. Armodafinil has shown promise as a cognitive enhancer in other patient populations. No studies have examined whether armodafinil improves cognition in patients with MS.
METHODS
We conducted a double-blind, placebo-controlled, crossover study testing the efficacy of armodafinil in reducing cognitive problems in patients with MS. We randomized 17 patients to receive a dose of lactose placebo about 2 hours before they underwent a neuropsychological testing session. After a week-long washout period, we gave them a single 250-mg dose of armodafinil about 2 hours before testing them a second time. We randomized another 16 patients to receive the active drug first, then the placebo. We excluded 3 of the participants before analyzing the data.
RESULTS
After correcting for multiple comparisons of the 8 neuropsychological dependent measures, we found that the patients had significantly improved delayed memory on a list-learning task after they took armodafinil (P = 0.0005), but no improvement on measures of executive function, visual memory, processing speed, or self-reported fatigue.
CONCLUSIONS
Results provide preliminary evidence that armodafinil may improve delayed verbal recall in patients with MS. A larger trial showing enhanced memory among patients taking long-term armodafinil could serve as a foundation for its possible clinical use as a memory enhancer in patients with MS.
Topics: Adult; Benzhydryl Compounds; Cognition; Cognition Disorders; Cross-Over Studies; Double-Blind Method; Executive Function; Fatigue; Female; Humans; Male; Memory; Middle Aged; Modafinil; Multiple Sclerosis; Neuropsychological Tests; Nootropic Agents; Pilot Projects; Treatment Outcome
PubMed: 22960434
DOI: 10.1097/WNN.0b013e31826df7fd -
Schizophrenia Research Aug 2011The efficacy, safety and tolerability of adjunctive armodafinil for cognitive performance, and negative and affective symptoms, were examined in 60 patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
The effect of adjunctive armodafinil on cognitive performance and psychopathology in antipsychotic-treated patients with schizophrenia/schizoaffective disorder: a randomized, double-blind, placebo-controlled trial.
BACKGROUND
The efficacy, safety and tolerability of adjunctive armodafinil for cognitive performance, and negative and affective symptoms, were examined in 60 patients with schizophrenia or schizoaffective disorder.
METHOD
This was a 6-week, double-blind, placebo-controlled, fixed dose trial of armodafinil (150 mg/d) augmentation in patients with clinically stable schizophrenia or schizoaffective disorder. Cognition, psychopathology, alertness/wakefulness and adverse effects were assessed with standardized rating instruments. The primary endpoint was performance on measures of attention/vigilance.
RESULTS
Patients were randomly allocated to adjunctive armodafinil or placebo. There was a significant Drug×Time interaction effect for attention/vigilance, due to modest non-significant worsening in the armodafinil group and improvement in the armodafinil group [CPT-Pairs d', F(1,40)=6.2, p=0.017]. However, it became non-significant after correction for multiple comparisons. There were no differences between armodafinil and placebo in other cognitive domains or psychopathology measures. However, armodafinil was associated with significant improvement in the Scale for the Assessment of Negative Symptoms (SANS) anhedonia-asociality [F(1,41)=4.1, p=0.05].
CONCLUSIONS
There were no significant differences in neurocognitive measures between adjunctive armodafinil and placebo in this 6-week study. Armodafinil improved anhedonia-asociality, but not other negative symptom domains.
Topics: Adolescent; Adult; Antipsychotic Agents; Benzhydryl Compounds; Cognition Disorders; Double-Blind Method; Factor Analysis, Statistical; Female; Humans; Male; Middle Aged; Modafinil; Neuropsychological Tests; Psychiatric Status Rating Scales; Psychopathology; Psychotic Disorders; Retrospective Studies; Schizophrenia; Treatment Outcome; Young Adult
PubMed: 21641776
DOI: 10.1016/j.schres.2011.05.015 -
Clinical Therapeutics Feb 2015Polypharmacy is common in psychiatry practice and can lead to an increased risk of drug interactions. Armodafinil, a wakefulness-promoting agent, has been studied as...
