A Modafinil-Based Placebo Controlled Double Blind Study

In this study, participants were assigned to modafinil or placebo using a computer-generated randomization schedule. Both the pharmacy and the participants were blind to treatment allocation.

ANCOVA analyses of the OSA scores at Cycle 4 revealed significant treatment-by-baseline interaction effects on BFI-3 and all individual domains, except for Social Outcome. Specifically, modafinil reduced CRF more in patients with higher baseline fatigue.

Study Design

Excessive daytime somnolence (EDS) is a common feature of Parkinson’s disease (PD), and it may be exacerbated by dopaminergic medications. Buy Modafinil Online, a wake-promoting agent used to treat narcolepsy, is also approved for the treatment of PD-related EDS. This study aimed to assess the efficacy of modafinil in alleviating PD-related fatigue using a placebo-controlled double-blind design.

The primary outcome measure was the Epworth Sleepiness Scale score and secondary measures included the Unified PD Rating Scale, Fatigue Severity Scale, Hamilton Depression Scale, and Multiple Sleep Latency Test (MSLT). Patients were treated with modafinil or placebo for 28 days. Statistical analyses were performed on an intent-to-treat basis. Missing data at Cycle 4 were imputed with a model that included drug (modafinil or placebo) and baseline BFI-3 scores.

Participants were randomized to receive modafinil (0 mg, 200 mg, or 400 mg as four pills taken once daily) or placebo using a central telephone system. A minimization algorithm was employed to reduce the predictability of early treatment assignments. The placebo capsules were over-encapsulated to ensure blinding for patients, clinicians, and investigators.

Patients were excluded if they met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria for cocaine dependence or took psychotropic medication that could interact with modafinil. Women of childbearing potential were randomized only if they agreed to use acceptable birth control methods.

Methods

The primary endpoint was a change in the FACIT-Fatigue score from baseline to day 28 adjusted for baseline fatigue and performance status. Other secondary endpoints included patient-reported measures of depression, daytime sleepiness, and quality of life.

The data were screened for outliers and compliance issues; no patients were omitted from the analyses. Missing values at Cycle 4 were imputed using multiple imputations.22 The rate of missing values for Modalert Tablet versus placebo was numerically higher, but this did not result in significant differences in the final analyses.

Patients were randomized to receive modafinil or placebo for 8 weeks. Eligible participants were those who met the Diagnostic and Statistical Manual of Mental Disorders criteria for cocaine dependence, had at least $200 worth of recent cocaine use as determined by a quantitative BE assay, and had not used alcohol or other drugs in the 30 days preceding study enrollment. The primary analysis used ANCOVA with the response variable being BFI-3 at Cycle 4 and the treatment factor was a drug (modafinil or placebo).

A significant interaction between treatment and baseline was observed. To address this, the group was further subdivided into 3 categories based on their presenting level of fatigue severity: mild (2 to 4 BFI-3 scores), moderate (5 to 6 BFI-3 scores), and severe (7 to 10 BFI-3 scores). An interaction between treatment and baseline was also observed for the other secondary outcomes.

Results

The modified intention-to-treat analysis (ITT) included all patients who completed assessments at baseline and day 28. Fatigue scores and some of the secondary outcome measures were analyzed using repeated measure analyses.

These models (eg, ANCOVA and GEE) included terms for the treatment group, with linear and quadratic time effects, as well as stratification factors for the trial center. Missing cocaine abstinence data were imputed, as is standard practice in trials where cocaine abstinence is a primary outcome measure.

Modafinil-treated patients had greater improvement in fatigue severity than placebo-treated patients on the 0-to-10 screening numeric rating scale for fatigue. The magnitude of this effect was consistent across subgroups, with the greatest effect seen in patients categorized as having severe fatigue at baseline.

This effect was not observed for other outcomes, including daytime sleepiness and depression, which were also not significantly different between groups.

Modafinil may decrease the effectiveness of hormonal birth control pills, rings, patch, or shot, so women should use an additional method of birth control while taking this medication and for 1 month after stopping it.

Conclusions

The results of this study suggest that modafinil significantly improves cancer-related fatigue in patients who are undergoing chemotherapy. However, further research is needed to determine the precise mechanism that explains this placebo effect.

This research could also help to identify the patient subgroups who are most likely to benefit from modafinil, and how to effectively incorporate this medication into a clinical trial context.

The pharmacological mechanism by which modafinil induces wakefulness is not fully understood, but it is thought that it may work by blocking the transporter for the dopamine molecule and increasing. This increase in dopamine is similar to the mechanism of action of other waking medications.

A full generalized estimating equation (GEE) model was used to address the primary objective. The response variable was BFI-3 at Cycle 4, and the factors were treatment (modafinil vs. placebo) and baseline fatigue. The analysis was adjusted for disease stage and age.

This study was designed to evaluate whether modafinil, when administered with a standardized placebo wash-in, would improve patient-reported fatigue during a cancer-treatment regimen. A total of 72 patients undergoing at least 4 planned cycles of chemotherapy with survival expected to exceed 6 months were eligible for the study.

The patients were randomized to receive either modafinil or placebo in weekly blister packs with a 9-day supply. The study physician was able to reduce the dose of modafinil in one pill increments, but not less than 2 pills/day, if tolerability problems occurred.

 

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