Dose Finding Study in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)(174007/P05805/MK-8777-003)

Study Overview
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Brief Summary
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This is a Phase 2 multicenter, randomized, double-blind trial of MK-8777 (Org 26576, SCH 900777) in adult subjects with Attention-Deficit/Hyperactivity Disorder (ADHD). MK-8777 or placebo will be administered in a crossover fashion for two 3-week treatment periods. The two 3-week treatment periods will be separated by a 2-week placebo washout period. The primary objective is to compare the efficacy of various doses of MK-8777 to that of placebo in the treatment of ADHD symptoms in adults.

Official Title
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A Double Blind, Placebo Controlled, Randomized, Two Period 4-Arm Trial to Investigate the Dose-Related Efficacy and Safety of Org 26576 in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)

Conditions
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Attention Deficit Hyperactivity Disorder

Intervention / Treatment
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* Drug: MK-8777
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: are between 18-50 years, inclusive; are male; or female who are non-pregnant, non-lactating and using an acceptable method of birth control (intrauterine device, double-barrier method, hormonal contraceptives); or female of non-childbearing potential if they are a) surgically sterile (tubal ligation, hysterectomy and/or bilateral oophorectomy) and provide documentation of the procedure by operative report or ultrasound scan, or b) post-menopausal for greater than one year with follicle stimulating hormone (FSH) level greater than or equal to 40 mIU/mL at screening. All females must have a negative serum pregnancy test at screening; are outpatients; provide written informed consent are fluent in the language of the investigator, are able to discontinue the use of any psychotropic medications for the treatment of ADHD symptoms at screening; meet strict operational criteria for adult ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TRTM) have a Clinical Global Impression ADHD score of 4 or higher at screening Exclusion Criteria: have any clinically significant concurrent medical condition (endocrine, renal, respiratory, cardiovascular, hematological, immunological, cerebrovascular, neurological, anorexia, obesity or malignancy) that has become unstable and may interfere with the interpretation of safety and efficacy evaluations. have any clinically significant abnormal laboratory, vital sign, physical examination, or electrocardiogram (ECG) findings at screening that, in the opinion of the investigator, may interfere with the interpretation of safety or efficacy evaluations. have any history of liver disease (e.g., cirrhosis, hepatitis), or liver injury;(history of hepatitis A greater than one year prior to screening is acceptable); any abnormal clinically significant findings at screening on liver laboratory parameters (serum glutamic-pyruvic transaminase [SGPT], serum glutamic oxaloacetic transaminase [SGOT], gamma-glutamyltransferase [GGT], lactate dehydrogenase [LDH], bilirubin, albumin, protein, alkaline phosphatase); have a seizure disorder beyond childhood or are taking any anticonvulsants to prevent seizures; have known serological evidence of human immunodeficiency virus (HIV) antibody; have a positive test result at screening on hepatitis B surface antigen or hepatitis A immunoglobulin M (IgM) antibodies or hepatitis C total antibodies; are pregnant as confirmed by a positive serum pregnancy test at screening; have QTc values >450 msec at screening using Fridericia's QTc formula; have a confirmed positive result in the alcohol/drug screen test for alcohol, illegal or non-prescribed drugs at screening (except marijuana/ tetrahydrocannabinol [THC]); have a confirmed positive result in the alcohol/drug screen re-test for marijuana/THC; have current or lifetime history of bipolar and psychotic disorders; have a current major depression disorder, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, panic disorder and eating disorder (also if treated but not currently symptomatic); have a current comorbid dysthymia or social anxiety disorder that is currently treated with psychotropic medication; have a current untreated social anxiety disorder that may interfere with the assessment of ADHD in the investigator's opinion; present an imminent risk of self-harm or harm to others; have any history of a significant suicide attempt, or possess a current risk of attempting suicide, in the investigator's opinion, based on clinical interview and responses provided on the Beck Scale for Suicidal Ideation (BSS); have a history of jailing or imprisonment in the past 6 months due to worsening of symptoms of ADHD;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-8777 FD→PBO<br>Participants receive a fixed dose (FD) of MK-8777 100 mg twice each day (BID) for 3 weeks (Treatment Period 1). After a 2-week placebo washout period, participants receive a fixed dose of placebo (PBO) BID for 3 weeks (Treatment Period 2). | Drug: MK-8777<br> <br> Drug: Placebo<br> <br> |
| Experimental: PBO→MK-8777 FD<br>Participants receive a fixed dose of placebo BID for 3 weeks (Treatment Period 1). After a 2-week placebo washout period, participants receive a fixed dose of MK-8777 100 mg BID for 3 weeks (Treatment Period 2). | Drug: MK-8777<br> <br> Drug: Placebo<br> <br> |
| Experimental: MK-8777 RD→PBO<br>Participants receive rising doses (RD) of MK-8777 100-300 mg BID for 3 weeks (Treatment Period 1). After a 2-week placebo washout period, participants receive rising doses of placebo BID for 3 weeks (Treatment Period 2). | Drug: MK-8777<br> <br> Drug: Placebo<br> <br> |