PURPOSE
Polypharmacy is common in psychiatry practice and can lead to an increased risk of drug interactions. Armodafinil, a wakefulness-promoting agent, has been studied as adjunctive therapy for the treatment of major depressive episodes associated with bipolar I disorder. Armodafinil and the mood stabilizer carbamazepine are both inducers of and substrates for cytochrome P450 (CYP3A4). This study was designed to evaluate the bidirectional carbamazepine-armodafinil pharmacokinetic drug-drug interaction.
METHODS
This was an open-label, single-center study conducted in healthy adult men. Subjects assigned to group 1 received a dose of carbamazepine (200 mg) alone and a dose after pretreatment with daily dosing of armodafinil (titrated to 250 mg/d). Subjects assigned to group 2 received a dose of armodafinil (250 mg) alone and a dose after pretreatment with carbamazepine BID (titrated to 400 mg/d). Pharmacokinetic parameters for carbamazepine, armodafinil, and their major circulating metabolites were determined when dosed alone and after pretreatment with the other drug. The safety and tolerability of armodafinil and carbamazepine were also assessed throughout the study.
FINDINGS
Eighty-one subjects enrolled in the study (group 1 = 40; group 2 = 41), of whom 79 (group 1 = 40; group 2 = 39) were evaluable for pharmacokinetic analysis and 80 (group 1 = 40; group 2 = 40) were evaluable for safety analysis. In group 1, pretreatment with armodafinil reduced systemic exposure to carbamazepine by 12% for Cmax and 25% for AUC (based on comparison of geometric means). Similarly, in group 2, pretreatment with carbamazepine reduced systemic exposure to armodafinil by 11% for Cmax and 37% for AUC. Systemic exposure to the metabolites of these agents that are formed via CYP3A4 were increased after pretreatment in each group. There were no new or unexpected adverse events.
IMPLICATIONS
Systemic exposure to both carbamazepine and armodafinil was reduced after pretreatment with the other drug; systemic exposure to the metabolites of each drug, which are formed via CYP3A4, was increased. These changes were consistent with the induction of CYP3A4. Both drugs were generally safe and well tolerated alone and in combination under the conditions studied. Dose adjustment may be required when initiating or discontinuing armodafinil and carbamazepine cotherapy.
Topics: Adult; Anticonvulsants; Benzhydryl Compounds; Bipolar Disorder; Carbamazepine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Depressive Disorder, Major; Drug Interactions; Healthy Volunteers; Humans; Male; Middle Aged; Modafinil; Wakefulness; Wakefulness-Promoting Agents
PubMed: 25438721
DOI: 10.1016/j.clinthera.2014.09.014 -
Sleep Medicine Clinics Jun 2020Excessive daytime sleepiness (EDS) is related to medical and social problems, including mental disorders, physical diseases, poor quality of life, and so forth.... (Review)
Review
Excessive daytime sleepiness (EDS) is related to medical and social problems, including mental disorders, physical diseases, poor quality of life, and so forth. According to the International Classification of Sleep Disorders, Third Edition, diseases that result from EDS are narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, hypersomnia due to a medical disorder, and others. EDS is usually treated using amphetamine-like central nervous system stimulants or modafinil and its R-enantiomer, armodafinil, wake-promoting compounds unrelated to amphetamines; a variety of new drugs are under development. The side effects of some stimulants are potent and careful selection and management are required.
Topics: Central Nervous System Stimulants; Disorders of Excessive Somnolence; Humans; Idiopathic Hypersomnia; Modafinil; Narcolepsy; Quality of Life; Sleepiness
PubMed: 32386693
DOI: 10.1016/j.jsmc.2020.02.006 -
Military Medicine Jul 2011This study was conducted to test the ability of armodafinil to promote vigilance among air traffic control operators 8 to 11 hours post-dose. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This study was conducted to test the ability of armodafinil to promote vigilance among air traffic control operators 8 to 11 hours post-dose.
