Trial to Determine the Maximum Tolerated Dose (MTD) Based on Safety and Tolerability, of Org 26576 in Participants With Major Depressive Disorder (174001/P05704/MK-8777-001)

Study Overview
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Brief Summary
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Trial to determine the maximum tolerated dose (MTD) based on safety and tolerability of MK-8777 (Org 26576, SCH 900777) in participants with major depressive disorder.

Detailed Description
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This is a randomized, placebo-controlled, safety and tolerability study examining MK-8777 in participants with major depressive disorder. In Part I of the trial, four different cohorts of six participants each will receive multiple rising doses of MK-8777 (ranging from 100 mg twice a day [BID] to 300 mg BID) or placebo for up to 16 days. In Part 2, a new cohort of participants will be randomly assigned to receive 100 mg BID of MK-8777, 400 mg BID of MK-8777, or placebo. Following titration (3 days per step), participants will be maintained on the assigned BID dose until Day 27, followed by one day of once a day (QD) dosing, for a total of 28 days. There were 11 treatment arms in total for Part 1 and Part 2 (see Interventions).

Official Title
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Single Center, Randomized, Placebo-Controlled Trial to Establish Maximum Tolerated Dose, Optimal Titration Schedule, Safety, Tolerability, and Pharmacokinetics of Org 26576 in Patients Diagnosed With Major Depressive Disorder (Protocol No. P174001)