| Placebo Comparator: PBO→MK-8777 RD<br>Participants receive rising doses of placebo BID for 3 weeks (Treatment Period 1). After a 2-week placebo washout period, participants receive rising doses of MK-8777 100-300 mg BID for 3 weeks (Treatment Period 2). | Drug: MK-8777<br> <br> Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Adult Attention-Deficit/Hyperactivity Disorder (ADHD) Investigator Symptom Rating Scale (AISRS) Score | The AISRS is an 18-item clinician-rated instrument for assessing the 18 core symptoms of ADHD corresponding to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) diagnostic symptoms for adults. Based on the clinician's rating for each of the symptoms using a 4-point scale (0=None to 3=Severe), the AISRS total score is derived by summing the score assigned to each of the 18 symptoms. Scores can range from 0 to 54, with a higher score indicating a more severe ADHD symptoms. Baseline was defined as the score at the baseline visit prior to starting dosing for Period 1 and as the last score in the 2-week placebo wash-out period for Period 2. For the statistical analyses, the average score from Day 14 and Day 21 was used. | Baseline (BL) and Day 7, Day 14, Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With at Least a 30% Reduction From Baseline in AISRS Score | The AISRS is an 18-item clinician-rated instrument for assessing the 18 core symptoms of ADHD corresponding to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) diagnostic symptoms for adults. Based on the clinician's rating for each of the symptoms using a 4-point scale (0=None to 3=Severe), the AISRS total score is derived by summing the score assigned to each of the 18 symptoms. Scores can range from 0 to 54, with a higher score indicating a more severe ADHD symptoms. Baseline was defined as the score at the baseline visit prior to starting dosing for Period 1 and as the last score in the 2-week placebo wash-out period for Period 2. Reduction was defined as the relative change from the baseline score within a treatment period to post-baseline score within that treatment period. | Baseline and Day 21 | 
| Percentage of Participants With at Least a 50% Reduction From Baseline in AISRS Score | The AISRS is an 18-item clinician-rated instrument for assessing the 18 core symptoms of ADHD corresponding to the DSM-IV diagnostic symptoms for adults. Based on the clinician's rating for each of the symptoms using a 4-point scale (0=None to 3=Severe), the AISRS total score is derived by summing the score assigned to each of the 18 symptoms. Scores can range from 0 to 54, with a higher score indicating a more severe ADHD symptoms. Baseline was defined as the score at the baseline visit prior to starting dosing for Period 1 and as the last score in the 2-week placebo wash-out period for Period 2. Reduction was defined as the relative change from the baseline score within a treatment period to post-baseline score within that treatment period. | Baseline and Day 21 | 
| Percentage of Participants Who Experience At Least One Adverse Event (AE) | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational product, whether or not related to the investigational product. AEs are reported by study drug taken at time of event and not by randomly assigned sequence. | Up to 7 days after last dose of study drug (Up to 63 days) | 
| Percentage of Participants Who Discontinue Study Drug Due to an AE | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational product, whether or not related to the investigational product. AEs are reported by study drug taken at time of event and not by randomly assigned sequence. | Up to last dose of study drug (Up to 56 days) | 
| Percentage of Participants With Clinician Global Impression Scale - Severity (CGI-S) Category Scores | The CGI-S is a 7-point clinician-rated scale for assessing the global severity of ADHD. Scores could range from 1=Normal, not at all ill to 7=Among the most extremely ill, with a higher score indicating more severe illness. Categorization was as follows: 1=Normal, not at all ill and Borderline mentally ill; 2=Mildly ill; 3=Moderately ill and 4=Markedly ill, Severely ill and Among the most extremely ill patients, with a higher category indicating more severe illness. Analysis of CGI-S was performed using a proportional odds model. For statistical analyses, CGI-S assessments were condensed to one assessment of severity per treatment period by taking the most severe score at the second and third visits within a treatment period. | Days 14-21 | 
| Percentage of Participants With Clinician Global Impression Scale - Improvement (CGI-I) Scores | The CGI-I is a 7-point clinician-rated scale for assessing the global improvement of ADHD. Scores could range from 1=Very much improved to 4=No change to 7=Very much worse, with a lower score indicating the most improvement. Analysis of CGI-I was performed using a proportional odds model. For statistical analyses, CGI-I assessments were condensed to one assessment of improvement per treatment period by taking the worst improvement score at the second and third visits within a treatment period. | Days 14-21 | 
| Change From Baseline in Epworth Sleepiness Scale (ESS) Score | The ESS is an 8-item scale used to assess sleepiness. The test consists of a list of 8 situations in which participants rate their tendency to become sleepy on a scale of 0=Would never doze to 3=High chance of dozing. The scores for each of the 8 situations are added to create a total score on a scale with a range from of 0 to 24. A higher score indicates a greater degree of sleepiness. Baseline was defined as the score at the baseline visit prior to starting dosing for Period 1 and as the last score in the 2-week placebo wash-out period for Period 2. | Baseline and Day 7, Day 14, Day 21 | 
| Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Score | The PSQI is a participant-rated scale to assess the quality of sleep. The PSQI consists of 7 component scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. Each component score can range from 0=better (i.e., 0 times per month) to 3=worse (i.e., 3 or more times per week). The sum of these 7 component scores yields one total score with a range of 0 (better) to 21 (worse). A total PSQI score <=5 is associated with good sleep quality; a total score >5 is associated with poor sleep quality. Baseline was defined as the score at the baseline visit prior to starting dosing for Period 1 and as the last score in the 2-week placebo wash-out period for Period 2. | Baseline and Day 7, Day 14, Day 21 | 
| Change From Baseline in Quick Inventory of Depression Symptomology - Clinician Rating (QIDS-C) Score | The QIDS-C is a clinician-administered rating scale to measure the severity of depressive symptoms within the 9 DSM-IV major depression disorder symptom (MDD) domains: depressed mood, loss of interest or pleasure, concentration/decision making, self-outlook, suicidal ideation, energy/fatigability, sleep, weight/appetite change, and psychomotor changes. There is one score (0=none to 3=severe) for each of the of the 9 domains. The total score is obtained by adding the scores for each of the 9 symptom domains. QIDS-C total scores can range from 0 to 27, with a higher score indicating more severe depression. Baseline was defined as the score at the baseline visit prior to starting dosing for Period 1 and as the last score in the 2-week placebo wash-out period for Period 2. | Baseline and Day 7, Day 14, Day 21 | 
| Change From Baseline in Time-Sensitive ADHD Symptom Scale (TASS) Score | The TASS is a participant-administered scale to assess study drug effects in the evening. Participants respond to 18 questions about ADHD symptoms, with scores from 0=Not at all to 3=Severe. Total scores can range from 0 to 54, with a higher score indicating more severe ADHD symtoms. Baseline was defined as the score at the baseline visit prior to starting dosing for Period 1 and as the last score in the 2-week placebo wash-out period for Period 2. | Baseline and Day 7, Day 14, Day 21 | 
| Computerized Cognition Assessment: Cognitive Flexibility | Cognition was assessed by a computerized cognitive testing (©CNS Vital Signs, Chapel Hill, NC) battery consisting of neuropsychological tests that measure the cognitive domain of cognitive flexibility (score range: -200 to 200), with a higher score indicating better cognition. | Baseline, Day 21 | 
| Computerized Cognition Assessment: Complex Attention | Cognition was assessed by a computerized cognitive testing battery consisting of neuropsychological tests that measure the cognitive domain of complex attention (score range: 0 to 250), with a lower score indicating better cognition. | Baseline, Day 21 | 
| Computerized Cognition Assessment: Composite Memory | Cognition was assessed by a computerized cognitive testing battery consisting of neuropsychological tests that measure the cognitive domain of composite memory (score range: -120 to 120), with a higher score indicating better cognition. | Baseline, Day 21 | 
| Computerized Cognition Assessment: Executive Functioning | Cognition was assessed by a computerized cognitive testing battery consisting of neuropsychological tests that measure the cognitive domain of executive functioning (score range: -200 to 200), with a higher score indicating better cognition. | Baseline, Day 21 | 
| Computerized Cognition Assessment: Speed of Processing | Cognition was assessed by a computerized cognitive testing battery consisting of neuropsychological tests that measure the cognitive domain of speed of processing (score range: -1000 to 200), with a higher score indicating better cognition. | Baseline, Day 21 | 
| Computerized Cognition Assessment: Reaction Time | Cognition was assessed by a computerized cognitive testing battery consisting of neuropsychological tests that measure the cognitive domain of reaction time (lowest time possible is 0 msec), with a lower reaction time indicating better cognition. | Baseline, Day 21 | 
| Computerized Cognition Assessment: Reasoning | Cognition was assessed by a computerized cognitive testing battery consisting of neuropsychological tests that measure the cognitive domain of reasoning (score range: -15 to 15), with a higher score indicating better cognition. | Baseline, Day 21 | 
| Computerized Cognition Assessment: Sustained Attention | Cognition was assessed by a computerized cognitive testing battery consisting of neuropsychological tests that measure the cognitive domain of sustained attention (score range -120 to 120), with a higher score indicating better cognition. | Baseline, Day 21 | 
| Computerized Cognition Assessment: Verbal Memory | Cognition was assessed by a computerized cognitive testing battery consisting of neuropsychological tests that measure the cognitive domain of verbal memory (score range: -60 to 60), with a higher score indicating better cognition. | Baseline, Day 21 | 
| Computerized Cognition Assessment: Visual Memory | Cognition was assessed by a computerized cognitive testing battery consisting of neuropsychological tests that measure the cognitive domain of visual memory (score range: -60 to 60), with a higher score indicating better cognition. | Baseline, Day 21 | 
| Computerized Cognition Assessment: Working Memory | Cognition was assessed by a computerized cognitive testing battery consisting of neuropsychological tests that measure the cognitive domain of working memory (score range: -48 to 48), with a higher score indicating better cognition. | Baseline, Day 21 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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randomized, double blind, placebo controlled