METHODS
Forty-eight U.S. Naval air traffic control students were assigned to one of two groups, 150 mg dose of armodafinil or placebo. At 8:00 a.m., participants were administered armodafinil or a placebo, after which they completed a standard work day. Participants returned at 3:45 p.m. to complete the 4-hour performance portion of the study, where they performed the psychomotor vigilance task.
RESULTS
The analysis showed a significant difference in vigilance between the armodafinil group and placebo (p < 0.05). Psychomotor vigilance task data revealed that participants receiving a 150 mg dose of armodafinil experienced significantly fewer lapses of attention compared to the control group.
CONCLUSIONS
These results justify additional investigation into the efficacy of armodafinil to promote sustained vigilance in military operational settings where fatigue-related performance decrements are especially problematic.
Topics: Adolescent; Adult; Aerospace Medicine; Arousal; Attention; Benzhydryl Compounds; Central Nervous System Stimulants; Dose-Response Relationship, Drug; Fatigue; Female; Humans; Male; Military Personnel; Modafinil; Psychomotor Performance; Young Adult
PubMed: 22128728
DOI: 10.7205/milmed-d-10-00250 -
Drugs & Aging Feb 2011Armodafinil (Nuvigil(®), Cephalon, Inc., Frazer, PA, USA), the longer-lasting isomer of racemic modafinil, is a nonamphetamine, wakefulness-promoting medication. In...
BACKGROUND
Armodafinil (Nuvigil(®), Cephalon, Inc., Frazer, PA, USA), the longer-lasting isomer of racemic modafinil, is a nonamphetamine, wakefulness-promoting medication. In patients with excessive sleepiness associated with shift work disorder, treated obstructive sleep apnoea, or narcolepsy, armodafinil has been found to improve wakefulness throughout the shift or day. In addition, while not approved for this indication, armodafinil has been found to improve excessive sleepiness associated with jet-lag disorder.
OBJECTIVE
This study evaluated systemic exposure to armodafinil and its two major circulating metabolites, R-modafinil acid and modafinil sulfone, and assessed the tolerability profile of armodafinil in elderly and young subjects.
METHODS
The pharmacokinetics and tolerability of armodafinil were assessed in an open-label, multiple-dose, parallel-group study in two groups (n = 25 in each group) of healthy men (elderly group aged ≥65 years and young group aged 18-45 years) who received armodafinil 50 mg on day 1, 100 mg on day 2 and 150 mg once daily on days 3 through 7. Plasma concentrations of armodafinil and its metabolites were quantified over 72 hours following the last dose on day 7. Pharmacokinetic parameters, including area under the plasma drug concentration-versus-time curve during a dosing interval (AUC(τ)) and maximum observed plasma drug concentration (C(max)), and tolerability were assessed.
RESULTS
All 50 subjects enrolled in the study were evaluable for tolerability and 49 were included in the pharmacokinetic analysis. One elderly subject was excluded from the pharmacokinetic analyses because of apparent noncompliance with armodafinil dosing. Systemic exposure following administration of armodafinil, as measured by steady-state AUC(τ) and C(max) values, was approximately 15% greater in elderly subjects compared with young subjects. Geometric mean ratios for AUC(τ) and C(max) in the two groups were 1.14 (95% CI 1.03, 1.25; p = 0.0086) and 1.15 (95% CI 1.08, 1.24; p = 0.0002), respectively. When data were analysed for elderly subgroups, systemic exposure in the old-elderly group (age ≥75 years; n = 7) was 27% greater than in young subjects, as compared with 10% greater in the young-elderly group (age 65-74 years; n = 17). Although steady-state exposure to the metabolite R-modafinil acid was also higher in elderly than in young subjects (geometric mean ratios for AUC(τ) and C(max) were 1.73 and 1.61, respectively; p < 0.0001), there were no significant differences in systemic exposure to modafinil sulfone. Armodafinil was generally well tolerated by both groups. Headache (four subjects in each group), nausea (one in the elderly group and four in the young group), insomnia (two in the elderly group and one in the young group), and dizziness (two in the young group) were the most common adverse events.