Conditions
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Depression

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: Female who is non-pregnant, nonlactating, using an acceptable method of birth control, or is not of child-bearing potential; be diagnosed with current major depressive disorder either mild or severe, as evidenced by a score of at least 9 but not more than 20 on the Quick Inventory of Depression Symptomatology - Clinician Rated (QIDS-C); be anti-depressant naïve; be able to refrain from all use of grapefruit containing products from the time of admission until the last assessment is performed at discharge; smokes less than or equal to 10 cigarettes or equivalent daily. Exclusion Criteria: has any current and primary Axis I disorder other than major depressive disorder; has any history of bipolar I or II disorder, dysthymia, psychotic depression, psychotic disorders, posttraumatic stress disorder, borderline personality disorder, obsessive compulsive disorder, or eating disorder; the duration of the current depressive episode is longer than 2 years at screening; has any history of a significant suicide attempt, or poses a current risk of attempting suicide; is known to be human immunodeficiency virus (HIV) positive, or positive for hepatitis B surface antigen or hepatitis A antibodies or hepatitis C total antibodies; has any clinically significant concurrent endocrine, renal, respiratory, cardiovascular, hematological, immunological, cerebrovascular, neurological, malignancy, or any other concurrent medical condition, or has any history of diabetes mellitus; donation of blood within 60 days prior to the anticipated first dose of trial medication.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Block A MK-8777<br>Participants receive MK-8777 initiated at 100 mg BID and titrated to a maximum of 600 mg BID. Participants receive MK-8777 for a total of 16 days. | Drug: MK-8777<br>* Orally administered capsules containing either 50 mg or 100 mg MK-8777.<br>|
| Placebo Comparator: Part 1: Block A Placebo<br>Participants receive placebo BID for a total of 16 days. | Drug: Placebo<br>* Orally administered matching placebo capsules.<br>|
| Experimental: Part 1: Block B MK-8777<br>Participants receive MK-8777 initiated at 200 mg BID and titrated to a maximum of 600 mg BID. Participants receive MK-8777 for a total of 13 days. | Drug: MK-8777<br>* Orally administered capsules containing either 50 mg or 100 mg MK-8777.<br>|
| Placebo Comparator: Part 1: Block B Placebo<br>Participants receive placebo BID for a total of 13 days. | Drug: Placebo<br>* Orally administered matching placebo capsules.<br>|
| Experimental: Part 1: Block C MK-8777<br>Participants receive MK-8777 initiated at 300 mg BID and titrated to a maximum of 600 mg BID. Participants receive MK-8777 for a total of 10 days. | Drug: MK-8777<br>* Orally administered capsules containing either 50 mg or 100 mg MK-8777.<br>|
| Placebo Comparator: Part 1: Block C Placebo<br>Participants receive placebo BID for a total of 10 days. | Drug: Placebo<br>* Orally administered matching placebo capsules.<br>|
| Experimental: Part 1: Block D MK-8777<br>Participants receive MK-8777 initiated at 100 mg BID and titrated to a maximum dose determined by the results of Block A. Participants receive MK-8777 for a total of 13 days. | Drug: MK-8777<br>* Orally administered capsules containing either 50 mg or 100 mg MK-8777.<br>|
| Placebo Comparator: Part 1: Block D Placebo<br>Participants receive placebo BID for a total of 13 days. | Drug: Placebo<br>* Orally administered matching placebo capsules.<br>|
| Experimental: Part 2: MK-8777 200 mg<br>Participants receive MK-8777 100 mg BID for 27 days followed by one day of 100 mg QD. Participants receive MK-8777 for a total of 28 days. | Drug: MK-8777<br>* Orally administered capsules containing either 50 mg or 100 mg MK-8777.<br>|
| Experimental: Part 2: MK-8777 800 mg<br>Participants receive MK-8777 200 mg BID for 3 days followed by 400 mg BID for 24 days followed by one day of 400 mg QD. Participants receive MK-8777 for a total of 28 days. | Drug: MK-8777<br>* Orally administered capsules containing either 50 mg or 100 mg MK-8777.<br>|
| Placebo Comparator: Part 2: Placebo<br>Participants receive placebo BID for 27 days followed by one day of placebo QD. Participants receive placebo for 28 days. | Drug: Placebo<br>* Orally administered matching placebo capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants With Moderate Intensity Adverse Events (AEs) | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. A moderate intensity AE is defined as an AE that causes no significant interference with functioning. | Up to 7 days following the last dose of study drug (Up to 23 days) | 
| Part 1: Number of Participants With Serious Adverse Events (SAEs) | An SAE is defined as any untoward medical occurrence that at any dose: results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. | Up to 30 days following the last dose of study drug (Up to 46 days) | 
| Part 1: Number of Participants With AEs Leading to Discontinuation of Study Drug | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. Discontinuation refers to discontinuation of study drug (MK-8777 or Placebo). | Up to the last dose of study drug (Up to 16 days) | 
| Part 2: Number of Participants With AEs | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. | Up to 7 days following the last dose of study drug (Up to 35 days) | 
| Part 2: Number of Participants With AEs Leading to Discontinuation of Study Drug | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. Discontinuation refers to discontinuation of study drug (MK-8777 or Placebo). | Up to the last dose of study drug (Up to 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Change From Baseline in the Montgomery-Ashberg Depression Rating Scale (MADRS) | The MADRS is a 10-item scale designed to assess the severity of depression. The questionnaire includes questions on the following symptoms: Apparent sadness, Reported sadness, Inner tension, Reduced sleep, Reduced appetite, Concentration difficulties, Lassitude, Inability to feel, Pessimistic thoughts, and Suicidal thoughts. Each of the 10 symptoms are rated on a scale of 1 to 6, with 1=absent to 6=severe. The MADRS score can range from 0 (symptoms absent) to 60 (severe depression), with a higher score indicating more severe depression. | Baseline and end of treatment (Up to Day 16) | 
| Part 2: Change From Baseline in the MADRS | The MADRS is a 10-item scale designed to assess the severity of depression. The questionnaire includes questions on the following symptoms: Apparent sadness, Reported sadness, Inner tension, Reduced sleep, Reduced appetite, Concentration difficulties, Lassitude, Inability to feel, Pessimistic thoughts, and Suicidal thoughts. Each of the 10 symptoms are rated on a scale of 1 to 6, with 1=absent to 6=severe. The MADRS score can range from 0 (symptoms absent) to 60 (severe depression), with a higher score indicating more severe depression. | Baseline and end of treatment (Up to Day 28) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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randomized, placebo controlled, maximum tolerated dose