Modafinil Versus Amphetamines for the Treatment of Narcolepsy Type 2 and Idiopathic Hypersomnia

Study Overview
=================
Brief Summary
-----------------
For diseases that cause excessive daytime sleepiness (such as narcolepsy and idiopathic hypersomnia), there are several medications that can be used to treat sleepiness. However, it can be difficult to decide which medication to use for a particular individual for several reasons: 1) there are very few studies that directly compare two medications to see which works best; 2) there are very few studies that include people with a disorder of sleepiness called idiopathic hypersomnia. To address this gap in knowledge, the researchers propose a randomized clinical trial comparing modafinil and amphetamine salts in patients with narcolepsy type 2 or idiopathic hypersomnia. All participants will either receive modafinil or amphetamine salts -- no participant will receive placebo. This study will evaluate which medication works better to improve sleepiness. The researchers will also see which medication is better for other symptoms including difficulty waking up and difficulty thinking, as well as seeing which medication causes fewer side. Finally, this study will see if any information about patients (such as age or sleep study features) predicts responding better to one medication or the other.

Detailed Description
-----------------
Currently, there are insufficient data to guide clinical practice regarding the use of amphetamines for the treatment of narcolepsy. This may be particularly important in the case of narcolepsy type 2, for which randomized, controlled trial data show that other treatments are less beneficial than they are for participants with narcolepsy type 1. For the closely related disorder of idiopathic hypersomnia, clinical trial data to guide treatment decision-making are even more limited, with only three published controlled trials ever performed. To address these evidence gaps, the researchers propose a randomized, active-treatment controlled trial comparing modafinil and amphetamine salts for the treatment of narcolepsy type 2 and idiopathic hypersomnia. The primary outcome will be reduction in excessive daytime sleepiness, as measured by change in Epworth Sleepiness Scale scores from baseline to week 12 on treatment. Other important patient-reported outcomes will be considered as secondary outcomes, including Patient Global Impression of Change for overall severity, sleep inertia, cognitive dysfunction, and sleepiness, as well as other symptom questionnaires. In addition to directly comparing the efficacy of these two medications for hypersomnolent patients, this study will also evaluate for relatively safety in this population. Further, this study will assess clinical predictors of treatment response. All three of these aims will be complementary in informing shared decision-making about whether to treat with modafinil or amphetamine salts. Forty-four adult patients seeking evaluation at the Emory Sleep Center for narcolepsy type 2 or idiopathic hypersomnia will be invited to participate and will be randomized to one of the treatment arms upon consent. Participants will receive study treatment for 12 weeks.

Official Title
-----------------
Informing Treatment Decisions in the Central Disorders of Hypersomnolence: A Pragmatic Clinical Trial of Modafinil Versus Amphetamines

Conditions
-----------------
Idiopathic Hypersomnia, Narcolepsy Without Cataplexy

Intervention / Treatment
-----------------
* Drug: Modafinil
* Drug: Amphetamine-Dextroamphetamine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: narcolepsy type 2 or idiopathic hypersomnia ability to give informed consent Exclusion Criteria: contraindication to modafinil or amphetamine salts (history of left ventricular hypertrophy, mitral valve prolapse, other cardiac structural abnormalities, severe cardiovascular disease, unstable angina, myocardial infarction, cardiomyopathy, severe arrhythmias, uncontrolled hypertension, severe hepatic impairment, substance abuse history, psychosis, glaucoma, Tourette's syndrome, and epilepsy) obstructive sleep apnea (Apnea-Hypopnea Index (AHI) > 15) severe periodic limb movements of sleep with arousals (periodic limb movements (PLM) arousal index > 30) allergy to either of the study drugs pregnancy or breastfeeding

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Modafinil<br>Participants in this study arm will take modafinil. | Drug: Modafinil<br>* Participants will received 100-400 milligrams (mg) per day of modafinil for 12 weeks.<br>* Other names: Provigil;|
| Experimental: Amphetamine-dextroamphetamine<br>Participants in this study arm will take amphetamine-dextroamphetamine (amphetamine salts). | Drug: Amphetamine-Dextroamphetamine<br>* Participants will receive 10-40 mg/day of oral amphetamine salts for 12 weeks.<br>* Other names: Adderall;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Epworth Sleepiness Scale (ESS) Score | The Epworth Sleepiness Scale (ESS) asks respondents to indicate how likely they are to doze off or fall asleep during daytime situations such as reading or talking to someone. There are 8 items which are answered on a scale of 0 to 4 where 0 = would never doze and 4 = high chance of dozing. Total score can range from 0 to 24, with higher scores indicating more sleepiness. A score of 0 to 5 can be interpreted as lower normal daytime sleepiness, a score of 6 to 10 is higher normal daytime sleepiness, score between 11 to 12 are mild excessive daytime sleepiness, scores of 13 to 15 are moderate excessive daytime sleepiness and scores of 16 to 24 indicate severe excessive daytime sleepiness. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Patient Global Impression of Change (PGIc) for Sleepiness Score | The PGIc for Sleepiness asks respondents to rate their sleepiness compared to baseline. Responses are indicated on a scale of 1 to 7 where 1 = very much improved and 7 = very much worse. | Weeks 4, 8, 12 | 
| Change in Patient Global Impression of Change (PGIc) for Sleep Inertia Score | The PGIc for Sleep Inertia asks respondents to rate their sleep interia compared to baseline. Sleep inertia is defined for participants as difficulty waking up and getting out of bed in the morning because of sleepiness. Responses are indicated on a scale of 1 to 7 where 1 = very much improved and 7 = very much worse. | Weeks 4, 8, 12 | 
| Change in Patient Global Impression of Change (PGIc) for Cognitive Dysfunction Score | The PGIc for Cognitive Dysfunction asks respondents to rate their cognitive dysfunction compared to baseline. Cognitive dysfunction is defined for participants as difficulty with thinking, problems with attention or concentration, and/or brain fog. Responses are indicated on a scale of 1 to 7 where 1 = very much improved and 7 = very much worse. | Weeks 4, 8, 12 | 
| Change in Patient Global Impression of Change (PGIc) for Overall Disease Severity Score | The PGIc for Overall Severity asks respondents to rate their overall disease compared to baseline. Responses are indicated on a scale of 1 to 7 where 1 = very much improved and 7 = very much worse. | Weeks 4, 8, 12 | 
| Change in Hypersomnia Severity Index (HSI) from Baseline | The HSI is a 9-item instrument assessing the severity of excessive sleepiness (hypersomnolence). Items are scored on a Likert scale where 0 = not at all and 4 = very much. Total scores range from 0 to 36 and higher scores indicate greater severity of symptoms of hypersomnia. | Baseline, Weeks 4, 8, 12 | 
| Change in Sleep Inertia Questionnaire (SIQ) from Baseline | The SIQ is an instrument with 21 items with responses on a 5-point scale where 1 = not at all and 5 = all the time. Two additional questions relate to how much time it takes for the respondent to wake up in the morning. Total scores range from 21 to 105 and higher scores indicate increased difficulty from tiredness. | Baseline, Weeks 4, 8, 12 |