CONCLUSIONS
Systemic exposure following administration of armodafinil is increased in the elderly in comparison with younger subjects, particularly in those aged ≥75 years. Although the increase in plasma armodafinil concentration in elderly subjects does not appear to result in more adverse events compared with young subjects, consideration should be given to the use of lower dosages of armodafinil for the management of excessive sleepiness in older patients, particularly the very elderly.
Topics: Adult; Age Factors; Aged; Area Under Curve; Benzhydryl Compounds; Central Nervous System Stimulants; Humans; Male; Modafinil; Wakefulness
PubMed: 21275439
DOI: 10.2165/11586370-000000000-00000 -
Sleep Medicine Clinics Sep 2019Idiopathic hypersomnia (IH) is characterized by excessive daytime sleepiness despite normal or prolonged sleep. IH is distinguished from narcolepsy by the female... (Review)
Review
Idiopathic hypersomnia (IH) is characterized by excessive daytime sleepiness despite normal or prolonged sleep. IH is distinguished from narcolepsy by the female predominance, severe morning inertia, continuous drowsiness (rather than sleep attacks), unrefreshing naps, absence of cataplexy, sleep onset in REM periods, and hypocretin deficiency. In IH, the multiple sleep latency test demonstrates low sensitivity, specificity, and reproducibility, compared with prolonged sleep monitoring. In some IH cases, an endogenous hypnotic peptide stimulating GABA receptors during wakefulness is suspected, which are improved by anti-GABA drugs. The benefits of modafinil, sodium oxybate, mazindol, and pitolisant were found in mostly retrospective studies.
Topics: Central Nervous System Stimulants; Clarithromycin; Flumazenil; GABA Modulators; Humans; Idiopathic Hypersomnia; Mazindol; Modafinil; Orexins; Piperidines; Polysomnography; Precision Medicine; Sleep; Sodium Oxybate; Wakefulness; Wakefulness-Promoting Agents
PubMed: 31375202
DOI: 10.1016/j.jsmc.2019.05.007 -
Sleep Medicine Apr 2016This study involves the analysis of a secondary outcome of a trial examining whether cognitive behavior therapy for insomnia (CBT-I), a wake-promoting medication... (Randomized Controlled Trial)
Randomized Controlled Trial
STUDY OBJECTIVES
This study involves the analysis of a secondary outcome of a trial examining whether cognitive behavior therapy for insomnia (CBT-I), a wake-promoting medication (armodafinil), or both results in greater improvement in prospectively assessed sleep continuity and daytime sleepiness than a placebo-alone group among a heterogeneous group of cancer survivors. Whether or not armodafinil alone, and/or when combined with CBT-I, affected adherence with CBT-I was evaluated.
DESIGN
This study is a randomized, placebo-controlled, clinical trial.
SETTING
This study was conducted at two northeastern academic medical centers.
PARTICIPANTS
Eighty-eight cancer survivors with chronic insomnia were recruited between October 2008 and November 2012. Participants were assigned to one of four conditions: 1) CBT-I and placebo (CBT-I+P); 2) CBT-I and armodafinil (CBT-I + A); 2) armodafinil alone (ARM); or 4) placebo alone (PLA).
INTERVENTIONS
CBT-I was delivered in seven weekly individual therapy sessions (three in person, four via telephone). The armodafinil dosage was 50 mg BID.
MEASUREMENTS AND RESULTS
Sleep continuity was measured with daily sleep diaries assessing sleep latency (SL), wake after sleep onset (WASO), and total sleep time (TST). The Epworth Sleepiness Scale (ESS) measured daytime sleepiness. Compared to the PLA group, the CBT-I+P and CBT-I+A groups reported a significant reduction in SL with effect sizes of 0.67 and 0.58, respectively. A significant reduction was observed in WASO in the CBT-I+A group with an effect size of 0.64. An increasing trend of TST was observed in the CBT-I+P, CBT-I+A, and PLA groups, but not in the ARM group. No statistically significant reductions in daytime sleepiness (ESS) were observed for any of the groups.
CONCLUSION
CBT-I alone and in combination with armodafinil caused significant improvement in sleep continuity. The addition of armodafinil did not appear to improve daytime sleepiness or enhance adherence to CBT-I.
Topics: Benzhydryl Compounds; Cognitive Behavioral Therapy; Disorders of Excessive Somnolence; Female; Humans; Male; Middle Aged; Modafinil; Neoplasms; Sleep Initiation and Maintenance Disorders; Sleep Stages; Survivors; Wakefulness-Promoting Agents
PubMed: 27318221
DOI: 10.1016/j.sleep.2015.12.010 -
Clinical Therapeutics Nov 2010Armodafinil (the R-isomer of racemic modafinil) and modafinil are wakefulness-promoting medications for excessive sleepiness associated with treated obstructive sleep... (Comparative Study)
Comparative Study Randomized Controlled Trial
Pharmacokinetics of armodafinil and modafinil after single and multiple doses in patients with excessive sleepiness associated with treated obstructive sleep apnea: a randomized, open-label, crossover study.
BACKGROUND
Armodafinil (the R-isomer of racemic modafinil) and modafinil are wakefulness-promoting medications for excessive sleepiness associated with treated obstructive sleep apnea (OSA). The R-isomer of racemic modafinil has a half-life of approximately15 hours; the S-isomer has a half-life of 4 to 5 hours. The R-and S-isomers are equipotent, producing equivalent pharmacologic activity at equal concentrations.
OBJECTIVE
The aim of this work was to compare the pharmacokinetic profiles of armodafinil (R-modafinil) and modafinil (racemic mixture with equal quantities of R- and S-isomers) at equal doses in patients with residual excessive sleepiness associated with continuous positive airway pressure-treated OSA.
METHODS
This open-label study was conducted at 5 US centers from July 2008 to March 2009. Patients were randomized to 1 of 2 crossover administration sequences, ABCD or BADC, where A was a single armodafinil 200-mg dose, B was a single modafinil 200-mg dose, C was multiple daily modafinil 200-mg doses, and D was multiple daily armodafinil 200-mg doses. During multiple-dose administration, patients received 100 mg once daily for days 1 and 2, and 200 mg once daily for days 3 through 10. The pharmacokinetic parameters of principal interest for assessing the bioequivalence of armodafinil and modafinil were maximum concentration at 7 to 11 hours after dosing and the concentration-versus-time curve for this period. Analysis was performed via achiral high-performance liquid chromatography with ultraviolet detection using blood samples obtained over 72 hours after single-dose administration and over 24 hours after the multiple-dose regimen. For post hoc evaluation of bioequivalence, 90% CI values were also constructed for the geometric mean ratios of armodafinil to modafinil. Tolerability was assessed by the reported adverse events, clinical laboratory testing, vital sign measurements, ECGs, and physical exams.
RESULTS
The study population was 83.3% male (35/42) and 76.2% white (32/42) with a mean (SD) age of 47.0 (8.30) years and a weight range of 66.3 to 127.4 kg. Plasma drug concentration-versus-time curves suggested comparable terminal half-lives (mean [SD] values were 16.5 [4.44] and 14.4 [3.22] hours for armodafinil and modafinil, respectively) but higher systemic exposure with armodafinil than modafinil (mean [SD] AUC(0-∞) values were 108.8 [31.66] and 66.4 [20.06] microg · h/mL for armodafinil and modafinil, respectively), as indicated by the high geometric mean ratios for the AUC (the AUC(0-∞)) ratio after a single dose was 1.64 [95% CI, 1.60-1.68; P < 0.001], and the AUC(0-τ) ratio after multiple doses was 1.69 [95% CI, 1.65-1.72; P < 0.001]) and, to a lesser extent, the ratio of the maximum plasma drug concentration after multiple doses (C(max) ratio = 1.37 [95% CI, 1.33-1.41; P < 0.001]). In addition, the ratios and associated 90% CIs for Cmax (137 [1.341.40]) and AUC(0-τ) (169 [1.66-1.75]) after multiple-dose administration did not meet the US Food and Drug Administration (FDA) criteria for bioequivalence (ie, ratio of geometric means between 80% and 125%). Reported adverse events were mild to moderate in intensity. The most frequently reported adverse events while receiving armodafinil or modafinil were headache (29% and 2%, respectively), diarrhea (12% and 5%), nausea (10% and 2%), and dizziness (10% and 5%).
CONCLUSIONS
In this crossover study of patients with treated OSA, overall systemic exposure after armodafinil 200-mg administration was greater than that following modafinil 200-mg administration after both single and multiple doses. The pharmacokinetic profiles of the 2 drugs were notably different and did not meet the FDA criteria for bioequivalence.
Topics: Area Under Curve; Benzhydryl Compounds; Central Nervous System Stimulants; Cross-Over Studies; Disorders of Excessive Somnolence; Female; Half-Life; Humans; Male; Middle Aged; Modafinil; Sleep Apnea, Obstructive; Therapeutic Equivalency
PubMed: 21118743
DOI: 10.1016/j.clinthera.2010.11.009 -
Journal of Clinical Sleep Medicine :... Dec 2021Excessive daytime sleepiness associated with obstructive sleep apnea affects 9%-22% of continuous positive airway pressure-treated patients. An indirect treatment... (Meta-Analysis)
Meta-Analysis
STUDY OBJECTIVES
Excessive daytime sleepiness associated with obstructive sleep apnea affects 9%-22% of continuous positive airway pressure-treated patients. An indirect treatment comparison meta-analysis was performed to compare efficacy and safety of medications (solriamfetol, modafinil, and armodafinil) approved to treat excessive daytime sleepiness associated with obstructive sleep apnea.
METHODS
Efficacy and safety measures assessed in this indirect treatment comparison included Epworth Sleepiness Scale (ESS), 20-minute Maintenance of Wakefulness Test (MWT20), Clinical Global Impression of Change (CGI-C), Functional Outcomes of Sleep Questionnaire (FOSQ), and incidence of treatment-emergent adverse events (any, serious, or leading to discontinuation).
RESULTS
A systematic literature review identified 6 parallel-arm, placebo-controlled randomized controlled trials that randomized 1,714 total participants to placebo, solriamfetol, modafinil, or armodafinil. In this indirect treatment comparison, all comparators were associated with greater improvements than placebo on the ESS, MWT20, and CGI-C after 4, 8, and 12 weeks of treatment. Relative to comparators and placebo at 12 weeks, solriamfetol at 150 mg or 300 mg had the highest probabilities of improvement in the ESS, MWT20, and CGI-C. Modafinil (200 or 400 mg) and solriamfetol (150 or 300 mg) were associated with greater improvement on the FOSQ than placebo at 12 weeks. Less than 2% of patients using placebo or comparators experienced serious or discontinuation-related treatment-emergent adverse events.
CONCLUSIONS
The results of this indirect treatment comparison show 12 weeks of treatment with solriamfetol, modafinil, and armodafinil resulted in varying levels of improvement on the ESS, MWT20, and CGI-C and similar safety risks in participants with excessive daytime sleepiness associated with obstructive sleep apnea.
CITATION
Ronnebaum S, Bron M, Patel D, et al. Indirect treatment comparison of solriamfetol, modafinil, and armodafinil for excessive daytime sleepiness in obstructive sleep apnea. . 2021;17(12):2543-2555.
Topics: Benzhydryl Compounds; Carbamates; Disorders of Excessive Somnolence; Double-Blind Method; Humans; Modafinil; Phenylalanine; Sleep Apnea, Obstructive; Treatment Outcome
PubMed: 34402784
DOI: 10.5664/jcsm.9610